Cyclic AMP response element binding protein (CBP) and / or 300KDA adenovirus E1A binding protein (P300) degrading compounds and methods of use

Abstract

The present invention relates to bivalent compounds (eg, bifunctional small molecule compounds), compositions containing one or more bivalent compounds, methods of using the bivalent compounds to treat certain diseases in subjects in need thereof, and methods of identifying such bivalent compounds.

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and in particular relates to cyclic AMP response element binding protein (CBP) and / or 300 kDa adenovirus E1A binding protein (P300) degradation compounds and use methods. Background of the Invention

[0003] Post-translational modifications of proteins, such as phosphorylation, acetylation, methylation, and ubiquitination, have greatly contributed to the diversity and regulation of proteins. P300 (encoded by EP300) and the closely related CBP (encoded by CREBBP) are two widely studied lysine acetyltransferases (HATs) that catalyze the transfer of acetyl groups to lysine residues of proteins. The most well-characterized substrates of P300 and CBP are histones. Acetylation of histones regulates the conformation of chromatin and often leads to transcriptional activation. Recruitment of P300 and / or CBP is essential for many transcription factors and other transcriptional regulators to effectively promote regional transcription (Dancy and Cole, 2015). Substrates of P300 and CBP also include many non-histone proteins with important physiological and pathological functions, such as p53, MYC, FOXO1, and NF-κB (Dancy and Cole, 2015). Because P300 and CBP functionally interact with a variety of signaling proteins, these two lysine acetyltransferases serve as convergence points for many signal transduction pathways (Bedford et al., 2010). By regulating the acetylation of multiple substrates and ligating a variety of binding partners, P300 and CBP are widely involved in biological processes such as cell proliferation, differentiation, development, DNA repair, inflammation, metabolism, and memory.

[0004] Because mice lacking P300 or CBP die early in embryogenesis, both P300 and CBP are essential for development (Goodman and Smolik, 2000). Abnormal P300 or CBP has been implicated in a variety of human diseases. Germline mutations that inactivate one of the CREBBP alleles cause Rubinstein-Taybi syndrome (Petrij et al., 1995), which may be due to impaired activation of the Hedgehog family of transcription factors. Both P300 and CBP are known to promote hematopoiesis through interaction with hematopoietic transcription factors such as GATA-1 (Blobel, 2000). Tumor suppressor roles for P300 and CBP have been established. Patients with Rubinstein-Taybi syndrome have a high prevalence of cancer. Inactivating mutations in P300 and CBP are frequently found in human cancers (Giles et al., 1998). However, these two HATs also promote tumorigenesis through different mechanisms. In a subset of acute myeloid leukemias, a recurrent chromosomal translocation t(8;16)(p11;p13) generates an in-frame fusion of the MOZ and CREBBP genes that directs expression of the oncogenic MOZ-CBP fusion protein (Rozman et al., 2004). CBP and, less commonly, P300 are also found fused to MLL in chemoresistant leukemias (Sobulo et al., 1997). Accumulating evidence suggests that most oncogenic transcription factors, such as MYC (Faiola et al., 2005; Vervoorts et al., 2003), NF-κB (Vanden Berghe et al., 1999), β-catenin (Sun et al., 2000), E2F1 (Ianari et al., 2004; Martinez-Balbas et al., 2000), and nuclear receptors (Chakravarti et al., 1996), recruit P300 and CBP as coactivators. Therefore, depletion of P300 and / or CBP may affect tumor growth by impairing the function of these oncogenic transcription factors. In addition, P300 has been reported to regulate immune cell function (Liu et al., 2013). Further, P300 and CBP are important transcriptional coactivators of STAT and NF-κB family transcription factors, which have key functions in immune cells (Nadiminty et al., 2006; Wang et al., 2005; Wang et al., 2017). Therefore, P300 / CBP antagonists can be used to modulate the activity of the immune system and the crosstalk between immune cells and cancer cells (Liu et al., 2013). Finally, there is a large body of literature demonstrating that histone acetylation is closely related to neurodegenerative diseases (Saha and Pahan, 2006; Valor et al., 2013).In conclusion, the development of novel therapeutics targeting P300 and CBP represents new opportunities for the treatment of cancer, inflammatory diseases, neurological indications, and other indications.

[0005] Therefore, there is an urgent need in the art for new drugs targeting CBP / P300. Summary of the invention

[0006] The present invention relates to bivalent compounds (e.g., bifunctional small molecule compounds), compositions containing one or more bivalent compounds, and methods for treating certain diseases using the bivalent compounds in subjects in need thereof. The present invention also relates to methods for identifying such bivalent compounds.

[0007] According to one aspect of the present invention, the bivalent compounds disclosed herein include cyclic AMP response element binding protein (CBP) and / or 300 kDa adenovirus E1A binding protein (P300) ligand bound to a degradation tag, or a pharmaceutically acceptable salt or analog thereof.

[0008] In one embodiment, the CBP / P300 ligand is capable of binding to a CBP / P300 protein, including CBP / P300, a CBP / P300 mutant, a CBP / P300 deletion, or a CBP / P300 fusion protein.

[0009] In one embodiment, the CBP / P300 ligand is a CBP / P300 inhibitor or a portion of a CBP / P300 inhibitor.

[0010] In another embodiment, the CBP / P300 ligand is selected from the group consisting of:

[0011] GNE-781, GNE-272, GNE-207, CPD 4d, CPD (S) -8, CPD (R) -2, CPD 6, CPD 19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD 11, CPD 41, CPD 30, CPD 5, CPD 29, CPD27, C646, A-485, naphthol-AS-E, MYBMIM, CCS1477, HBS1, OHM1, KCN1, ICG-001, YH249, YH250, and analogs thereof. In another embodiment, the CBP / P300 ligand is GNE-781 or an analog thereof.

[0012] In other embodiments, the degradation tag is bound to a ubiquitin ligase or is a hydrophobic group or tag that causes misfolding of the CBP / P300 protein.

[0013] In other embodiments, the ubiquitin ligase is an E3 ligase.

[0014] In further embodiments, the E3 ligase is selected from the group consisting of cereblon E3 ligase, VHL E3 ligase, IAP ligase, MDM2 ligase, TRIM24 ligase, TRIM21 ligase, KEAP1 ligase, DCAF16 ligase, RNF4 ligase, RNF114 ligase, and AhR ligase.

[0015] In another embodiment, the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, CPD36, GDC-0152, CRBN-1, CRBN-2, CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, CRBN-11 and analogs thereof. In another embodiment, the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, CRBN-1, CRBN-9, and analogs thereof. In another embodiment, the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, and analogs thereof.

[0016] In other embodiments, the CBP / P300 ligand is conjugated to the degradation tag via a linker moiety.

[0017] In other embodiments, the CBP / P300 ligand comprises a moiety of Formula 1:

[0018]

[0019] in,

[0020] The linker portion of the divalent compound is bound to R 2 ;

[0021] X 1 and X 3 Independently selected from: C and N, provided that X 1 and X 3 At least one of them is C and X 1 and X 3 At most one of them is N;

[0022] X 2 Selected from: CR', O and NR', where

[0023] R' is selected from: H, optionally substituted C 1 -C 8 alkyl and optionally substituted 3-10 membered carbocyclyl;

[0024] A is selected from: None, CR 4 R 5 , CO, O, S, SO, SO 2 and NR 4 ,in

[0025] R 4 and R 5 are independently selected from: hydrogen, halogen, hydroxy, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0026] Ar is selected from the group consisting of aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl, each of which is replaced by R 1 substituted and optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, CN, NO 2 , OR 6 , SR 6 NR 6 R 7 ,OCOR 6 、OCO 2 R 6 、OCONR 6 R 7 , COR 6 , CO 2 R 6 ,CONR6 R 7 、SOR 6 、SO 2 R 6 、SO 2 NR 6 R 7 NR 8 CO 2 R 6 NR 8 COR 6 NR 8 C(O)NR 6 R 7 NR 8 SOR 6 NR 8 SO 2 R 6 NR 8 SO 2 NR 6 R 7 , optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl,

[0027] Alternatively, Ar and R 4 , Ar and R 5 , and / or R 4 and R 5 Together with the atoms to which they are attached, they form an optionally substituted 3-20 membered cycloalkyl or heterocyclyl ring;

[0028] R 6 , R 7 and R 8 are independently selected from: hydrogen, optionally substituted C1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0029] R 6 and R 7 , R 6 and R 8 Together with the atoms to which they are attached, they form a 4-20 membered heterocyclyl ring;

[0030] R 1 Selected from: hydrogen, halogen, CN, NO 2 , OR 9 , SR 9 NR 9 R 10 ,OCOR 9 、OCO 2 R 9 、OCONR 9 R 10 , COR 9 , CO 2 R 9 ,CONR 9 R 10 、SOR 9 、SO 2 R 9 、SO 2 NR 9 R 10 NR 11 CO 2 R 9 NR 11 COR 9 NR 11 C(O)NR 9 R 10 NR 11 SOR 9 NR 11 SO 2 R 9 NR 11 SO2 NR 9 R 10 , optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0031] R 9 , R 10 and R 11 are independently selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0032] R 9 and R 10 , R 9 and R 11 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring;

[0033] R 2 connected to the linker portion of the divalent compound, and R2 Selected from: None, -R"O-, -R"S-, -R"N(R 12 )-, -R"OC(O)-, -R"OC(O)O-, -R"OCON(R 12 )-, -R"C(O)-, -R"C(O)O-, -R"CON(R 12 )-、-R"S(O)-、-R"S(O) 2 -、-R"SO 2 N(R 12 )-、-R"N(R 13 )C(O)O-、-R"N(R 13 )C(O)-、-R"N(R 13 )C(O)N(R 12 )-、-R"N(R 13 )S(O)-、-R"N(R 13 )S(O) 2 -、-R”N(R 13 )S(O) 2 N(R 12 )-, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0034] R" is none, or a divalent moiety selected from the following optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0035] R 12 and R 13 Independently selected from: optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0036] R 12 and R 13 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring; and

[0037] R 3 Selected from: Hydrogen, COR 14 , CO 2 R 14 ,CONR 14 R 15 、SOR 14 、SO 2 R 14 、SO 2 NR 14 R 15 , optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0038] R14 and R 15 are independently selected from: hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0039] R 14 and R 15 Together with the atoms to which they are attached, they form a 4-20 membered heterocyclyl ring.

[0040] In another embodiment, X 1 is C; and X 2 and X 3 is N. Formula I is Formula 1A:

[0041]

[0042] Among them, A, Ar, R 1 , R 2 and R 3 Same as in formula 1.

[0043] In another embodiment, A-Ar-R 1 For the formula A1 part:

[0044]

[0045] in,

[0046] A and R 1 In the same formula 1,

[0047] X is selected from: CR"' and N, where

[0048] R"' and is selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted C 1 -C 6alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkyloxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0049] R a Optionally forms a ring with A, and R a Selected from: None, Hydrogen, Halogen, R b NR 16 , R b OR 16 , R b SR 16 , R b NR 16 R 17 , R b OCOR 16 , R b OCO 2 R 16 , R b OCONR 16 R 17 , R b COR 16 , R b CO 2 R 16 , R b CONR 16 R 17 , R b SOR 16 , R b SO 2 R 16 , R b SO 2 NR 16 R 17 , R b NR 18 CO 2 R 16 , R b NR 18 COR 16 , R b NR 18 C(O)NR 16 R 17 , R b NR 18 SOR 16 , R b NR 18 SO 2 R 16 , R b NR 18 SO 2 NR 16 R17 , optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 2 -C 8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0050] R b is none, or is a divalent or trivalent moiety selected from the following: optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0051] R 16 , R 17 and R 18 are independently selected from: none, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1-C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0052] R 16 and R 17 , R 16 and R 18 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl or heterocyclyl ring.

[0053] In other embodiments, A is none.

[0054] In another embodiment, A is nothing; Ar is a bicyclic aryl or a bicyclic heteroaryl; and A-Ar-R 1 For the formula A2 or A3 part:

[0055]

[0056] Among them, R 1 Same as in formula 1.

[0057] In another embodiment, A is NR 4 ,in

[0058] R 4 Selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0059] In another embodiment, A is NR 4 ; and A-Ar-R 1 For the formula A4, A5 or A6 part:

[0060]

[0061] Among them, R 1 Same as in formula 1.

[0062] In another embodiment, R 1 is selected from the group consisting of an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted aryl and an optionally substituted heteroaryl.

[0063] In another embodiment, R 1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.

[0064] In another embodiment, R 1 Selected from: optionally substituted C 6 aryl and optionally substituted 5- or 6-membered heteroaryl.

[0065] In another embodiment, R 1 is selected from: optionally substituted pyrazolyl and optionally substituted pyridinyl.

[0066] In another embodiment, R 2 Selected from: optionally substituted C 1 -C 8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0067] In another embodiment, R 2 Selected from: optionally substituted 4-8 membered heterocyclic group.

[0068] In another embodiment, R 2 is selected from: optionally substituted 4-8 membered heterocyclic groups containing 1 or 2 N. In another embodiment, R 2 for

[0069] In another embodiment, R 3 Selected from: COR 14 and CONR 14 R 15 .

[0070] In another embodiment, R 3 Selected from: COMe and CONHMe.

[0071] In other embodiments, the CBP / P300 ligand comprises a moiety of Formula 2:

[0072]

[0073] in,

[0074] The linker portion of the divalent compound is bound to R 1 ;as well as

[0075] X 1 and X 3 Independently selected from: C and N, provided that X 1 and X 3 At least one of them is C and X 1 and X 3 At most one of them is N;

[0076] X 2 Selected from: CR', O and NR', where

[0077] R' is selected from: H, optionally substituted C 1 -C 8 alkyl and optionally substituted 3-10 membered carbocyclyl;

[0078] A is selected from: None, CR 4 R 5 , CO, O, S, SO, SO 2 and NR 4 ,in

[0079] R 4 and R 5 are independently selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0080] Ar is selected from the group consisting of aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl, each of which is replaced by R 1 substituted and optionally substituted by one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, CN, NO 2 , OR 6, SR 6 NR 6 R 7 ,OCOR 6 、OCO 2 R 6 、OCONR 6 R 7 , COR 6 , CO 2 R 6 ,CONR 6 R 7 、SOR 6 、SO 2 R 6 、SO 2 NR 6 R 7 NR 8 CO 2 R 6 NR 8 COR 6 NR 8 C(O)NR 6 R 7 NR 8 SOR 6 NR 8 SO 2 R 6 NR 8 SO 2 NR 6 R 7 , optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl,

[0081] Alternatively, Ar and R4 , Ar and R 5 , and / or R 4 and R 5 Together with the atoms to which they are attached, they form an optionally substituted 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring;

[0082] R 6 , R 7 and R 8 are independently selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0083] R 6 and R 7 , R 6 and R 8 Together with the atoms to which they are attached, they form a 4-20 membered heterocyclyl ring; and

[0084] R 1 connected to the linker portion of the divalent compound, and R 1 Selected from: None, -R"O-, -R"S-, -R"N(R 12 )-, -R"OC(O)-, -R"OC(O)O-, -R"OCON(R 12 )-, -R"C(O)-, -R"C(O)O-, -R"CON(R 12 )-、-R"S(O)-、-R"S(O) 2 -、-R"SO 2 N(R 12 )-、-R"N(R 13 )C(O)O-、-R"N(R 13 )C(O)-、-R"N(R 13 )C(O)N(R 12 )-、-R"N(R 13 )S(O)-、-R"N(R 13 )S(O)2 -、-R”N(R 13 )S(O) 2 N(R 12 )-, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0085] R" is none, or a divalent moiety selected from the following: optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0086] R 12 and R 13 Independently selected from: optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0087] R 12 and R 13 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring; and

[0088] R 2 Selected from: hydrogen, halogen, CN, NO 2 , OR 9 , SR 9 NR 9 R 10 ,OCOR 9 、OCO 2 R 9 、OCONR 9 R 10 , COR 9 , CO 2 R 9 ,CONR 9 R 10 、SOR 9 、SO 2 R 9 、SO 2 NR 9 R 10 NR 11 CO 2 R 9 NR 11 COR 9 NR 11 C(O)NR 9 R 10 NR 11 SOR 9 NR 11 SO 2 R 9 NR 11 SO 2 NR 9 R 10 , optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0089] R 9 , R 10 and R 11 are independently selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0090] R 9 and R 10 , R 9 and R 11 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring; and

[0091] R 3 Selected from: Hydrogen, COR 14 , CO 2 R 14 ,CONR 14 R 15 、SOR 14 、SO 2 R 14 、SO 2 NR 14 R 15 , optionally substituted C 1-C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, wherein

[0092] R 14 and R 15 are independently selected from: hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-6 membered cycloalkyl, and optionally substituted 3-6 membered heterocyclyl, or

[0093] R 14 and R 15 Together with the atoms to which they are attached, they form a 4-6 membered heterocyclyl ring.

[0094] In another embodiment, X 1 is C; and X 2 and X 3 is N. Formula 2 is Formula 2A:

[0095]

[0096] Among them, A, Ar, R 1 , R 2 and R 3 Same as in formula 2.

[0097] In another embodiment, A-Ar-R 1 For the formula B1 part:

[0098]

[0099] in,

[0100] * indicates the connection with the linker part of the divalent compound;

[0101] A and R 1 Same as in formula 2;

[0102] X is selected from: CR"' and N, where

[0103] R"' and is selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6Alkenyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted C 1 -C 6 alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkyloxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl; and

[0104] R a Optionally forming a ring with A and selected from: none, hydrogen, halogen, R b NR 16 , R b OR 16 , R b SR 16 , R b NR 16 R 17 , R b OCOR 16 , R b OCO 2 R 16 , R b OCONR 16 R 17 , R b COR 16 , R b CO 2 R 16 , R b CONR 16 R 17 , R b SOR 16 , R b SO 2 R 16 , R b SO 2 NR 16 R 17 , R b NR 18 CO 2 R 16 , R b NR 18 COR 16 , R b NR 18 C(O)NR 16 R 17 , R b NR 18 SOR 16 , R b NR18 SO 2 R 16 , R b NR 18 SO 2 NR 16 R 17 , optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 2 -C 8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0105] R b is none, or is a divalent or trivalent moiety selected from the following: optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0106] R 16 , R 17 and R 18 are independently selected from: none, a bond, hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0107] R 16 and R 17 , R 16 and R 18 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring.

[0108] In other embodiments, A is none.

[0109] In another embodiment, A is nothing; Ar is a bicyclic aryl or a bicyclic heteroaryl; and A-Ar-R 1 For the formula B2 or B3 part:

[0110]

[0111] in,

[0112] * indicates connection to the linker portion of the divalent compound; and

[0113] R 1 Same as in formula 2.

[0114] In another embodiment, A is NR 4 ,in

[0115] R 4 Selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0116] In another embodiment, A is NR 4 ; and A-Ar-R 1 For the formula B4, B5 or B6 part:

[0117]

[0118] in,

[0119] * indicates connection to the linker portion of the divalent compound; and

[0120] R 1 Same as in formula 2.

[0121] In another embodiment, R 1 is selected from the group consisting of an optionally substituted 3-10 membered carbocyclylene, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted aryl and an optionally substituted heteroaryl.

[0122] In another embodiment, R 1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.

[0123] In another embodiment, R 1 is selected from: optionally substituted pyrazolyl and optionally substituted pyridinyl.

[0124] In another embodiment, R 2 Selected from: optionally substituted C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0125] In another embodiment, R 3 Selected from: COR 14 and CONR 14 R 15 .

[0126] In another embodiment, R 3 Selected from: COMe and CONHMe.

[0127] In other embodiments, the CBP / P300 ligand is of Formula 1. In other embodiments, the CBP / P300 ligand is of Formula 1A.

[0128] In other embodiments, the CBP / P300 ligand is derived from any of the following:

[0129]

[0130] In other embodiments, the CBP / P300 ligand is derived from the following CBP / P300 inhibitors: C646, naphthol-AS-E, Compound 1-10, MYBMIM, CCS1477, ICG-001, YH249, YH250, HBS1, OHM1, and KCN1.

[0131] In another embodiment, the CBP / P300 ligand is selected from the group consisting of:

[0132]

[0133] The dotted key Indicates the connection to the linker portion of a divalent compound.

[0134] In other embodiments, the CBP / P300 ligand is of Formula 3U or 3W.

[0135] In another embodiment, the CBP / P300 ligand is selected from the group consisting of: Formula 3A 1 , 3B 1 、3C 1 and 3D 1 :

[0136]

[0137] Wherein, * represents the connection with the linker part of the divalent compound.

[0138] In another embodiment, the CBP / P300 ligand is of Formula 3A 1 Or 3C 1 .

[0139] In another embodiment, the degradation tag is a moiety of Formula 5, and the degradation tag is represented by Z E a linker moiety connected to the divalent compound;

[0140]

[0141] in,

[0142] Z E For example, E z ) nE - a divalent group shown in FIG. 1; wherein the subscript n E =0, 1, 2, 3, 4, 5 or 6; where R E Z , at each occurrence, independently R E r or R E w ; Among them, RE w , at each occurrence, is a bond or is selected from the group consisting of: -CO-, -CR E 5 R E 6 -、-NR E 5 -, -O-, optionally substituted C 1 -C 10 Alkylene, optionally substituted C 1 -C 10 Alkenylene, optionally substituted C 1 -C 10 Alkyne; and R E r , at each occurrence, is a bond, or is selected from the group consisting of optionally substituted 3-10 membered carbocyclyl such as 3-8 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl such as 3-8 membered heterocyclyl, optionally substituted C 3 -C 13 Fused cycloalkyl, optionally substituted C 3 -C 13 A fused heterocyclic group, optionally substituted C 3 -C 13 A bridged cycloalkyl, optionally substituted C 3 -C 13 A bridged heterocyclic group, an optionally substituted C 3 -C 13 Spirocycloalkyl, optionally substituted C 3 -C 13 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; provided that -R E z -R E z -Not-OO-;R E 5 and R E 6 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 8 membered carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; or, R E 5 and R E 6 Together with the atoms to which they are attached, they form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring;

[0143] R E 1 Selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C 1-C 6 Alkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl;

[0144] L E is a divalent group selected from the following group: none, -L E 1 -and-L E 1 -L E 2 -; among them, L E 1 and L E 2 Independently selected from the group consisting of -CO-, -O-, -CR E 10 R E 11 -and-NR E 10 -, the limiting condition is -L E 1 -L E 2 - is not –OO-; where R E 10 and R E 11 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkoxy and optionally substituted C 1 -C 6 Alkylamino;

[0145] Ring A E is a divalent group selected from the following group: E 1. A E 2. A E 3. A E 4 and A E 5

[0146]

[0147] in,

[0148] *Indicates the same as L E The connection of Z E Connect to Ring A E Any possible position;

[0149] is a single bond or a double bond;

[0150] V E1 、V E 2 、V E 3 、V E 4 and V E 5 , at each occurrence, is independently selected from the group consisting of a bond, C, CR E 2 , N and NR E 2 Or, V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E 4 or V E 4 and V E 5 are optionally taken together to form a 6-membered aryl or 5-, 6-, or 7-membered heteroaryl ring;

[0151] R E 2 , at each occurrence, is independently selected from the group consisting of absence, hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted C 1 -C 6 alkylamino, optionally substituted 3-8 membered carbocyclyl, and optionally substituted 3-8 membered heterocyclyl; or, R E 2 and another R E 2 Together with the atoms to which they are attached, they form an optionally substituted 3-8 membered cycloalkyl, an optionally substituted 3-8 membered heterocyclyl ring, an optionally substituted aryl, and an optionally substituted heteroaryl;

[0152] W E 1 , W E 2 , W E 3 and W E4 Each is independently selected from the following group: -N=, -C≡, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N = N-; or, W E 1 and W E 2 , W E 2 and W E 3 or W E 3 and W E 4 are optionally taken together to form a 6-membered aryl or 5-, 6-, or 7-membered heteroaryl ring;

[0153] R E 3 and R E 4 , at each occurrence, is independently selected from the group consisting of absence, hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C 1 -C 6 alkyl, optionally substituted 3- to 8-membered carbocyclyl, and optionally substituted 3- to 8-membered heterocyclyl; or, R on the same atom or on adjacent atoms E 3 and R E 4 Together with the atoms to which they are attached, they form an optionally substituted 3-8 membered cycloalkyl or heterocyclyl ring.

[0154] In another embodiment, Ring A E is a divalent group selected from the following group: E 1. A E 2. A E 3 and A E 4; V E 1 、V E 2 、V E 3 、V E 4 and V E5 , at each occurrence, is independently selected from the group consisting of a bond, C, CR E 2 and N; or, V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E 4 , or V E 4 and V E 5 Taken together optionally form a 6-membered aryl ring or a 5-, 6-, or 7-membered heteroaryl ring.

[0155] In another embodiment, R E 2 , at each occurrence, is independently selected from the group consisting of absence, hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted C 1 -C 6 alkylamino, optionally substituted 3- to 8-membered carbocyclyl, and optionally substituted 3- to 8-membered heterocyclyl.

[0156] In another embodiment, the degradation tag is a moiety of formula 5, and wherein V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , at each occurrence, independently selected from the group consisting of: C, CR E 2 and N; or, V E 1 and V E 2 、V E 2 and V E 3 、VE 3 and V E 4 , or V E 4 and V E 5 Taken together optionally form a 6-membered aryl ring or a 5-, 6-, or 7-membered heteroaryl ring.

[0157] In another embodiment, the degradation tag is a moiety of Formula 5, and wherein Ring A E Formula A E 1, and wherein V E 1 、V E 2 、V E 3 and V E 4 Each independently selected from the following group: C, CR E 2 and N.

[0158] In another embodiment, the degradation tag is a moiety of Formula 5, and wherein Ring A E A group consisting of: E 2, and where V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , at each occurrence, independently selected from the group consisting of: C, CR E 2 and N.

[0159] In another embodiment, the degradation tag is a moiety of Formula 5, and wherein Ring A E A group consisting of: E 3, and among them, V E 1 、V E 2 、V E 3 、V E 4 and V E 5 Each independently selected from the following group: CR E 2 and N; or, V E 1 and V E2 、V E 2 and V E 3 、V E 3 and V E 4 , or V E 4 and V E 5 Taken together optionally form a 6-membered aryl ring or a 5-, 6-, or 7-membered heteroaryl ring.

[0160] In another embodiment, the degradation tag is a moiety of Formula 5, and wherein Ring A E A group consisting of: E 4, and among them, For single bond and W E 1 , W E 2 , W E 3 and W E 4 Each independently selected from the following group: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0161] In another embodiment, the degradation tag is a moiety of formula 5, and wherein R E 1 Selected from: hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3-8 membered carbocyclyl and optionally substituted 3-8 membered heterocyclyl; preferably R E 1 Selected from: hydrogen, halogen, cyano, nitro and C 1 -C 5 Alkyl; more preferably R E 1 Selected from: H, CH 3 or F.

[0162] In another embodiment, the degradation tag is a moiety of formula 5, and wherein R E 2 Selected from: hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C 1 -C 6Alkyl, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted C 1 -C 6 alkylamino, optionally substituted 3 to 8 membered carbocyclyl and optionally substituted 3 to 8 membered heterocyclyl; preferably R E 2 Selected from: hydrogen, halogen, cyano, nitro, C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted 3 to 8 membered carbocyclic group and optionally substituted 3 to 8 membered heterocyclic group; more preferably R E 2 Selected from: H, F, OMe, O-iPr or O-cPr.

[0163] In another embodiment, the degradation tag is a moiety of formula 5, and wherein R E 3 and R E 4 are independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 8 membered carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; or, R E 3 and R E 4 Together with the atoms to which they are attached, they form a 3-8 membered carbocyclic group or a 3-8 membered heterocyclic group.

[0164] In another embodiment, R E r Selected from Group R E and group R E '.

[0165] Group R E ' is composed of the following optionally substituted groups:

[0166]

[0167] Group R E ' is composed of the following optionally substituted groups:

[0168]

[0169] In another embodiment, R E r Selected from Group R E .

[0170] In another embodiment, R E r Selected from Group R E '.

[0171] In additional embodiments, the degradation tag is a moiety of Formula 5, and wherein in Z E In a group, at most one R E Z For R E r .

[0172] In another embodiment, the degradation tag is a moiety of formula 5, and wherein n E =0, 1, 2 or 3.

[0173] In another embodiment, the degradation tag is a moiety of formula 5, and wherein Z E is a divalent group selected from the following group: -R E w -、-(R E w ) 2 -、-(R E w ) 3 -、-R E r -、-R E w -R E r -R E w -、-R E r -R E w -and-R E r -(R E w ) 2 -.

[0174] In another embodiment, the degradation tag is a moiety of formula 5, and wherein R E 5 and R E 6 , at each occurrence, is independently selected from: a bond, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 8 membered carbocyclyl, and optionally substituted 3 to 8 membered heterocyclyl; or, R E 5 and R E 6Together with the atoms to which they are attached, they form a 3-8 membered cycloalkyl or heterocyclyl ring.

[0175] In another embodiment, the degradation tag is a moiety of formula 5, and wherein R E Z Selected from: -CO-, -CR E 5 R E 6 -、-NR E 5 -, -O-, optionally substituted C 1 -C 10 Alkylene, optionally substituted C 1 -C 10 Alkenylene, optionally substituted C 1 -C 10 alkylene, optionally substituted 3- to 8-membered carbocyclyl, or optionally substituted 3- to 8-membered heterocyclyl.

[0176] In another embodiment, the degradation tag is a moiety of formula 5, and wherein Z E Selected from: bond, CH 2 , CH=CH, C≡C, NH and O.

[0177] In another embodiment, the degradation tag is a moiety of formula 5, and wherein ring A E Formula A E 4 and L E Not for nothing.

[0178] In another embodiment, the degradation tag is a moiety of Formula 5, and wherein Ring A E Formula A E 4 and L E Selected from the group consisting of -NH-, -N(C 1 -C 4 alkyl)-, -CO-, -NH-CO-, -N(C 1 -C 4 Alkyl)-CO-, -CO-NH- and -CO-N(C 1 -C 4 alkyl)-.

[0179] In another embodiment, the degradation tag is a moiety selected from the group consisting of Formula 5-1, 5-2, 5-3, 5-4, and 5-5, and the degradation tag is ligated via a divalent group Z E a linker moiety connected to the divalent compound;

[0180]

[0181] in,

[0182] Z E , R E 1 , L E , V E 1 、V E 2 、V E 3 、V E 4 、V E 5 , W E 1 , W E 2 , W E 3 and W E 4 As defined in Eq. 5.

[0183] In additional embodiments, the degradation tag is a moiety selected from the group consisting of Formula 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J, 5K, and 5L;

[0184]

[0185] in,

[0186] V E 6 、V E 7 、V E 8 and V E 9 Each independently selected from: a bond, C, CR E 12 and N; or, V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E 4 , or V E 4 and V E 5 are optionally taken together to form a 6-membered aryl ring or a 5-, 6-, or 7-membered heteroaryl ring;

[0187] R E12 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted C 1 -C 6 Alkylamino, optionally substituted 3-8 membered carbocyclyl and optionally substituted 3-8 membered heterocyclyl;

[0188] W E 6 and W E 7 Each independently selected from: -CR E 2 = and -N =;

[0189] W E 1 , W E 2 , W E 3 , W E 4 、V E 1 、V E 2 、V E 3 、V E 4 、V E 5 , R E 1 , R E 3 and Z E As defined in Eq. 5.

[0190] In another embodiment, W E 1 Selected from: -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 -, and -N=N-.

[0191] In another embodiment, the degradation tag is a moiety of Formula 5-1 or Formula 5-3,

[0192]

[0193] in,

[0194] V E 1 、V E 2 、V E 3 and V E 4 Each independently selected from: a bond, C, CR E 2 and N; or, V E 1 and V E 2 、V E 2 and V E 3 , or V E 3 and V E 4 are optionally taken together to form a 6-membered aryl ring or a 5-, 6-, or 7-membered heteroaryl ring;

[0195] represents a single bond or a double bond; wherein, (i) when W E 1 and W E 2 When there is a single bond between E 1 and W E 2 Between represents a single bond), W E 1 , W E 2 and W E 3 Each independently selected from the following group: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E3 - and -N=N-; or, (ii) when W E 1 and W E 2 When there is a double bond between E 1 and W E 2 Between represents a double bond), W E 1 and W E 2 Each independently selected from the group consisting of -N=, -C≡ and -CR E 3 =;W E 3 Selected from the following group: -O-, -N=, -NR E 3 -、-C(O)NR E 3 -、-CR E 3 =CR E 4 -and-CR E 3 =N-;

[0196] Z E , R E 2 , R E 3 , R E 4 and R E 1 As defined in Eq. 5.

[0197] In another embodiment, the degradation tag is a moiety of formula 5-1 or 5-3, and wherein V E 1 、V E 2 、V E 3 and V E 4 Each independently selected from: C, N and CR E 2 In additional embodiments, the moiety of Formula 5 is a moiety of Formula 5A, 5B, 5E, 5F, or 5G.

[0198]

[0199] Among them, W E 6 and W E 7Each independently selected from: -CR E 2 = and -N =; and V E 1 、V E 2 、V E 3 、V E 4 , W E 1 , W E 3 , Z E , R E 3 and R E 1 As defined in Equation 5-1.

[0200] In other embodiments, the degradation tag is a moiety of formula 5A, 5B, 5E, 5F or 5G, and wherein V E 1 、V E 2 、V E 3 and V E 4 Each independently selected from: a bond, C, CR E 2 and N (preferably C, CR E 2 and N).

[0201] In other embodiments, the degradation tag is a moiety of formula 5A, 5B, 5E, 5F or 5G, and wherein W E 1 and W E 3 Independently selected from: -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N=N-; preferably W E 1 and W E 3 Independently selected from: -CO-, -O-, -CR E 3 R E 4-and-NR E 3 -.

[0202] In another embodiment, the moiety of formula 5-3 is the moiety of formula 5C

[0203]

[0204] Among them, W E 3 N or CR E 3 ; and V E 1 、V E 2 、V E 3 、V E 4 , Z E and R E 1 As defined in Formula 5-3. In another embodiment, the degradation tag is a moiety of Formula 5C, wherein V E 1 、V E 2 、V E 3 and V E 4 Independently selected from: bond, CR E 2 and N.

[0205] In another embodiment, the degradation tag is a moiety of formula 5-2:

[0206]

[0207] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 Independently selected from: a bond, C, CR E 2 and N; or, V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E4 , or V E 4 and V E 5 are optionally taken together to form a 6-membered aryl ring or a 5-, 6-, or 7-membered heteroaryl ring;

[0208] is a single bond or a double bond; (i) when W E 1 and W E 2 When there is a single bond between E 1 and W E 2 Between represents a single bond), W E 1 and W E 4 Independently selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N=N-, and W E 2 and W E 3 Each independently selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -; or, (ii) W E 1 and W E 2 When there is a double bond between E 1 and W E 2 Between represents a double bond), W E 1 and W E 2 Each independently selected from: -N=, C and -CRE 2 =;W E 3 Selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -; and W E 4 Selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and - N = N -;

[0209] Z E , R E 2 , R E 3 , R E 4 and R E 1 As defined in Eq. 5.

[0210] In another embodiment, the degradation tag is a moiety of formula 5-2, wherein V E 1 、V E 2 、V E 3 、V E 4 and V E 5 Independently selected from: a bond, C, CR E 2 and N.

[0211] In another embodiment, the degradation tag is a moiety of formula 5-2, wherein, Represents a single bond.

[0212] In another embodiment, the degradation tag is a moiety of formula 5-2, wherein, Represents a single bond, W E1 and W E 4 Each independently selected from: -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -, and W E 2 and W E 3 Independently selected from: -N=, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0213] In another embodiment, the degradation tag is a moiety of formula 5-2, which is a moiety of formula 5D

[0214]

[0215] Among them, V E 1 、V E 2 、V E 3 、V E 4 、V E 5 , W E 1 , Z E and R E 1 As defined in Equation 5-2.

[0216] In another embodiment, the degradation tag is a moiety of formula 5D, wherein W E 1 Selected from: -CO-, -O-, -CR E 3 R E 4 -、-NR E 3 -、-CR E 3 =CR E 4 -、-N=CR E 3 - and -N=N-; preferably W E 1Selected from: -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0217] In another embodiment, the degradation tag is a moiety of formula 5D, wherein V E 1 、V E 2 、V E 3 、V E 4 and V E 5 Each independently selected from: a bond, C, CR E 2 and N; or, V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E 4 , or V E 4 and V E 5 Taken together, optionally form a 6-membered aryl ring or a 5-, 6- or 7-membered heteroaryl ring; preferably V E 1 、V E 2 、V E 3 、V E 4 and V E 5 Each independently selected from: a bond, C, CR E 2 and N.

[0218] In another embodiment, the degradation tag is a moiety of formula 5-4:

[0219]

[0220] Among them, V E 1 、V E 2 、V E 3 、V E 4、V E 5 , L E , Z E and R E 1 As defined in Eq. 5.

[0221] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein L E In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein L E Selected from the following group: -NH-, -N(C1-C 4 alkyl)-, -CO-, -NH-CO-, -N(C 1 -C 4 Alkyl)-CO-, -CO-NH- and -CO-N(C 1 -C 4 alkyl)-.

[0222] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein,

[0223] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 , at each occurrence, independently selected from the group consisting of: C, CR E 2 and N; or,

[0224] V E 1 and V E 2 、V E 2 and V E 3 、V E 3 and V E 4 , or V E 4 and V E 5 Combined together optionally to form The ring shown, where V E 6 、V E 7 、V E 8 and V E9 Each independently selected from the following group: C, CR E 12 and N;

[0225] R E 12 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkenyl, optionally substituted C 1 -C 6 Alkynyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted C 1 -C 6 alkylamino, optionally substituted 3- to 8-membered carbocyclyl, and optionally substituted 3- to 8-membered heterocyclyl.

[0226] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein V E 6 、V E 7 、V E 8 and V E 9 Each independently selected from the following group: CR E 12 and N.

[0227] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein R E 12 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted C 1 -C 6 alkyl.

[0228] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein,

[0229] Select from the following group:

[0230]

[0231] in,

[0232] V E 1 、V E 2 、V E 3 、VE 4 and V E 5 Each independently selected from the following group: C, CR E 2 and N; and V E 6 、V E 7 、V E 8 and V E 9 Each independently selected from the following group: CR E 12 and N.

[0233] In another embodiment, the degradation tag is a moiety of formula 5-4, and wherein Z E None, -CH 2 -, -O- or -NH-.

[0234] In another embodiment, the moiety of formula 5-4 is a moiety of formula 5H or 5I

[0235]

[0236] Among them, V E 1 、V E 2 、V E 3 、V E 4 、V E 5 、V E 6 、V E 7 、V E 8 and V E 9 Each independently selected from: a bond, C, CR E 2 and N; and Z E and R E 1 As defined in Equation 5-4.

[0237] In another embodiment, the degradation tag is a moiety of formula 5-5:

[0238]

[0239] in, W E 1 , W E 2 , WE 3 , W E 4 , Z E and R E 1 As defined in Eq. 5.

[0240] In another embodiment, the degradation tag is a moiety of formula 5-5, and wherein W E 1 , W E 2 , W E 3 and W E 4 Each is independently selected from the following group: -N=, -C≡, -CR E 3 =, -CO-, -O-, -CR E 3 R E 4 -and-NR E 3 -.

[0241] In another embodiment, the degradation tag is a moiety of formula 5-5, and wherein W E 1 , W E 2 , W E 3 and W E 4 Each is independently selected from the following group: -N=, -C≡, -CH=, -CO-, -O-, -N-, -CH 2 - and -NH-.

[0242] In other embodiments, the degradation tag of the moiety of formula 5-5 is a moiety of formula 5J, 5K or 5L;

[0243]

[0244] Among them, W E 1 , W E 2 , W E 3 , W E 4 , Z E , R E 3 and R E 1 As defined in Formula 5-5.

[0245] In another embodiment, the degradation tag is a moiety of Formula 6A, 6B and 6C:

[0246]

[0247] in,

[0248] R E 1 and R E 2 are independently selected from: hydrogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Aminoalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

[0249] R E 3 Selected from: hydrogen, optionally substituted C(O)C 1 -C 8 Alkyl, optionally substituted C(O)C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C(O)C 1 -C 8 haloalkyl, optionally substituted C(O)C 1 -C 8 Hydroxyalkyl, optionally substituted C(O)C 1 -C 8 aminoalkyl, optionally substituted C(O)C 1 -C 8 Alkylamino C 1 -C 8alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(O)C 2 -C 8 Alkenyl, optionally substituted C(O)C 2 -C 8 Alkynyl, optionally substituted C(O)OC 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C(O)OC 1 -C 8 Haloalkyl, optionally substituted C(O)OC 1 -C 8 Hydroxyalkyl, optionally substituted C(O)OC 1 -C 8 Aminoalkyl, optionally substituted C(O)OC 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC 2 -C 8 Alkenyl, optionally substituted C(O)OC 2 -C 8 Alkynyl, optionally substituted C(O)NC 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C(O)NC 1 -C 8 haloalkyl, optionally substituted C(O)NC 1 -C 8 Hydroxyalkyl, optionally substituted C(O)NC 1 -C 8 aminoalkyl, optionally substituted C(O)NC 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(3-10 membered heterocyclyl), optionally substituted C(O)NC 2 -C 8 Alkenyl, optionally substituted C(O)NC 2 -C 8 Alkynyl, optionally substituted P(O)(OH) 2 , optionally substituted P(O)(OC 1 -C8 alkyl) 2 and optionally substituted P(O)(OC 1 -C 8 Aryl) 2 ,and

[0250] R E 4 Selected from: NR E 7 R E 8 , Optionally substituted C 1 -C 8 alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0251] R E 7 Selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Cycloalkyl, optionally substituted C 1 -C 8 Alkyl-CO, optionally substituted C 1 -C 8 Cycloalkyl-CO, optionally substituted C 1 -C 8 Cycloalkyl-C 1 -C 8 alkyl-CO, optionally substituted 3-10 membered heterocyclyl-CO, optionally substituted 3-10 membered heterocyclyl-C 1 -C 8 Alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-C 1 -C 8 alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-C 1 -C 8 alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;

[0252] R E 8 Selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl and optionally substituted C 1 -C 8 Cycloalkyl;

[0253] R E 9, at each occurrence, is independently selected from: hydrogen, halogen, cyano, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Cycloalkyl, optionally substituted C 1 -C 8 Heterocycloalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Cycloalkoxy, halogenated C 1 -C 8 Alkyl, halogenated C 1 -C 8 Cycloalkyl, halogenated C 1 -C 8 Alkoxy, halogenated C 1 -C 8 Cycloalkoxy and halogenated C 1 -C 8 Heterocycloalkyl;

[0254] X E Selected from: CH and N; and

[0255] n E is 0, 1, 2, 3, or 4;

[0256] R E 5 Selected from: hydrogen and halogen, preferably H and F;

[0257] R E 6 Selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Cycloalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Cycloalkoxy, optionally substituted C 1 -C 8 Heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, preferably halogen, cyano, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted oxadiazole, optionally substituted triazole, 4-methylthiazol-5-yl or oxazol-5-yl.

[0258] In another embodiment, the degradation tag is a moiety of formula 7A:

[0259]

[0260] in,

[0261] V E 1 、V E 2 、V E 3 、V E 4 and V E 5 Independently selected from: CR E 4 and N; and

[0262] R E 1 , R E 2 , R E 3 and R E 4 are independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl and optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 alkylamino, optionally substituted 3-10 membered carbocyclyl and optionally substituted 3-10 membered heterocyclyl.

[0263] In another embodiment, the degradation tag is a moiety of formula 7B:

[0264]

[0265] in,

[0266] R E 1 , R E 2 and R E 3 are each independently selected from: hydrogen, halogen, optionally substituted C1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 3 -C 7 Cycloalkyl, optionally substituted 3-7 membered heterocyclic group, optionally substituted C 2 -C 8 Alkenyl and optionally substituted C 2 -C 8 Alkynyl;

[0267] R E 4 and R E 5 Independently selected from: hydrogen, COR E 6 , CO 2 R E 6 ,CONR E 6 R E 7 、SOR E 6 、SO 2 R E 6 、SO 2 NR E 6 R E 7 , optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted aryl-C 1 -C 8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0268] R E 6 and R E7 are independently selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0269] R E 6 and R E 7 Together with the atoms to which they are attached, they form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0270] In other embodiments, the degradation tag is a moiety of formula 5-1, 5-2, 5-3 or 5-4.

[0271] In other embodiments, the degradation tag is a moiety of Formula 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J, 5K or 5L.

[0272] In additional embodiments, the degradation tag is a moiety of Formula 5A, 5B, 5C, 5H or 5I.

[0273] In other embodiments, the degradation tag is derived from any of the following:

[0274]

[0275]

[0276] In another embodiment, the degradation tag is derived from any one of the following: thalidomide, pomalidomide, lenalidomide, CRBN-1, CRBN-2, CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, CRBN-11, CRBN-12, CRBN-13, CRBN-14 and CRBN-15.

[0277] In other embodiments, the degradation tag is derived from any one of the following: thalidomide, pomalidomide, lenalidomide, CRBN-1, and CRBN-9.

[0278] In another embodiment, the degradation tag is selected from the group Deg, which consists of:

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286] Among them, the key Indicates the connection to the linker portion of a divalent compound.

[0287] In another embodiment, the degradation tag is selected from the group consisting of Formula 8A, 8B, 8C, 8D, 8E, 8F, 8G, 8H, 8I, 8J, 8K, 8L, 8M, 8O, 8P, 8Q, 8R, 8AQ, 8AR, 8AS, 8AT, 8AU, 8AV, 8AW, 8AX, 8AY, 8AZ, 8BA, 8BB, 8BC, 8BD, 8BE, 8BF, 8BG, 8BH, 8BI, 8BJ, 8BK, 8BL, 8BM, 8BN, 8BO, 8BP, 8BQ, 8BR, 8BS, 8CB, 8C C, 8CD, 8CE, 8CF, 8CG, 8CH, 8CI, 8CJ, 8CK, 8CL, 8CM, 8CN, 8CO, 8CP, 8CQ, 8CR, 8CS, 8CT, 8CU, 8CV, 8CW, 8CX, 8CY, 8CZ, 8DA , 8DB, 8DC, 8DD, 8DE, 8DF, 8DG, 8DH, 8DI, 8DJ, 8DK, 8DL, 8DM, 8DN, 8DO, 8DP, 8DQ, 8DR, 8DS, 8DT, 8DU, 8DV, 8DW, 8DX, 8DY, 8 DZ, 8EA, 8EB, 8EC, 8ED, 8EE, 8EF, 8EG, 8EH, 8EI, 8EJ, 8EK, 8EL, 8EM, 8EN, 8EO, 8EP, 8EO, 8GU, 8GV, 8GW, 8GX, 8GY, 8GZ, 8H A. 8HB, 8HC, 8HD, 8HE, 8HF, 8HG, 8HH, 8HI, 8HJ, 8HK, 8HL, 8HM, 8HN, 8HO, 8HP, 8HQ, 8HR, 8HS, 8HT, 8HU, 8HV, 8HW, 8HX, 8HY, 8HZ, 8IA, 8IB, 8IC, 8ID, 8IE, 8IF, ​​8IG, 8IH, 8II, 8IJ, 8IK, 8IL, 8IM, 8IN, 8IO, 8IP, 8IQ, 8IR, 8IS, 8IT, 8IU, 8IV, 8IW, 8I X, 8IY, 8IZ, 8JA, 8JB, 8JC, 8JD, 8JE, 8JF, 8JG, 8JH, 8JI, 8JJ, 8JK, 8JL, 8JM, 8JN, 8JO, 8JP, 8JQ, 8JR, 8JS, 8JT, 8JU and 8JV.

[0288] In some embodiments, the connector portion is as shown in Formula 9:

[0289]

[0290] in,

[0291] A L , W L and B L , at each occurrence, is independently selected from: None, or a divalent moiety selected from: RL d -R L e 、R L d COR L e 、R L d CO 2 R L e 、R L d C(O)N(R L 1 )R L e 、R L d C(S)N(R L 1 )R L e 、R L d OR L e 、R L d SR L e 、R L d SOR L e 、R L d SO 2 R L e 、R L d SO 2 N(R L 1 )R L e 、R L d N(R L 1 )R L e 、R L e N(R L 1 )COR L e 、R L e N(R L 1 )CON(R 2 )R L e 、R L dN(R L 1 )C(S)R L e , optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein,

[0292] R L d and R L e Independently selected from: none, optionally substituted (C 1 -C 8 Alkylene)-R L r (Preferably, CH 2 -R L r ), optionally substituted R L r -(C 1 -C 8 alkylene), optionally substituted (C 1 -C 8 Alkylene)-R L r -(C 1 -C 8 alkylene), or a moiety consisting of: optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8Hydroxyalkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0293] R L r is selected from the group consisting of an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 4-13 membered fused cycloalkyl, an optionally substituted 5-13 membered fused heterocyclyl, an optionally substituted 5-13 membered bridged cycloalkyl, an optionally substituted 5-13 membered bridged heterocyclyl, an optionally substituted 5-13 membered spirocycloalkyl, an optionally substituted 5-13 membered spiroheterocyclyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

[0294] R L 1 and R L 2 are each independently selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0295] R L d and R L e , R L 1 and R L 2 , R L d and R L 1 , R L d and R L 2 , R L e and R L 1 , R L e and R L 2 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring; and

[0296] m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0297] In another embodiment, W L and m are as defined above; and A L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -、(CH 2 )0-8 -NH-CO, (CH 2 ) 0-8 -CO-NH, NH-CO-(CH 2 ) 0-8 、CO-NH-(CH 2 ) 0-8 、(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -CO-NH, (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -NH-CO, -CO-NH, CO-NH-(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 、(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 、-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 、

[0298] -(CH 2 ) 0-3 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(CO-NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、

[0299] -(CH 2 ) 0-3 -(NH-CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、和-(CH 2 ) 0-3 -(NH)-(CH 2) 0-3 -R L r -(CH 2 ) 0-3 -.

[0300] In another embodiment, W L and m are as defined above; and A L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -、(CH 2 ) 1-2 -NH-CO, (CH 2 ) 1-2 -CO-NH, NH-CO-(CH 2 ) 1-2 、CO-NH-(CH 2 ) 1-2 , (CH 2 ) 1-2 -NH-(CH 2 ) 1-2 -CO-NH, (CH 2 ) 1-2 -NH-(CH 2 ) 1-2 -NH-CO, -CO-NH, CO-NH-(CH 2 ) 1-2 -NH-(CH 2 ) 1-2 , (CH 2 ) 1-2 -NH-(CH 2 ) 1-2 、-(CH 2 ) 0-2 -R L r -(CH 2 ) 0-2 ,

[0301] -(CH 2 ) 0-2 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -、-(CH 2 )0-2 -(CO-NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -、

[0302] -(CH 2 ) 0-2 -(NH-CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -、-(CH 2 ) 0-2 -(NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -.

[0303] In another embodiment, R L r Selected from: Formula C1, C2, C3, C4 and C5

[0304]

[0305] in,

[0306] A L 1 , B L 1 , C L 1 and D L 1 , at each occurrence, is independently selected from: None, O, CO, SO, SO 2 NR L b , CR L b R L c , R L b ;

[0307] A L 2 , B L 2 , C L 2 , D L 2 and E L 2, at each occurrence, independently selected from: N, CR L b ;

[0308] A L 3 , B L 3 , C L 3 , D L 3 and E L 3 , at each occurrence, is independently selected from: N, O, S, NR L b , CR L b ;

[0309] R L b and R L c , at each occurrence, is independently selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heteroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0310] m L 1 、n L 1 , o L 1 and p L 1Independently selected from: 0, 1, 2, 3, 4 and 5.

[0311] In another embodiment, R L r Selected from Group R L ; and group R L It is composed of the following optionally substituted groups:

[0312]

[0313] In one embodiment, the linker portion is as shown in Formula 9A:

[0314]

[0315] in,

[0316] R L 1 , R L 2 , R L 3 and R L 4 , at each occurrence, is independently selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or,

[0317] R L 1 and R L 2 , R L3 and R L 4 and together with the atoms to which they are attached form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring;

[0318] A L , W L and B L , at each occurrence, is independently selected from: None, or a divalent moiety selected from: R L d -R L e , R L d COR L e , R L d CO 2 R L e , R L d C(O)N(R L 5 )R L e , R L d C(S)N(R L 5 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R L d SO 2 R L e , R L d SO 2 N(R L 5 )R L e , R L d N(R L 5 )R L e , R L d N(R L5 )COR L e , R L d N(R L 5 )CON(R L 6 )R L e , R L d N(R L 5 )C(S)R L e , optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0319] R L d and R L e Independently selected from: none, optionally substituted (C 1 -C 8 Alkyl)-R L r (Preferably, CH 2 -R L r ), optionally substituted R L r -(C 1 -C 8 alkylene), optionally substituted (C 1 -C 8 Alkylene)-R L r -(C1 -C 8 alkylene), or a moiety consisting of: optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0320] R L ris selected from the group consisting of an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 4-13 membered fused cycloalkyl, an optionally substituted 5-13 membered fused heterocyclyl, an optionally substituted 4-13 membered bridged cycloalkyl, an optionally substituted 5-13 membered bridged heterocyclyl, an optionally substituted 5-13 membered spirocycloalkyl, an optionally substituted 5-13 membered spiroheterocyclyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

[0321] R L 5 and R L 6 are independently selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0322] R L d and R L e , R L 5 and R L 6 , R L d and R L 5 , R L d and R L 6 , R L e and R L 5 , R L e and R L 6 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring;

[0323] mL is 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15);

[0324] n L , at each occurrence, is from 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15); and

[0325] o L is 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15).

[0326] In another embodiment, A L , W L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -、(CH 2 ) 0-8 -NH-CO, (CH 2 ) 0-8 -CO-NH, NH-CO-(CH 2 ) 0-8 、CO-NH-(CH 2 ) 0-8 , (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -CO-NH, (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -NH-CO, -CO-NH, CO-NH-(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 , (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 、-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 、-(CH 2 )0-3 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(CO-NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(NH-CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 - and - (CH 2 ) 0-3 -(NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -.

[0327] In another embodiment, W L and m are as defined above; and A L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -、(CH 2 ) 1-2 -NH-CO, (CH 2 ) 1-2 -CO-NH, NH-CO-(CH 2 ) 1-2 、CO-NH-(CH 2 ) 1-2 , (CH 2 ) 1-2 -NH-(CH 2 ) 1-2 -CO-NH, (CH 2 ) 1-2 -NH-(CH 2 ) 1-2-NH-CO, -CO-NH, CO-NH-(CH 2 ) 1-2 -NH-(CH 2 ) 1-2 , (CH 2 ) 1-2 -NH-(CH 2 ) 1-2 、-(CH 2 ) 0-2 -R L r -(CH 2 ) 0-2 、-(CH 2 ) 0-2 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -、-(CH 2 ) 0-2 -(CO-NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -、-(CH 2 ) 0-2 -(NH-CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -、-(CH 2 ) 0-2 -(NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -.

[0328] In another embodiment, R L r Selected from the group consisting of Formula C1, C2, C3, C4 and C5; Formula C1, C2, C3, C4 and C5 are as defined in Formula 9.

[0329] In another embodiment, R L r Selected from Group R L , and group R L As defined above.

[0330] In one embodiment, the CBP / P300 ligand of the bivalent compound binds to A in Formula 9A L .

[0331] In another embodiment, A L (When A L When attached to CBP / P300 ligand) is selected from: None, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -、(CH 2 ) 0-8 -NH-CO, (CH 2 ) 0-8 -CO-NH, NH-CO-(CH 2 ) 0-8 、CO-NH-(CH 2 ) 0-8 , (CH 2 ) 0-8 -NH-(CH 2 ) 0-8 -CO-NH, (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -NH-CO, CO-NH-(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 , (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 、-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 、-(CH 2 ) 0-3 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(CO-NH)-(CH 2 ) 0-3 -R L r -(CH2 ) 0-3 -、-(CH 2 ) 0-3 -(NH-CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -,in

[0332] R L r Selected from: Group R as defined above L ;as well as

[0333] W L and B L For nothing.

[0334] In one embodiment, the linker portion is as shown in Formula 9A:

[0335] in,

[0336] R L 1 , R L 2 , R L 3 and R L 4 , at each occurrence, is independently selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl (preferably C 1 -C 4 alkyl), or

[0337] R L 1 and R L 2 , R L 3 and R L 4 and together with the atoms to which they are attached form a 3-20 membered cycloalkyl (preferably, a 3-5 membered cycloalkyl) ring or a 4-20 membered heterocyclyl ring;

[0338] A L As defined above; and W and B are none;

[0339] mL is 0 to 15 (preferably, m is 0, 1 or 2);

[0340] n L , at each occurrence, is 1 to 15 (preferably, n is 1); and

[0341] o L is 1 to 15 (preferably, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13).

[0342] In another embodiment, A L Independently selected from: None or a divalent moiety selected from: R L d -R L e , R L d COR L e , R L d CO 2 R L e , R L d C(O)N(R 5 )R L e , R L d C(S)N(R 5 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R L d SO 2 R L e , R L d SO 2 N(R 5 )R L e , R L d N(R 5 )R L e , R Ld N(R 5 )COR L e , R L d N(R 5 )CON(R 6 )R L e , R L d N(R 5 )C(S)R L e ; R L d and R L e As defined above.

[0343] In another embodiment, R L d and R L e Independently selected from: none, optional (C 1 -C 8 Alkyl)-R r (Preferably, CH 2 -R L r ), or optionally substituted C 1 -C 8 Alkyl (preferably, optionally substituted C 1 -C 2 alkyl).

[0344] In another embodiment, the linker portion is as shown in Formula 9B:

[0345]

[0346] in,

[0347] R L 1 and R L 2 , at each occurrence, is independently selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino, C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0348] R L 1 and R L 2 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring;

[0349] A L and B L , at each occurrence, is independently selected from: None, or a divalent moiety selected from: R L d -R L e , R L d COR L e , R L d CO 2 R L e , R L d C(O)N(R L 3 )R L e , R L d C(S)N(R L 3 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R L d SO 2 R L e , RL d SO 2 N(R L 3 )R L e , R L d N(R L 3 )R L e , R L d N(R L 3 )COR L e , R L d N(R L 3 )CON(R L 4 )R L e , R L d N(R L 3 )C(S)R L e , optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein,

[0350] R L d and R L e Independently selected from: none, optionally substituted (C 1 -C8 Alkylene)-R L r (Preferably, CH 2 -R L r ), optionally substituted R L r -(C 1 -C 8 alkylene), optionally substituted (C 1 -C 8 Alkylene)-R L r -(C 1 -C 8 alkylene), or a moiety consisting of: optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0351] R L r is selected from the group consisting of an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 4-13 membered fused cycloalkyl, an optionally substituted 5-13 membered fused heterocyclyl, an optionally substituted 5-13 membered bridged cycloalkyl, an optionally substituted 5-13 membered bridged heterocyclyl, an optionally substituted 5-13 membered spirocycloalkyl, an optionally substituted 5-13 membered spiroheterocyclyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

[0352] R L 3 and R L 4 are each independently selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0353] R L d and R L e , R L 3 and R L 4 , R L d and R L 3 , R L d and RL 4 , R L e and R L 3 , R L e and R L 4 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring;

[0354] Each m L is 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15); and

[0355] n L is 0 to 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15).

[0356] In another embodiment, A L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -、(CH 2 ) 0-8 -NH-CO, (CH 2 ) 0-8 -CO-NH, NH-CO-(CH 2 ) 0-8 、CO-NH-(CH 2 ) 0-8 , (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -CO-NH, (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -NH-CO, CO-NH-(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 , (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 、-(CH 2 ) 0-3 -RL r -(CH 2 ) 0-3 、-(CH 2 ) 0-3 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(CO-NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(NH-CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -.

[0357] In another embodiment, R L r Selected from the group consisting of Formula C1, C2, C3, C4 and C5; Formula C1, C2, C3, C4 and C5 are as defined in Formula 9.

[0358] In another embodiment, R L r Selected from Group R L , and group R L As defined in Equation 9.

[0359] In another embodiment, the linker portion is as shown in Formula 9C:

[0360]

[0361] in,

[0362] X L Selected from: O and NR L 7 ;

[0363] R L 1 , R L 2 , R L 3 , R L 4 , R L 5 and R L 6 , at each occurrence, is independently selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxy, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0364] A L and B L Independently selected from: None, or a divalent moiety selected from: R L d -R L e , R L d COR L e , R L d CO 2 R L e , R L d C(O)N(R L 8 )R Le , R L d C(S)N(R L 8 )R L e , R L d OR L e , R L d SR L e , R L d SOR L e , R L d SO 2 R L e , R L d SO 2 N(R L 8 )R L e , R L d N(R L 8 )R L e , R L d N(R L 8 )COR L e , R L d N(R L 8 )CON(R L 9 )R L e , R L d N(R L 8 )C(S)R L e , optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C 8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0365] R L d and R L e Independently selected from: none, optionally substituted (C 1 -C 8 Alkylene)-R L r (Preferably, CH 2 -R L r ), optionally substituted R L r -(C 1 -C 8 alkylene), optionally substituted (C 1 -C 8 Alkylene)-R L r -(C 1 -C 8 alkylene), or a moiety consisting of: optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Alkylene, optionally substituted C 2 -C8 Alkenylene, optionally substituted C 2 -C 8 Alkyne, optionally substituted C 1 -C 8 Hydroxyalkylene, optionally substituted C 1 -C 8 Alkoxy C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 Alkylamino C 1 -C 8 Alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 4-13 membered fused cycloalkyl, optionally substituted 5-13 membered fused heterocyclyl, optionally substituted 5-13 membered bridged cycloalkyl, optionally substituted 5-13 membered bridged heterocyclyl, optionally substituted 5-13 membered spirocycloalkyl, optionally substituted 5-13 membered spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0366] R L r is selected from the group consisting of an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 4-13 membered fused cycloalkyl, an optionally substituted 5-13 membered fused heterocyclyl, an optionally substituted 5-13 membered bridged cycloalkyl, an optionally substituted 5-13 membered bridged heterocyclyl, an optionally substituted 5-13 membered spirocycloalkyl, an optionally substituted 5-13 membered spiroheterocyclyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

[0367] R L 7 , R L 8 and R L 9 are independently selected from: hydrogen, optionally substituted C 1 -C 8 Alkyl, optionally substituted C 2 -C 8 Alkenyl, optionally substituted C 2 -C 8 Alkynyl, optionally substituted C 1 -C 8 Alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 Hydroxyalkyl, optionally substituted C 1 -C 8 Alkylamino C1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0368] R L d and R L e , R L 8 and R L 9 , R L d and R L 8 , R L d and R L 9 , R L e and R L 8 , R L e and R L 9 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring;

[0369] m L , at each occurrence, is from 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15);

[0370] n L , at each occurrence, is from 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15);

[0371] o L is 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15); and

[0372] p L is 0 to 15 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15).

[0373] In another embodiment, A L and B L are independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH2 ) 0-8 -, (CH 2 ) 0-8 -NH-CO, (CH 2 ) 0-8 -CO-NH, NH-CO-(CH 2 ) 0-8 、CO-NH-(CH 2 ) 0-8 、(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -CO-NH, (CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -NH-CO, -CO-NH, CO-NH-(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 、(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 、-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 、-(CH 2 ) 0-3 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(CO-NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(NH-CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 - and -(CH 2 ) 0-3 -(NH)-(CH 2 )0-3 -R L r -(CH 2 ) 0-3 -.

[0374] In another embodiment, R L r Selected from the group consisting of Formula C1, C2, C3, C4 and C5; Formula C1, C2, C3, C4 and C5 are as defined in Formula 9.

[0375] In another embodiment, R L r Selected from Group R L , and group R L As defined in Equation 9.

[0376] In another embodiment, A L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, CH 2 -NH-CO, CH 2 -CO-NH, NH-CO-CH 2 、CO-NH-CH 2 , CH 2 -NH-CH 2 -CO-NH, CH 2 -NH-CH 2 -NH-CO, -CO-NH, CO-NH-CH 2 -NH-CH 2 , CH 2 -NH-CH 2 .

[0377] In another embodiment, o L 0 to 5.

[0378] In other embodiments, the linker moiety comprises one or more rings selected from the group consisting of a 3- to 13-membered ring, a 3- to 13-membered fused ring, a 3- to 13-membered bridged ring, and a 3- to 13-membered spiro ring.

[0379] In another embodiment, the linker portion is as shown in Formula 9A.

[0380] In another embodiment, A L , W L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -、-(CH 2 )0-3 -CO-(CH 2 ) 0-8 -、(CH 2 ) 0-8 -NH-CO、(CH 2 ) 0-8 -CO-NH、NH-CO-(CH 2 ) 0-8 、CO-NH-(CH 2 ) 0-8 、(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -CO-NH、(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 -NH-CO、CO-NH-(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 、(CH 2 ) 1-3 -NH-(CH 2 ) 1-3 、-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 、-(CH 2 ) 0-3 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(CO-NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -、-(CH 2 ) 0-3 -(NH-CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 - and -(CH 2 ) 0-3 -(NH)-(CH2 ) 0-3 -R L r -(CH 2 ) 0-3 -.

[0381] In another embodiment, R L r Selected from: formula C1, C2, C3, C4 and C5 as defined above.

[0382] In another embodiment, R L r Selected from Group R L , and group R L As defined in Equation 9.

[0383] In another embodiment, in Formula 9A, A L and B L are independently as defined above, and W is none.

[0384] In other embodiments, the linker is from 0 to 40 chain atoms in length.

[0385] In other embodiments, the linker is 3 to 20 chain atoms in length.

[0386] In other embodiments, the linker is 5 to 15 chain atoms in length.

[0387] In another embodiment, when the CBP / P300 ligand of the bivalent compound is attached to A L When A L Selected from: -(CO)-, -(CH 2 ) 1-2 (CO)-NH-, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 、-(CH 2 ) 0-3 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 ,in

[0388] RL r Selected from Group R L , and group R L As defined in Equation 9.

[0389] In another embodiment, when the CBP / P300 ligand of the bivalent compound is attached to A L When A L Selected from: -(CO)-, -(CH 2 ) 1-2 (CO)-NH-, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 、-(CH 2 ) 0-3 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 ,in

[0390] R L r Selected from Group R L , and group R L As defined in Equation 9.

[0391] In another embodiment, the linker is -(CO)-(CH 2 ) 3-7 -.

[0392] In another embodiment, the linker is -(CH 2 ) 1-2 (CO)-NH-(CH 2 ) 3-7 -.

[0393] In another embodiment, the linker is -(CH 2 ) 0-10 -or-(CH 2 ) 0-3 -CO-(CH 2 ) 0-10 -.

[0394] In another embodiment, the linker is -(CH 2) 0-11 -or-(CH 2 ) 0-3 -CO-(CH 2 ) 0-10 -.

[0395] In another embodiment, the linker is -(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -or-(CH 2 ) 0-3 -(CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-3 -, where R L r Selected from: Group R L , and group R L As defined in Equation 9.

[0396] In another embodiment, -(CH 2 ) 0-3 - is none, -(CH 2 )-、-(CH 2 ) 2 -or-(CH 2 ) 3 -. In another embodiment, -(CH 2 ) 0-10 - is none, -(CH 2 )-、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 7 -、-(CH 2 ) 8 -、-(CH 2 ) 9 -or-(CH 2 ) 10 -. In another embodiment, -(CH 2 ) 0-11 - is none, -(CH 2)-、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 7 -、-(CH 2 ) 8 -、-(CH 2 ) 9 -、-(CH 2 ) 10 -or-(CH 2 ) 11 -. In another embodiment, -(CH 2 ) 1-2 -for-(CH 2 )-or-(CH 2 ) 2 -. In another embodiment, -(CH 2 ) 0-8 - is none, -(CH 2 )-、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 7 -or-(CH 2 ) 8 -.

[0397] In some embodiments, the divalent compound is not any specific divalent compound in PCT / CN2020 / 076648.

[0398] In some embodiments, the divalent compound is not any specific divalent compound in Table 1 of PCT / CN2020 / 076648.

[0399] In some embodiments, the divalent compound is not any specific divalent compound in Table 1B of PCT / CN2020 / 076648.

[0400] In some embodiments, the bivalent compound is selected from the group consisting of P-187 to P-265 and CPD-1180 to CPD-1207, or a pharmaceutically acceptable salt or analog thereof.

[0401] In some embodiments, the bivalent compound is selected from the group consisting of P-187, P-188, P-192, P-193, P-194, P-196, P-198, P-200, P-201, P-202, P-211, P-212, P-221, P-222, P-224, P-227, P-228, P-229, P-231, P-234, P-240, P-241, P-242, P-243, P-244, P-249, P-250, P-251, P-252, P-253, P-254, P-256, and pharmaceutically acceptable salts or analogs.

[0402] In one embodiment, the divalent compound is 4-(3-(1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-187).

[0403] In one embodiment, the divalent compound is 4-((2-(1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-188).

[0404] In one embodiment, the divalent compound is 4-(4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-192).

[0405] In one embodiment, the divalent compound is 4-(((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-193).

[0406] In one embodiment, the divalent compound is 3-(7-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-194).

[0407] In one embodiment, the divalent compound is 3-(4-(((5-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)pyridin-2-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-196).

[0408] In one embodiment, the divalent compound is 3-(7-(((4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)morpholin-2-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-198).

[0409] In one embodiment, the divalent compound is 3-(4-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-200).

[0410] In one embodiment, the divalent compound is 4-(3-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)butyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-201).

[0411] In one embodiment, the divalent compound is 3-(4-((3-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-202).

[0412] In one embodiment, the divalent compound is 3-(5-((1-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-211).

[0413] In one embodiment, the divalent compound is 3-(5-((1-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-212).

[0414] In one embodiment, the divalent compound is 3-(5-(2-(1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-221).

[0415] In one embodiment, the divalent compound is 3-(5-(2-(1-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-222).

[0416] In one embodiment, the divalent compound is 3-(4-(3-(4-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperazin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-224).

[0417] In one embodiment, the divalent compound is 3-(4-((1-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-227).

[0418] In one embodiment, the divalent compound is 3-(4-(2-(1-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-228).

[0419] In one embodiment, the divalent compound is 3-(4-((1-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-229).

[0420] In one embodiment, the divalent compound is 3-(4-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-231).

[0421] In one embodiment, the divalent compound is 3-(5-(3-(4-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-234).

[0422] In one embodiment, the divalent compound is 5-((7-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-7-oxoheptyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide (P-240).

[0423] In one embodiment, the divalent compound is 5-((5-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-5-oxopentyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide (P-241).

[0424] In one embodiment, the divalent compound is 5-((6-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide (P-242).

[0425] In one embodiment, the divalent compound is 3-(5-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-243).

[0426] In one embodiment, the divalent compound is 3-(5-(2-(1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-244).

[0427] In one embodiment, the divalent compound is 4-(4-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-249).

[0428] In one embodiment, the divalent compound is 3-(4-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-250).

[0429] In one embodiment, the divalent compound is 3-(4-((1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-251).

[0430] In one embodiment, the divalent compound is 3-(4-(2-(1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-252).

[0431] In one embodiment, the divalent compound is 5-((4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide (P-253).

[0432] In one embodiment, the divalent compound is 5-((2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide (P-254).

[0433] In one embodiment, the divalent compound is 5-(4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide (P-256).

[0434] According to one aspect of the present disclosure, the composition disclosed herein comprises the divalent compound or a pharmaceutically acceptable salt or analog thereof, and a pharmaceutically acceptable carrier or diluent.

[0435] According to one aspect of the present disclosure, the method of treating a CBP / P300-mediated disease disclosed herein comprises administering the bivalent compound or a pharmaceutically acceptable salt or analog thereof to a subject suffering from a CBP / P300-mediated disease.

[0436] In one embodiment, the CBP / P300-mediated disease is caused by CBP / P300 expression, mutation, deletion or fusion.

[0437] In one embodiment, a subject suffering from a CBP / P300 mediated disease has increased CBP / P300 function relative to a healthy subject not suffering from the CBP / P300 mediated disease.

[0438] In one embodiment, the divalent compound is selected from the group consisting of P-187 to P-265 and CPD-1180 to CPD-1207, or an analog thereof.

[0439] In one embodiment, the bivalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

[0440] In one embodiment, the method further comprises administering to the subject an additional therapeutic regimen for treating cancer, an inflammatory disorder, or an autoimmune disease.

[0441] In one embodiment, the additional treatment regimen is selected from surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.

[0442] In one embodiment, the CBP / P300-mediated cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative change), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor-positive breast cancer, parenchymal thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, Multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

[0443] In one embodiment, the CBP / P300-mediated cancer is selected from the group consisting of prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and melanoma.

[0444] In one embodiment, the CBP / P300-mediated inflammatory disorder or autoimmune disease is selected from the group consisting of Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, disease), bullous skin diseases, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, cholangitis, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock, thyroiditis, diabetes mellitus, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

[0445] In one embodiment, the CBP / P300-mediated disease is recurrent cancer.

[0446] In one embodiment, the CBP / P300-mediated disease is refractory to one or more prior therapies.

[0447] According to one aspect of the present invention, a method for identifying a divalent compound that mediates the degradation or reduction of CBP / P300 is disclosed. The method comprises:

[0448] providing a heterobifunctional test compound comprising a CBP / P300 ligand conjugated to a degradation tag via a linker;

[0449] contacting the heterobifunctional test compound with cells comprising a ubiquitin ligase and CBP / P300;

[0450] determining whether CBP / P300 levels in the cells are reduced; and

[0451] Heterobifunctional test compounds that mediate degradation or reduction of CBP / P300 are identified as bivalent compounds.

[0452] In one embodiment, the cell is a cancer cell.

[0453] In one embodiment, the cancer cell is a CBP / P300-dependent cancer cell.

[0454] Incorporation by reference

[0455] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0456] BRIEF DESCRIPTION OF THE DRAWINGS

[0457] The novel features of the present invention are particularly set forth in the appended claims. The features and advantages of the present invention may be better understood by reference to the following detailed description of illustrative embodiments, in which the principles of the present invention are utilized, and the accompanying drawings:

[0458] Figure 1 Shown are immunoblots of P300 protein expressed by LNCaP cells after treatment with 5 nM GNE-781 or heterobifunctional compounds P-001 to P-036.

[0459] Figure 2 Shown are immunoblots of P300 protein expressed by LNCaP cells treated with the indicated concentrations of GNE-781, P-003, P-004, P-005, P-015, P-016, or P-020.

[0460] Figure 3 Shown is an immunoblot of P300 protein expressed by LNCaP cells at various time points after treatment with GNE-781, P-004, P-005, P-015, or P-020.

[0461] Figure 4 Shown is a graph of LNCaP cell viability versus GNE-781, P-001, P-002, and P-019 concentration.

[0462] Figure 5 Shown are immunoblots of P300 and CBP proteins expressed by LNCaP cells treated with GNE-781 or heterobifunctional compounds P-056, P-57, P-58, P-59, P-060, P-062, P-063, P-067, P-068, or P-069.

[0463] Figure 6 Shown are immunoblots of P300 protein expressed by LNCaP cells treated with the indicated concentrations of P-084 to P-093, P-096, P-097, P-100, P-102, or P-104 to P-108.

[0464] Figure 7 A shows immunoblot of P300 protein expressed by LNCaP cells after treatment with the indicated concentrations of heterobifunctional compound P-034 or P-034-neg.

[0465] Figure 7 B shows immunoblot of P300 protein expressed by 22RV1 cells after treatment with the indicated concentrations of heterobifunctional compound P-034 or P-034-negative.

[0466] Figure 8 Shown are immunoblots of P300 and CBP proteins expressed by LNCaP cells after treatment with 10 nM GNE-781, P-007, P-034, or P-100 in the presence or absence of pomalidomide, MG-132, bortezomib, or MLN4924.

[0467] Fig. 9 Shown are immunoblots for P300 and CBP proteins expressed in subcutaneous 22RV1 xenograft tumors following treatment with a single dose of 40 mg / kg of P-100, P-007, or P-034 by intraperitoneal injection (ip) or oral gavage (po).

[0468] Fig.10 Shown are the changes of LNCaP cells ( Fig.10 AB) or 22RV1 cells ( Fig.10 CE) Immunoblotting of expressed P300 and CBP proteins.

[0469] Fig.11 Shown are the changes in LNCaP cells ( Fig.11 BE) or 22RV1 cells ( Fig.11 A) Immunoblotting of expressed P300 and CBP proteins.

[0470] Fig.12 Shown is an immunoblot of CBP protein expressed in lung tissue of ICR mice after treatment with a single dose of 40 mg / kg of the indicated heterobifunctional compounds by oral gavage (po).

[0471] Fig.13 Shown are the changes in LNCaP cells ( Fig.13 AC) Immunoblotting of expressed P300 and CBP proteins. DETAILED DESCRIPTION OF THE INVENTION

[0473] Post-translational modifications of proteins, such as phosphorylation, acetylation, methylation, and ubiquitination, have greatly contributed to the diversity and regulation of proteins. P300 (encoded by EP300) and the closely related CBP (encoded by CREBBP) are two widely studied lysine acetyltransferases (HATs) that catalyze the transfer of acetyl groups to lysine residues of proteins. The most well-characterized substrates of P300 and CBP are histones. Acetylation of histones regulates the conformation of chromatin and often leads to transcriptional activation. Recruitment of P300 and / or CBP is essential for many transcription factors and other transcriptional regulators to effectively promote regional transcription (Dancy and Cole, 2015). Substrates of P300 and CBP also include many non-histone proteins with important physiological and pathological functions, such as p53, MYC, FOXO1, and NF-κB (Dancy and Cole, 2015). Because P300 and CBP functionally interact with a variety of signaling proteins, these two lysine acetyltransferases serve as convergence points for many signal transduction pathways (Bedford et al., 2010). By regulating the acetylation of multiple substrates and ligating a variety of binding partners, P300 and CBP are widely involved in biological processes such as cell proliferation, differentiation, development, DNA repair, inflammation, metabolism, and memory.

[0474] Because mice lacking P300 or CBP die early in embryogenesis, both P300 and CBP are essential for development (Goodman and Smolik, 2000). Abnormal P300 or CBP has been implicated in a variety of human diseases. Germline mutations that inactivate one of the CREBBP alleles cause Rubinstein-Taybi syndrome (Petrij et al., 1995), which may be due to impaired activation of the Hedgehog family of transcription factors. Both P300 and CBP are known to promote hematopoiesis through interaction with hematopoietic transcription factors such as GATA-1 (Blobel, 2000). Tumor suppressor roles for P300 and CBP have been established. Patients with Rubinstein-Taybi syndrome have a high prevalence of cancer. Inactivating mutations in P300 and CBP are frequently found in human cancers (Giles et al., 1998). However, these two HATs also promote tumorigenesis through different mechanisms. In a subset of acute myeloid leukemias, a recurrent chromosomal translocation t(8;16)(p11;p13) generates an in-frame fusion of the MOZ and CREBBP genes that directs expression of the oncogenic MOZ-CBP fusion protein (Rozman et al., 2004). CBP and, less commonly, P300 are also found fused to MLL in chemoresistant leukemias (Sobulo et al., 1997). Accumulating evidence suggests that most oncogenic transcription factors, such as MYC (Faiola et al., 2005; Vervoorts et al., 2003), NF-κB (Vanden Berghe et al., 1999), β-catenin (Sun et al., 2000), E2F1 (Ianari et al., 2004; Martinez-Balbas et al., 2000), and nuclear receptors (Chakravarti et al., 1996), recruit P300 and CBP as coactivators. Therefore, depletion of P300 and / or CBP may affect tumor growth by impairing the function of these oncogenic transcription factors. In addition, P300 has been reported to regulate immune cell function (Liu et al., 2013). Further, P300 and CBP are important transcriptional coactivators of STAT and NF-κB family transcription factors, which have key functions in immune cells (Nadiminty et al., 2006; Wang et al., 2005; Wang et al., 2017). Therefore, P300 / CBP antagonists can be used to modulate the activity of the immune system and the crosstalk between immune cells and cancer cells (Liu et al., 2013). Finally, there is a large body of literature demonstrating that histone acetylation is closely related to neurodegenerative diseases (Saha and Pahan, 2006; Valor et al., 2013).In conclusion, the development of novel therapeutics targeting P300 and CBP represents new opportunities for the treatment of cancer, inflammatory diseases, neurological indications, and other indications.

[0475] P300 and CBP have nearly 75% similarity and 63% identity in protein sequence. Greater homology is found in functional domains that are highly conserved during evolution. Most of these domains mediate protein-protein interactions, such as the cysteine-histidine-rich domain 1 (CH1), the CREB-interacting KIX domain, the cysteine-histidine cluster domain (CH3), and the nuclear receptor coactivator binding domain (Wang et al., 2013a). However, these domains are not very suitable for small molecule-mediated intervention. Only a few inhibitors have been reported. For example, naphthol-AS-E (Uttarkar et al., 2015), compounds 1-10 (Wang et al., 2013b), and MYBMIM (Ramaswamy et al., 2018) have been reported as KIX domain inhibitors. KCN1 (Shi et al., 2012; Yin et al., 2012), OHM1 (Lao et al., 2014), HBS1 (Kushal et al., 2013), and KCN1 (Ferguson et al., 2017) analogs were found to be disruptors of TAZ1 / HIF-1α protein interaction. ICG-001 (Emami et al., 2004) was reported to be a selective inhibitor of CBP NRID / β-catenin interaction. In addition, YH249 and YH250 (Yusuke et al., 2016) were reported to selectively inhibit P300-dependent transcription. Recent efforts to develop small molecule probes for P300 and CBP have focused on the HAT domain and the bromodomain. The HAT domain is responsible for catalyzing the transfer of the acetyl group, while the bromodomain binds to the acetylated lysine residues, thereby promoting the interaction of P300 and CBP with acetylated chromatin.Various small molecule compounds, including GNE-781 (Bronner et al., 2017), GNE-272 (Bronner et al., 2017), GNE-207 (Lai et al., 2018), CPD 4d (Hewings et al., 2011), CPD(S)-8 (Hewings et al., 2013), CPD(R)-2 (Rooney et al., 2014), CPD6 (Unzue et al., 2016), CPD19 (Unzue et al., 2016), XDM-CBP (Hugle et al., 2017; Unzue et al., 2016), I-CBP112 (Picaud et al., 2015), TPOP146 (Popp et al., 2016), CPI-637 (Taylor et al., 2016), SGC-CBP30 (Hammitzsch et al., 2015; Hay et al., 2014), CPD CPD 11 (Denny et al., 2017), CPD 41 (Denny et al., 2017), CPD 30 (Lai et al., 2018), CPD5 (Bronner et al., 2017), CPD 27 (Bronner et al., 2017), CPD 29 (Bronner et al., 2017), and CCS1477 (clinical trial number: NCT03568656), have been described as targeting the bromodomain of P300, and CBP HAT domain-targeted P300 / CBP inhibitors, C646 (Oike et al., 2014) and A-485 (Lasko et al., 2017). Transcription dependent on P300 or CBP is partially disrupted by these compounds (Wei et al., 2018). These HAT or bromodomain inhibitors have demonstrated anticancer activity in a wide range of human cancers, including but not limited to prostate cancer (Jin et al., 2017; Lasko et al., 2017), breast cancer (Yang et al., 2013), lung cancer (Ogiwara et al., 2016; Oike et al., 2014), acute myeloid leukemia (Giotopoulos et al., 2016), and melanoma (Wang et al., 2018). However, there are some significant caveats in using these small molecule inhibitors to modulate the activities of P300 and CBP. First, P300 and CBP have multiple functional domains. Blockade of the HAT domain or bromodomain only results in partial inhibition of their activities. These small molecule inhibitors cannot effectively modulate the scaffold functions of P300 and CBP. Second, the HAT domain and bromodomain of P300 and CBP have significant homology, so most small molecule compounds cannot effectively distinguish between these two targets. Instead, P300 and CBP have different tissue type-dependent effects.For example, in prostate cancer, P300 is the major coactivator of the androgen receptor, while CBP has a limited effect (Ianculescu et al., 2012). Therefore, targeting both P300 and CBP simultaneously is not always necessary and may result in more significant side effects than selectively targeting one of them. Not to mention that many P300 / CBP inhibitors have unclear off-target effects. To improve the selectivity and activity of anti-P300 / CBP therapy, approaches that selectively degrade the target protein are expected to have substantial advantages.

[0476] Without wishing to be bound by any theory, the present disclosure is believed to be based, at least in part, on the discovery that novel heterobifunctional small molecules (“proteolysis targeting chimeras” / “PROTACs” and “specific and non-genetic IAP-dependent protein erasure” / “SNIPERs”) that degrade CBP / P300, CBP / P300 fusion proteins, and / or CBP / P300 mutant proteins can be used to treat CBP / P300-mediated diseases, particularly prostate cancer (Jin et al., 2017; Lasko et al., 2017), breast cancer (Yang et al., 2013), lung cancer (Ogiwara et al., 2016; Oike et al., 2014), acute myeloid leukemia (Giotopoulos et al., 2016), and melanoma (Wang et al., 2018).

[0477] Selective degradation of target proteins induced by small molecules can be achieved by recruiting E3 ubiquitin ligases and mimicking protein misfolding with hydrophobic tags (Buckley and Crews, 2014). In addition, PROTACs are bivalent inhibitors, one part of which binds to the E3 ubiquitin ligase and the other part to the target protein (Buckley and Crews, 2014). The induced proximity leads to ubiquitination of the target, followed by proteolytic degradation mediated by the proteasome. Several types of high-affinity small molecule E3 ligase ligands have been identified or developed. They include (1) immunomodulatory drugs (IMiDs), such as thalidomide and pomalidomide, which bind to cereblon (CRBN or CRL4CRBN), a component of the cullin-RING ubiquitin ligase (CRL) complex (Bondeson et al., 2015; Chamberlain et al., 2014; Fischer et al., 2014; Ito et al., 2010; Winter et al., 2015); and (2) VHL-1, a hydroxyproline-containing ligand that binds to the von Hippel-Lindau complex. Hippel-Lindau) protein (VHL or CRL2VHL) (another component of the CRL complex) (Bondeson et al., 2015; Buckley et al., 2012a; Buckley et al., 2012b; Galdeano et al., 2014; Zengerle et al., 2015); (3) compound 7, which selectively binds to KEAP1 (a component of the CRL3 complex) (Davies et al., 2016); (4) AMG232, which selectively binds to MDM2 (a heterodimeric RING E3 ligase) (Sun et al., 2014); (5) LCL161, which selectively binds to IAP (a homodimeric RING E3 ligase) (Ohoka et al., 2017; Okuhira et al., 2011; Shibata et al., 2017). PROTAC technology has been applied to degrade a variety of protein targets (Bondeson et al., 2015; Buckley et al., 2015; Lai et al., 2016; Lu et al., 2015; Winter et al., 2015; Zengerle et al., 2015). In addition, a hydrophobic tagging method using a bulky and hydrophobic adamantyl group has been developed to mimic protein misfolding, thereby leading to target protein degradation by the proteasome (Buckley and Crews, 2014). This approach has been applied to the selective degradation of the pseudokinase HER3 (Xie et al., 2014).The inventors are unaware of any efforts to apply any of these methods to the degradation of CBP / P300, CBP / P300 mutants, CBP / P300 deletions, or CBP / P300 fusion proteins.

[0478] Currently available small molecules targeting CBP / P300 focus on inhibiting the protein interaction or acetyltransferase activity of CBP / P300. A variety of selective small molecule CBP / P300 inhibitors have been reported, such as GNE-781, GNE-272, GNE-207, CPD4d, CPD(S)-8, CPD(R)-2, CPD6, CPD19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD11, CPD41, CPD30, CPD5, CPD27, CPD29, CCS1477 (clinical trial number: NCT03568656), C646 (Oike et al., 2014), A-485, naphthol-AS-E (Uttarkar et al., 2015), compounds 1-10 (Wang et al., 2013b), MYBMIM (Ramaswamy et al., 2018), KCN1 (Shi et al., 2012; Yin et al., 2012), OHM1 (Lao et al., 2014), HBS1 (Kushal et al., 2013), and KCN1 analogs (Ferguson et al., 2017), ICG-001 (Emami et al., 2004), YH249 (Yusuke et al., 2016) and YH250 (Yusuke et al., 2016).

[0479] In the present disclosure, a new approach is adopted: develop compounds that not only directly and selectively regulate the protein-protein interaction and acetyltransferase activity of CBP / P300, but also regulate their protein levels. The strategy of inducing protein degradation includes recruiting E3 ubiquitin ligases, simulating protein misfolding and inhibiting molecular chaperones with hydrophobic tags. Compared with technologies such as gene knockout or short hairpin RNA-mediated (shRNA) silencing (knockdown), this method based on the use of bivalent small molecule compounds allows more flexible regulation of protein levels in vitro and in vivo. Different from gene knockout or shRNA silencing, small molecule methods further provide opportunities for studying dose and time dependence in disease models by regulating the route of administration, concentration and frequency of administration of the corresponding small molecules.

[0480] Divalent compounds

[0481] In some aspects, the present disclosure provides a bivalent compound comprising a CBP / P300 ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof. The CBP / P300 ligand may be bound to the degradation tag directly or through a linker portion. In certain embodiments, the CBP / P300 ligand may be directly bound to the degradation tag. In certain embodiments, the CBP / P300 ligand may be bound to the degradation tag through a linker portion.

[0482] As used herein, the terms "cyclic AMP response element binding protein and / or 300 kDa adenovirus E1A binding protein" and "CBP / P300 ligand" or "CBP / P300 targeting moiety" should be interpreted as covering any molecule ranging from small molecules to large proteins that is associated with or binds to CBP and / or P300 proteins. In certain embodiments, the CBP / P300 ligand is capable of binding to a CBP / P300 protein, including CBP / P300, a CBP / P300 mutant, a CBP / P300 deletion, or a CBP / P300 fusion protein. The CBP / P300 ligand can be, for example, but not limited to, a small molecule compound (i.e., a molecule with a molecular weight of less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, a nucleic acid or oligonucleotide, a carbohydrate such as an oligosaccharide, or an antibody or fragment thereof.

[0483] CBP / P300 ligand

[0484] The CBP / P300 ligand or targeting moiety can be a CBP / P300 inhibitor or a portion of a CBP / P300 inhibitor. In certain embodiments, the CBP / P300 inhibitor includes one or more of the following (e.g., GNE-781, GNE-272, GNE-207, CPD4d, CPD(S)-8, CPD(R)-2, CPD6, CPD19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD11, CPD41, CPD30, CPD5, CPD27, CPD29, CCS1477 (clinical trial number: NCT03568656), C646 (Oike et al., 2014), A-485, naphthol-AS-E (Uttarkar et al., 2014), 15), compounds 1-10 (Wang et al., 2013b), MYBMIM (Ramaswamy et al., 2018), KCN1 (Shi et al., 2012; Yin et al., 2012), OHM1 (Lao et al., 2014), HBS1 (Kushal et al., 2013), and KCN1 analogs (Ferguson et al., 2017), ICG-001 (Emami et al., 2004), YH249 (Yusuke et al., 2016) and YH250 (Yusuke et al., 2016) and their analogs), which can inhibit the protein-protein interaction or acetyltransferase activity of CBP / P300. As used herein, "CBP / P300 inhibitor" refers to an agent that inhibits, interferes with or otherwise causes an inhibition of a physiological, chemical or enzymatic action or function and causes a reduction in binding of at least 5%. Inhibitors may also or alternatively refer to drugs, compounds or agents that prevent or reduce the expression, transcription or translation of a gene or protein. Inhibitors may reduce or prevent the function of a protein, for example by binding to or activating / inactivating another protein or receptor.

[0485] In certain embodiments, the CBP / P300 ligand is as defined above.

[0486] In certain embodiments, the CBP / P300 ligand is derived from a CBP / P300 inhibitor comprising:

[0487]

[0488] In certain embodiments, the CBP / P300 ligands include, but are not limited to, GNE-781, GNE-272, GNE-207, CPD4d, CPD(S)-8, CPD(R)-2, CPD6, CPD19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD11, CPD41, CPD30, CPD5, CPD27, CPD29, CCS1477 (clinical trial number: NCT03568656), C646 (Oike et al., 2014), A-485, naphthol-AS -E (Uttarkar et al., 2015), compounds 1-10 (Wang et al., 2013b), MYBMIM (Ramaswamy et al., 2018), KCN1 (Shi et al., 2012; Yin et al., 2012), OHM1 (Lao et al., 2014), HBS1 (Kushal et al., 2013), and KCN1 analogs (Ferguson et al., 2017), ICG-001 (Emami et al., 2004), YH249 (Yusuke et al., 2016), and YH250 (Yusuke et al., 2016).

[0489] In other embodiments, the CBP / P300 ligand comprises a moiety of Formula 1:

[0490]

[0491] Among them, R 1 , R 2 , R 3 , A, Ar, X 1 , X 2 and X 3 As defined above.

[0492] In another embodiment, Formula 1 is Formula 1A:

[0493]

[0494] Among them, A, Ar, R 1 , R 2 and R 3 Same as in formula 1.

[0495] In other embodiments, the CBP / P300 ligand comprises a moiety of Formula 2:

[0496]

[0497] Among them, R 1 , R 2 , R 3, A, Ar, X 1 , X 2 and X 3 As defined above.

[0498] In another embodiment, Formula 2 is Formula 2A:

[0499]

[0500] Among them, A, Ar, R 1 , R 2 and R 3 Same as in formula 2.

[0501] In other embodiments, the CBP / P300 ligand is of Formula 1. In other embodiments, the CBP / P300 ligand is of Formula 1A.

[0502] In other embodiments, the CBP / P300 ligand is derived from the following CBP / P300 inhibitors: C646, naphthol-AS-E, Compound 1-10, MYBMIM, CCS1477, ICG-001, YH249, YH250, HBS1, OHM1, and KCN1.

[0503] In another embodiment, the CBP / P300 ligand is selected from the group consisting of: Formula 3A 1 , 3B 1 、3C 1 and 3D 1 :

[0504]

[0505] Degradable Label

[0506] As used herein, the term "degradation tag" refers to a compound that associates with or binds to a ubiquitin ligase to recruit the corresponding ubiquitination machinery to CBP / P300, or a hydrophobic group or tag that causes misfolding of the CBP / P300 protein and subsequent proteasomal degradation or loss of function.

[0507] In other embodiments, the degradation tag is as defined above.

[0508] In another embodiment, the degradation tag is a moiety of Formula 5, and the degradation tag is represented by Z E a linker moiety connected to the divalent compound;

[0509]

[0510] Among them, Z E , R E 1 , LE and Ring A E As defined above.

[0511] In another embodiment, the degradation tag is a moiety of Formula 6A, 6B and 6C:

[0512]

[0513] Among them, R E 1 , R E 2 , R E 3 , R E 4 , R E 5 and R E 6 As defined above.

[0514] In another embodiment, the degradation tag is a moiety of formula 7A:

[0515]

[0516] Among them, R E 1 , R E 2 , R E 3 、V E 1 、V E 2 、V E 3 、V E 4 and V E 5 As defined above.

[0517] In another embodiment, the degradation tag is a moiety of formula 7B:

[0518]

[0519] Among them, R E 1 , R E 2 , R E 3 , R E 4 and R E 5 As defined above.

[0520] In other embodiments, the degradation tag is derived from any of the following:

[0521]

[0522]

[0523] In a further embodiment, the degradation tag is selected from the group Deg as defined above.

[0524] Connector

[0525] As used herein, a "linker" or "linker moiety" is a bond, molecule, or group of molecules that binds two separate objects to each other. The linker provides an optimal spacing between two entities. In some aspects, the term "linker" refers to any agent or molecule that bridges the CBP / P300 ligand to the degradation tag. One of ordinary skill in the art recognizes that sites on the CBP / P300 ligand or degradation tag that are not essential for the function of the PROTAC or SNIPER of the present disclosure are ideal sites for connecting a linker, provided that the linker, once connected to the conjugate of the present disclosure, does not interfere with the function of the CBP / P300 ligand (i.e., its ability to bind CBP / P300), or the function of the degradation tag (i.e., its ability to recruit ubiquitin ligase).

[0526] The length of the connector of the bivalent compound can be adjusted to minimize the molecular weight of the bivalent compound, avoid collision of the CBP / P300 ligand or targeting moiety with the ubiquitin ligase and / or induce CBP / P300 misfolding by the hydrophobic tag. In certain embodiments, the connector comprises an acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, ammonia, ether, urea, carbamate, aromatic, heteroaromatic, heterocycle or carbonyl. In some embodiments, the length of the connector is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more atoms.

[0527] In some embodiments, the connector portion is as shown in Formula 9:

[0528]

[0529] Among them, A L , W L , B L and m L As defined above.

[0530] In one embodiment, the linker portion is as shown in Formula 9A:

[0531]

[0532] Among them, R L 1 , R L2 , R L 3 , R L 4 , A L , W L , B L 、m L 、n L and L As defined above.

[0533] In another embodiment, W L and m are as defined above; and A L and B L , at each occurrence, is independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -、-(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -、(CH 2 ) 1-2 -NH-CO, (CH 2 ) 1-2 -CO-NH, NH-CO-(CH 2 ) 1-2 、CO-NH-(CH 2 ) 1-2 , (CH 2 ) 1-2 -NH-(CH 2 ) 1-2 -CO-NH, (CH 2 ) 1-2 -NH-(CH 2 ) 1-2 -NH-CO, -CO-NH, CO-NH-(CH 2 ) 1-2 -NH-(CH 2 ) 1-2 , (CH 2 ) 1-2 -NH-(CH 2 ) 1-2 、-(CH 2 ) 0-2 -R L r -(CH 2 ) 0-2 、-(CH 2 ) 0-2 -(CO)-(CH 2 ) 0-3 -R L r-(CH 2 ) 0-2 -、-(CH 2 ) 0-2 -(CO-NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -、-(CH 2 ) 0-2 -(NH-CO)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -、-(CH 2 ) 0-2 -(NH)-(CH 2 ) 0-3 -R L r -(CH 2 ) 0-2 -.

[0534] In another embodiment, the linker portion is as shown in Formula 9B:

[0535]

[0536] Among them, R L 1 , R L 2 , A L , B, m L and n L As defined above.

[0537] In another embodiment, the linker portion is as shown in Formula 9C:

[0538]

[0539] Among them, R L 1 , R L 2 , R L 3 , R L 4 , R L 5 , R L 6 , X L , A L , B L 、m L 、nL and L As defined above.

[0540] Without wishing to be bound by any particular theory, it is contemplated herein that, in some embodiments, attachment of pomalidomide or VHL-1 to either portion of the molecule can recruit cereblon E3 ligase or VHL E3 ligase to CBP / P300.

[0541] Compared to WT (wild-type) cells, the bivalent compounds disclosed herein can selectively affect CBP / P300-mediated disease cells (i.e., the bivalent compounds can kill or inhibit the growth of CBP / P300-mediated disease cells while also having a relatively low ability to lyse or inhibit the growth of WT cells), for example, having a GI of 1.5 times lower, 2 times lower, 2.5 times lower, 3 times lower, 4 times lower, 5 times lower, 6 times lower, 7 times lower, 8 times lower, 9 times lower, 10 times lower, 15 times lower, or 20 times lower to one or more CBP / P300-mediated disease cells. 50 , compared to the GI of one or more WT cells (e.g., WT cells of the same species and tissue type as the CBP / P300-mediated disease cells) 50 .

[0542] In some aspects, a method for identifying a bivalent compound that mediates CBP / P300 degradation or reduction is provided herein, the method comprising: providing a heterobifunctional test compound comprising a CBP / P300 ligand conjugated to a degradation tag conjugated via a connector; contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and CBP / P300; determining whether the CBP / P300 level in the cell is reduced; and identifying the heterobifunctional test compound that mediates the degradation or reduction of CBP / P300 as a bivalent compound. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cancer cell is a CBP / P300-mediated cancer cell.

[0543] Synthesis and testing of divalent compounds

[0544] The binding affinity of the newly synthesized divalent compound can be assessed using standard biophysical assays known in the art (e.g., isothermal titration calorimetry (ITC), surface plasmon resonance (SPR)). Cellular analysis can then be used to assess the ability of the divalent compound to induce CBP / P300 degradation and inhibit cancer cell proliferation. In addition to assessing the induced changes in the protein level of the divalent compound to CBP / P300, CBP / P300 mutants or CBP / P300 fusion proteins, the enzymatic activity of protein-protein interactions or acetyltransferases can also be assessed. Applicable assays for any or all of these steps are known in the art, including, for example, Western blots, quantitative mass spectrometry (MS) analysis, flow cytometry, enzyme activity assays, ITC, SPR, cell growth inhibition, xenografts, orthotopic and patient-derived xenograft models. Cell lines suitable for any or all of these steps are known in the art, including LNCaP, 22RV1, HEL, MV4; 11, RS4; 11, NCI-H929, MM.1S, Pfeiffer, NCI-H520 and other cell lines. Suitable mouse models for any or all of these steps are known in the art and include subcutaneous xenograft models, orthotopic models, patient-derived xenograft models, and patient-derived orthotopic models.

[0545] As non-limiting examples, detailed synthetic schemes are described in the Examples for specific exemplary divalent compounds.

[0546] Pharmaceutically acceptable isotopic variants of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in the Examples (substituting appropriate reagents with appropriate isotopic variants of those reagents). In particular, an isotopic variant is a compound in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Useful isotopes are known in the art and include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Exemplary isotopes include, for example 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 35 S. 18 F and 36 Cl.

[0547] Isotopic variants (e.g., containing 2H) may offer therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In addition, certain isotopic variants (particularly those containing radioactive isotopes) are useful in drug or substrate tissue distribution studies. In particular, the radioactive isotope tritium ( 3 H) and carbon 14 ( 14 C), can be used for this purpose given their ease of binding and existing detection methods.

[0548] Pharmaceutically acceptable solvates of the compounds disclosed herein are contemplated. Solvates may be prepared, for example, by replacing the solvent used to crystallize the compounds disclosed herein with an isotopic variant (e.g., D 2 O replaces H 2 O,d 6 -acetone instead of acetone, or d 6 -DMSO instead of DMSO).

[0549] Pharmaceutically acceptable fluorinated variants of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in the Examples (replacing appropriate reagents with appropriate fluorinated variants of those reagents). Specifically, fluorinated variants are compounds in which at least one hydrogen atom is replaced by a fluorine atom. Fluorinated variants can provide therapeutic advantages due to higher metabolic stability (e.g., increasing half-life in vivo or reducing dosage requirements).

[0550] Pharmaceutically acceptable prodrugs of the compounds disclosed herein are contemplated and can be synthesized using conventional methods known in the art or methods corresponding to those described in the examples (e.g., converting a hydroxyl or carboxylic acid group into an ester group). As used herein, "prodrug" refers to a compound that can be converted into a therapeutic agent by some chemical or physiological process (e.g., enzymatic process and metabolic hydrolysis). Therefore, the term "prodrug" also refers to a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs may be inactive when administered to a subject, i.e., esters, but are converted into active compounds in vivo, such as by hydrolysis into free carboxylic acids or free hydroxyls. Prodrug compounds generally provide advantages of solubility, tissue compatibility, or delayed release in an organism. The term "prodrug" is also intended to include any covalently bonded carriers that release active compounds in vivo when such prodrugs are administered to a subject. Prodrugs of active compounds can be prepared by modifying functional groups present in the active compound in a manner that is modified in conventional operations or cleaved into the parent active compound in vivo. Prodrugs include compounds in which a hydroxyl, amino or thiol group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxyl, free amino or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols, or acetamide, formamide and benzamide derivatives of amine functional groups in the active compound.

[0551] Characterization of Exemplary Divalent Compounds

[0552] Specific exemplary bivalent compounds were characterized in LNCaP or 22RV1 cells. LNCaP or 22RV1 cells expressing CBP / P300 protein were treated with GNE-781 or bivalent compounds disclosed herein (P-001 to P-265) for the indicated hours. Cells were collected, lysed, and immunoblotted using antibodies specific for P300 or CBP protein. Tubulin or focal adhesion protein was included as a loading control. DMSO was used as a negative control. After treatment with various bivalent compounds, P300 and CBP protein levels in LNCaP or 22RV1 cells were significantly reduced ( Figure 1 , 2 , 5, 6, 10 and 13). Selected bivalent compounds disclosed herein were shown to be particularly effective in reducing CBP and P300 protein levels, as the concentration required to reduce target protein levels by 50% (DC50) for some compounds was less than 1 nM ( Figure 6 ).

[0553] In addition, LNCaP cells were treated with 20 nM of P-004, P-005, P-015, or P-020 for the indicated times. Subsequently, changes in P300 protein levels were measured by immunoblotting. Tubulin was included as a loading control. Significant degradation of P300 was readily detected as early as 2 hours after compound administration ( Figure 3 ).

[0554] Targeting the bromodomain or lysine acetyltransferase domain of CBP / P300 using ligands has been shown to impair cancer cell proliferation and survival (Jin et al., 2017; Lasko et al., 2017; Picaud et al., 2015; Popp et al., 2016). LNCaP cells seeded in 96-well plates were treated with 10 μM of GNE-781 or a 12-point 3-fold serial dilution of selected bivalent compounds (i.e., P-001, P-002, and P-019). Three days after treatment, cell viability was determined using the Cell Titer-Glo kit (Promega) according to the manufacturer's instructions. Cell viability was normalized to the mean of 3 replicates of untreated cells. Dose-dependent responses were analyzed using GraphPad Prism 5.0 software according to the least squares nonlinear regression method. The bivalent compounds dose-dependently inhibited the viability of LNCaP cells, such as P-001, P-002, and P-019 ( Figure 4 , Tables 2-3). These results collectively demonstrate that downregulation of CBP / P300 protein levels using the bivalent compounds described herein induces anti-tumor activity.

[0555] Interaction with cereblon is critical for the ability of the bivalent compounds to induce P300 / CBP protein degradation, as chemical modifications that disrupt cereblon binding abolished P-034-induced P300 degradation in LNCap and 22RV1 cells ( Figure 7 This degradation is also dependent on the ubiquitin-proteasome system, as it can be neutralized by the proteasome inhibitors MG-132 and bortezomib, the cullin E3 ligase inhibitor MLN4924, or high concentrations of pomalidomide that compete with cereblon for binding, such as P-007, P-034, and P-100 ( Figure 8 ).

[0556] Together, these findings demonstrate that the bivalent compounds induce P300 / CBP protein degradation through a mechanism specifically mediated by cereblon, cullin E3 ligases, and the proteasome. In addition to cultured cells, athymic nude mice bearing 22RV1 subcutaneous xenografts on the right flank were treated intraperitoneally or orally with 40 mg / kg of the bivalent compounds. Six hours after dosing, the animals were sacrificed for immunoblotting of P300 and CBP in homogenized xenograft tumor masses. The bivalent compounds, exemplified by P-100, P-007, and P-034, demonstrated the ability to significantly reduce P300 and CBP protein levels after a single dose ( Fig. 9 ). In addition, ICR mice were treated orally with 40 mg / kg of the divalent compound. Six hours after administration, the animals were sacrificed for immunoblotting of CBP in homogenized lung tissue. Fig.12 For example, the bivalent compound showed the ability to significantly reduce CBP protein levels after a single dose.

[0557] Definition of terms

[0558] As used herein, the terms "including" and "comprising" are used in their open, non-limiting sense.

[0559] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, and contains no unsaturation. An alkyl group may contain one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, an alkyl group contains from one to fifteen carbon atoms (e.g., C 1 -C 15 In certain embodiments, the alkyl group contains from one to thirteen carbon atoms (e.g., C 1 -C 13 In certain embodiments, the alkyl group contains from one to eight carbon atoms (e.g., C 1 -C 8 In certain embodiments, the alkyl group contains from one to six carbon atoms (e.g., C 1 -C 6 In certain embodiments, the alkyl group contains one to four carbon atoms (e.g., C 1 -C 4 In certain embodiments, the alkyl group contains one, two, three, four, five, six, seven, or eight carbon atoms (e.g., C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 or C 8In another embodiment, the alkyl group contains five to fifteen carbon atoms (e.g., C 5 -C 15 In certain embodiments, the alkyl group contains five to eight carbon atoms (e.g., C 5 -C 8 In certain embodiments, the alkyl group contains five, six, seven, eight, nine, ten, eleven, twelve, thirty, fourteen, or fifteen carbon atoms (e.g., C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 or C 15 Alkyl). The alkyl group is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (i-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), pentyl, 3-methylhexyl, 2-methylhexyl, etc.

[0560] "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond. An alkenyl group may contain two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, an alkenyl group contains two to twelve carbon atoms (e.g., C 2 -C 12 In certain embodiments, the alkenyl group contains two to eight carbon atoms (e.g., C 2 -C 8 In certain embodiments, the alkenyl group contains two to six carbon atoms (e.g., C 2 -C 6 In certain embodiments, the alkenyl group contains two to four carbon atoms (e.g., C 2 -C 4 The alkenyl group is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.

[0561] As used herein, the term "allyl" refers to -CH 2 CH=CH 2 Group.

[0562] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond. The alkynyl group may contain two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, the alkynyl group contains two to twelve carbon atoms (e.g., C 2 -C 12 In certain embodiments, the alkynyl group contains two to eight carbon atoms (e.g., C 2 -C 8 In certain embodiments, the alkynyl group contains two to six carbon atoms (e.g., C 2 -C 6 In certain embodiments, the alkynyl group contains two to four carbon atoms (e.g., C 2 -C 4 Alkynyl). Alkynyl is attached to the rest of the molecule by a single bond. Examples of such groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.

[0563] As used herein, the term "alkoxy" refers to an alkyl group as defined herein that is attached to the remainder of the molecule via an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0564] As used herein, the term "aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms. The aryl group may contain 6 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system consistent with the Hückel theory. In certain embodiments, the aryl group contains six to fourteen carbon atoms (e.g., C 6 -C 14 In certain embodiments, the aryl group contains six to ten carbon atoms (e.g., C 6 -C 10 As used herein, the terms "Ph" and "phenyl" refer to -C 6 H 5 Group.

[0565] The term "heteroaryl" refers to a group derived from a 3- to 18-membered aromatic group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is completely unsaturated, that is, it contains a cyclic, delocalized (4n+2)π-electron system consistent with the Hückel theory. In certain embodiments, a heteroaryl group refers to a group derived from a 3- to 10-membered aromatic ring group (3-10 membered heteroaryl). In certain embodiments, a heteroaryl group refers to a group derived from a 5- to 7-membered aromatic ring (5-7 membered heteroaryl). In certain embodiments, a heteroaryl group refers to a group derived from a 5-, 6- or 7-membered aromatic ring (5, 6 or 7 membered heteroaryl). Heteroaryl includes a fused ring or a bridged ring system. The heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. Heteroaryl is connected to the rest of the molecule by any atom of the ring. Examples of such groups include but are not limited to pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furanpyridinyl etc. In certain embodiments, heteroaryl is connected to the rest of the molecule by a ring carbon atom. In certain embodiments, the heteroaryl group is connected to the rest of the molecule via a nitrogen atom (N-connected) or a carbon atom (C-connected). For example, a group derived from pyrrole can be pyrrole-1-yl (N-connected) or pyrrole-3-yl (C-connected). For example, a group derived from imidazole can be imidazole-1-yl (N-connected) or imidazole-3-yl (C-connected).

[0566] As used herein, the term "heterocyclyl" refers to a non-aromatic, monocyclic, bicyclic, tricyclic or tetracyclic group having a total of 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms in its ring system and containing 3 to 12 carbon atoms and 1 to 4 heteroatoms independently selected from O, S and N, provided that the ring of the group does not contain two adjacent O atoms or two adjacent S atoms. The heterocyclyl group may include a fused ring, a bridged ring or a spiro ring system. In certain embodiments, the heterocyclyl group includes 3 to 10 ring atoms (3-10 membered heterocyclyl). In certain embodiments, the heterocyclyl group includes 3 to 8 ring atoms (3-8 membered heterocyclyl). In certain embodiments, the heterocyclyl group includes 4 to 10 ring atoms (4-10 membered heterocyclyl). In certain embodiments, the heterocyclyl group includes 4 to 8 ring atoms (4-8 membered heterocyclyl). The heterocyclyl group may include an oxo substituent on any available atom that can produce a stable compound. For example, such a group can include an oxo group at an available carbon atom or nitrogen atom. If chemically feasible, such a group can include more than one oxo group. In addition, it should be understood that when such a heterocyclic group contains a sulfur atom, the sulfur atom can be oxidized by one or two oxygen atoms to provide a sulfoxide or sulfone. An example of a 4-membered heterocyclic group is an azetidinyl group (derived from azetidine). An example of a 5-membered cycloheteroalkyl group is a pyrrolidinyl group. An example of a 6-membered cycloheteroalkyl group is a piperidinyl group. An example of a 9-membered cycloheteroalkyl group is an indolinyl group. An example of a 10-membered cycloheteroalkyl group is a 4H-quinolinyl group. Other examples of such heterocyclic groups are, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidine, morpholine, thiomorpholine, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepane, thiepane, oxazepine, diazepine, thiazepine, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indole, The term "heteroaryl" refers to a group of 1- oxo-2- aryl, 1- oxo-3- aryl, 1- oxo-4- aryl, 1- oxo-5- aryl, 1- oxo-6- aryl, 1- oxo-7- aryl, 1- oxo-8- aryl, 1- oxo-9- aryl, 1- oxo-1- aryl, 1- oxo-2- aryl, 1- oxo-3- aryl, 1- oxo-4- aryl, 1- oxo-5- aryl, 1- oxo-6- aryl, 1- oxo-1- aryl, 1- oxo-2- aryl, 1- oxo-3 ...

[0567] The term "cycloalkyl" or "carbocyclyl" refers to a saturated, monocyclic, bicyclic, tricyclic or tetracyclic group having a total of 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms in its ring system. The cycloalkyl group can be fused, bridged or spirocyclic. In certain embodiments, the cycloalkyl group includes 3 to 8 carbon ring atoms (3-8 membered carbocyclyl). In certain embodiments, the cycloalkyl group includes 3 to 10 carbon ring atoms (3-10 membered carbocyclyl). Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, etc.

[0568] The term "cycloalkylene" is a bidentate group obtained by removing a hydrogen atom from a cycloalkyl group as defined above. Examples of such groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and the like.

[0569] As used herein, the term "chain atom" refers to an atom located on the main chain of a linker moiety.

[0570] As used herein, the term "spirocycle" has its conventional meaning, i.e., any ring system comprising two or more rings, wherein the two rings have a common ring carbon. As defined herein, each ring of a spirocycle system independently comprises 3 to 20 ring atoms. Preferably, there are 3 to 10 ring atoms. Non-limiting examples of spirocycle systems include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

[0571] The term "cyano" refers to a -C≡N group.

[0572] An "aldehyde" group refers to a -C(O)H group.

[0573] "Alkoxy" means an -O-alkyl group, as defined herein.

[0574] "Alkoxycarbonyl" means a -C(O)-alkoxy group, as defined herein.

[0575] "Alkylaminoalkyl" refers to an -alkyl-NR-alkyl group as defined herein.

[0576] "Alkylsulfonyl" refers to -SO 2 Alkyl is as defined herein.

[0577] "Amino" refers to an optionally substituted -NH 2 .

[0578] "Aminoalkyl" means an -alkyl-amino group, as defined herein.

[0579] "Aminocarbonyl" means a -C(O)-amino group, as defined herein.

[0580] "Arylalkyl" means an -alkylaryl group in which alkyl and aryl are as defined herein.

[0581] An "aryloxy" group refers to both -O-aryl and -O-heteroaryl groups, as defined herein.

[0582] "Aryloxycarbonyl" means a -C(O)-aryloxy group, as defined herein.

[0583] "Arylsulfonyl" refers to -SO 2 Aryl is as defined herein.

[0584] "Carbonyl" means a -C(O)- group, as defined herein.

[0585] A "carboxylic acid" group refers to a -C(O)OH group.

[0586] "Cycloalkoxy" means an -O-cycloalkyl group, as defined herein.

[0587] A "halo" or "halogen" group refers to fluoro, chloro, bromo or iodo.

[0588] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0589] "Hydroxy" refers to an -OH group.

[0590] The "nitro" group refers to -NO 2 Group.

[0591] An "oxo" group refers to a =0 substituent.

[0592] "Trihalomethyl" refers to a methyl group substituted with three halogen atoms.

[0593] The term "substituted" means that the specified group or moiety bears one or more substituents independently selected from the following: 1 -C 4 Alkyl, aryl, heteroaryl, aryl-C 1 -C 4 Alkyl-, heteroaryl-C 1 -C 4 Alkyl-, C 1 -C 4 Haloalkyl, -OC 1 C 4 Alkyl, -OC 1 -C 4 Alkylphenyl, -C 1 -C 4 Alkyl-OH, -OC 1 -C 4 Haloalkyl, halogen, -OH, -NH 2 , -C 1 -C4 Alkyl-NH 2 、-N(C 1 -C 4 Alkyl)(C 1 -C 4 Alkyl), -NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 Alkyl)(C 1 -C 4 Alkylphenyl), -NH(C 1 C 4 alkylphenyl), cyano, nitro, oxo, -CO 2 H、-C(O)OC 1 -C 4 Alkyl, -CON(C 1 -C 4 Alkyl)(C 1 -C 4 alkyl), -CONH(C 1 -C 4 Alkyl), -CONH 2 、-NHC(O)(C 1 -C 4 alkyl), -NHC(O)(phenyl), N(C 1 -C 4 Alkyl)C(O)(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl)C(O)(phenyl), -C(O)C 1 -C 4 Alkyl, C(O)C 1 -C 4 Alkylphenyl, -C(O)C 1 -C 4 Haloalkyl, -OC(O)C 1 -C 4 Alkyl, -SO 2 (C 1 -C 4 Alkyl), -SO 2 (phenyl), -SO 2 (C 1 -C 4 Haloalkyl), -SO 2 NH 2 、SO 2 NH(C 1 -C 4 Alkyl), -SO 2 NH(phenyl), -NHSO2 (C 1 -C 4 Alkyl), -NHSO 2 (phenyl) and -NHSO 2 (C 1 -C 4 haloalkyl).

[0594] The term "none" refers to the absence of atoms or moieties and the presence of bonds between adjacent atoms in the structure.

[0595] The term "optionally substituted" means that the specified group may be unsubstituted or substituted with one or more substituents as defined herein. It is understood that in the compounds of the present invention, when a group is referred to as "unsubstituted", or "substituted" with fewer groups than fill the valences of all the atoms in the compound, the remaining valences of the group are filled with hydrogen. For example, if C 6 The aryl group, also referred to herein as "phenyl", is substituted with an additional substituent, and one of ordinary skill in the art will understand that such a group is 6 There are 4 open positions on the carbon atoms of the aromatic ring (6 original positions, minus one position to which the rest of the compound of the invention is attached and one additional substituent, leaving 4 open positions). In this case, the remaining 4 carbon atoms are each bonded to a hydrogen atom to fill their valences. Similarly, if the C 6 When an aryl group is referred to as "disubstituted", a person skilled in the art will understand that this means that 6 The aryl group has 3 unsubstituted remaining carbon atoms. Each of the three unsubstituted carbon atoms is bonded to a hydrogen atom to fill their valence. Unless otherwise indicated, an optionally substituted group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, or 4) substituents selected from the group consisting of halogen, CN, NO 2 , OR m , SR m NR n R o , COR m , CO 2 R m ,CONR n R o 、SOR m 、SO 2 R m 、SO 2 NR n R o NR n COR o NR m C(O)NR n R oNR n SOR o NR n SO 2 R o , C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkylamino C 1 -C 8 Alkyl, C 3 -C 7 Cycloalkyl, 3-7 membered heterocyclic group, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, aryl and heteroaryl, wherein R m , R n and R o Independently selected from: none, hydrogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, C 3 -C 7 Cycloalkyl, 3-7 membered heterocyclic, aryl and heteroaryl, or R n and R o Together with the atoms to which they are attached, they form a 4-8 membered cycloalkyl or heterocyclyl ring.

[0596] As used herein, the same symbols in different formulae represent different definitions. For example, R 1 The definition of is the same as that of Formula 1. In Formula 6, R 1 The definition of is the same as that of formula 6.

[0597] As used herein, when m (or n or o or p) is defined by a range, for example, "m is 0 to 15" or "m=0-3" means that m is an integer from 0 to 15 (i.e., m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) or m is an integer from 0 to 3 (i.e., m is 0, 1, 2 or 3) or is any integer within the defined range.

[0598] As used herein, (CH 2 ) a-b(a and b are integers) means (CH 2 ) c A group, and c is an integer from a to b (i.e., c is a, a+1, a+2, ..., b-1 or b). For example, (CH 2 ) 0-3 Represents the following groups: None, (CH 2 )、(CH 2 ) 2 or (CH 2 ) 3 .

[0599] "Pharmaceutically acceptable salts" include acid and base addition salts. Pharmaceutically acceptable salts of any of the divalent compounds described herein are intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0600] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, toluates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginate, gluconate and galacturonate (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997), which is incorporated herein by reference in its entirety). Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to the skilled artisan.

[0601] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared by the addition of inorganic or organic bases to the free acids. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, salts of substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0602] Pharmaceutical composition

[0603] In some aspects, the compositions and methods described herein include the manufacture and use of pharmaceutical compositions and medicaments comprising one or more bivalent compounds disclosed herein. Also included are the pharmaceutical compositions themselves.

[0604] In some aspects, the compositions disclosed herein may include other compounds, drugs or agents for treating cancer. For example, in some cases, the pharmaceutical compositions disclosed herein may be combined with one or more (e.g., one, two, three, four, five or less than ten) compounds. Such additional compounds may include, for example, conventional chemotherapeutic agents or any other cancer treatment known in the art. When co-administered, the divalent compounds disclosed herein may act in conjunction with conventional chemotherapeutic agents or any other cancer treatment known in the art to produce a mechanical additive or synergistic therapeutic effect.

[0605] In some aspects, the pH of the compositions disclosed herein can be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the divalent compound or its delivery form.

[0606] Pharmaceutical compositions typically include a pharmaceutically acceptable excipient, adjuvant or carrier. As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally considered to be physiologically tolerable and that do not generally produce allergic or similar adverse reactions, such as stomach discomfort, dizziness, etc., when administered to humans. Pharmaceutically acceptable excipients, adjuvants or carriers are substances that can be administered to patients together with the compounds of the present invention, and do not impair their pharmacological activity and are nontoxic when administered in a dose sufficient to deliver a therapeutic amount of the compound. Exemplary conventional non-toxic pharmaceutically acceptable excipients, adjuvants and carriers include, but are not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, etc., that are compatible with drug administration.

[0607] In particular, pharmaceutically acceptable excipients, adjuvants and carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopheryl polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins can also be advantageously used to enhance the delivery of compounds of the formula described herein.

[0608] Depending on the dosage form selected for delivering the divalent compounds disclosed herein, different pharmaceutically acceptable excipients, adjuvants and carriers can be used. In the case of oral tablets, pharmaceutically acceptable excipients, adjuvants and carriers that can be used include lactose and corn starch. Lubricants such as magnesium stearate are usually also added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension or emulsion is taken orally, the active ingredient can be suspended or dissolved in an oil phase and mixed with an emulsifier or suspending agent. If necessary, certain sweeteners, flavorings or coloring agents can be added.

[0609] As used herein, the divalent compounds disclosed herein are defined as including pharmaceutically acceptable derivatives or prodrugs thereof. "Pharmaceutically acceptable derivatives" refer to any pharmaceutically acceptable salts, solvates or prodrugs of compounds or medicaments disclosed herein, such as carbamates, esters, phosphates, salts of esters or other derivatives, which can provide (directly or indirectly) compounds described herein or their active metabolites or residues after being applied to a recipient. Particularly preferred derivatives and prodrugs are those that increase the bioavailability of compounds disclosed herein when the compounds disclosed herein are applied to a subject (e.g., by making the orally administered compound more easily absorbed into the blood) or enhance the delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives that are groups that enhance water solubility or active transport through the intestinal membrane attached to the formula structure described herein. Those skilled in the art can identify such derivatives without much experimentation. Nevertheless, reference is made to Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Volume 1: Principles and Practices, which are incorporated herein by reference within the scope of teaching such derivatives.

[0610] The divalent compounds disclosed herein include pure enantiomers, enantiomeric mixtures, pure diastereomers, diastereomeric mixtures, diastereomeric racemates, mixtures of diastereomeric racemates and meso forms and pharmaceutically acceptable salts thereof, solvent complexes, morphological forms or deuterated derivatives. Single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by the resolution of racemates. The resolution of racemates can be accomplished by, for example, conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column. In addition, compounds include Z- and E- forms (or cis and trans) of compounds with carbon-carbon double bonds. When the compounds described herein exist in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound.

[0611] The bivalent compounds disclosed herein also include crystalline and amorphous forms of these compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof. "Crystalline form," "polymorph," and "new form" are used interchangeably herein and are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is mentioned. Similarly, "pharmaceutically acceptable salts" of bivalent compounds also include crystalline and amorphous forms of these compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the pharmaceutically acceptable salts, and mixtures thereof.

[0612] "Solvates" are formed by the interaction of a solvent and a compound. The term "compound" is intended to include solvates of the compound. Similarly, "pharmaceutically acceptable salts" include solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrates.

[0613] In some aspects, the pharmaceutical compositions disclosed herein may include an effective amount of one or more bivalent compounds. As used herein, the terms "effective amount" and "effective treatment" refer to the amount or concentration of one or more compounds or pharmaceutical compositions described herein, which effectively cause the expected effect or physiological result (e.g., treatment or prevention of cell growth, cell proliferation or cancer) within the scope of its administration over a period of time (including acute or chronic administration and regular or continuous administration). In some aspects, the pharmaceutical composition may further include one or more additional compounds, drugs or agents (e.g., conventional chemotherapeutic agents) for the treatment of cancer, the amount of which can effectively cause the expected effect or physiological result (e.g., treatment or prevention of cell growth, cell proliferation or cancer).

[0614] In some aspects, the pharmaceutical compositions disclosed herein can be formulated for sale in, imported into, or exported from the United States.

[0615] Administration of the pharmaceutical composition

[0616] Pharmaceutical compositions disclosed herein can be formulated or adjusted for any approach approved by the Food and Drug Administration (FDA) for example, to be applied to a subject. Exemplary methods are described in the FDA Data Standards Manual (DSM) (available at http: / / www.fda.gov / Drugs / DevelopmentApprovalProcess / FormsSubmissionRequirements / ElectronicSu bmissions / DataStandardsManualmonographs). In particular, pharmaceutical compositions can be formulated for oral, parenteral or transdermal delivery. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0617] For example, a pharmaceutical composition disclosed herein can be administered, for example, topically, rectally, nasally (e.g., by inhalation spray or nebulizer), orally, vaginally, subcutaneously (e.g., by injection or via an implanted reservoir), or ophthalmically.

[0618] For example, the pharmaceutical compositions of the present invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.

[0619] For example, the pharmaceutical compositions of the present invention can be used for rectal administration in the form of suppositories. These compositions can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0620] For example, the pharmaceutical compositions of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as saline solutions, using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons or other solubilizing or dispersing agents known in the art.

[0621] For example, the pharmaceutical composition of the present invention can be administered by injection (e.g., as a solution or powder). Such compositions can be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable carriers and solvents, mannitol, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile, fixed oils are generally used as solvents or suspension media. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives can be used to prepare injections, and natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated forms, can also be used to prepare injections. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants, which are generally used to prepare pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. Other commonly used surfactants such as Tweens, Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0622] In some aspects, effective doses of the pharmaceutical compositions of the invention include, but are not limited to, for example, about 0.00001, 0.0001, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0. or 10,000 mg / kg / day, or as required for a particular pharmaceutical composition.

[0623] When the pharmaceutical compositions disclosed herein comprise a bivalent compound described herein and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents that are useful in treating cancer or any other condition or disease, including conditions or diseases known to be associated with or caused by cancer), the dosage levels of both the bivalent compound and the additional compound may be between about 1% and 100%, more preferably between about 5% and 95% of the dose typically administered in a monotherapy regimen. The additional agents may be administered separately from the compounds of the invention as part of a multiple dosage regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compounds of the invention in a single composition.

[0624] In some aspects, a pharmaceutical composition disclosed herein may be included in a container, pack, or dispenser together with instructions for administration.

[0625] Treatment

[0626] Methods disclosed herein contemplate administering an effective amount of a compound or composition to achieve a desired or prescribed effect. Typically, the compound or composition of the present invention is administered about 1 to about 6 times a day, or, or, or in addition, as a continuous infusion. This administration can be used as a chronic or acute treatment. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary according to the treated host and a specific mode of administration. Typical preparations will contain about 5% to about 95% of the active compound (w / w). Alternatively, such preparations may contain about 20% to about 80% of the active compound.

[0627] In some aspects, provided herein are bivalent compounds described herein for use in preventing or treating a disease or disorder.

[0628] In some aspects, provided herein are bivalent compounds as described herein for use in treating or preventing one or more diseases or conditions disclosed herein in a subject in need thereof. In certain embodiments, the disease or condition is a CBP / P300-mediated disease or condition. In certain embodiments, the disease or condition is caused by CBP / P300 expression, mutation, deletion or fusion. In certain embodiments, the disease or condition is cancer. In certain embodiments, the disease or condition includes: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative change), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor-positive breast cancer, parenchymal thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, Multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer and Wilms' tumor. In some embodiments, the disease or condition is recurrent cancer. In some embodiments, the disease or condition is an inflammatory condition or an autoimmune disease.In certain embodiments, the disease or condition comprises: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusive disease, hepatitis, hypophysitis, immunodeficiency syndrome, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, cholangitis, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis. In certain embodiments, the disease or condition is refractory to one or more prior therapies.

[0629] In some aspects, provided herein is the use of a bivalent compound in the preparation of a medicament for preventing or treating one or more diseases or conditions disclosed herein.

[0630] In some aspects, the disclosed methods include administering a therapeutically effective amount of one or more compounds or compositions described herein to a subject (e.g., a mammalian subject, such as a human subject) in need or determined to be in need of such treatment. In some aspects, the disclosed methods include selecting a subject and administering an effective amount of one or more compounds or compositions described herein to the subject, and optionally repeating the administration as needed to prevent or treat cancer.

[0631] In some respects, the selection of subject may include obtaining sample from subject (e.g., candidate subject) and test sample to indicate that subject is suitable for the selection. In some respects, it is possible, for example, by a health care professional, to confirm or identify that subject is already suffering from, has an elevated risk of suffering from or suffering from a certain illness or disease. In some respects, suitable subject includes, for example, suffering from or having suffered from illness or disease but solving the disease or its aspect of the subject, presenting the subject of disease symptom alleviation (e.g., relative to other subjects (e.g., most subjects) suffering from the same illness or disease), or surviving a long time in illness or disease (e.g., relative to other subjects (e.g., most subjects) suffering from the same illness or disease), for example, being in asymptomatic state (e.g., relative to other subjects (e.g., most subjects) suffering from the same illness or disease). In some respects, the display of the positive immune response for illness or disease can be made by patient record, family history or the indication of detecting the positive immune response. In some respects, the selection of subject may be multi-party participation. For example, the first party may obtain sample from candidate subject, and the second party may test the sample. In some respects, subject may be selected or mentioned by a medical practitioner (e.g., general practitioner). In some aspects, selection of a subject may include obtaining a sample from the selected subject and storing the sample or using the sample in the methods disclosed herein. The sample may include, for example, a cell or a population of cells.

[0632] In some aspects, the method of treatment may include the need for preventing or treating a disease or condition disclosed herein (e.g., a CBP / P300-mediated disease), single administration, multiple administration, and repeated administration of one or more compounds disclosed herein. In some aspects, the method of treatment may include assessing the disease level of a subject before, during, or after treatment. In some aspects, treatment may continue until the disease level of the subject is detected to be reduced.

[0633] As used herein, the term "subject" refers to any animal. In some cases, the subject is a mammal. In some cases, the term "subject" used herein refers to a human (e.g., a man, woman, or child).

[0634] As used herein, the terms "administering," "applying," or "administration" refer to implanting, ingesting, injecting, inhaling, or otherwise absorbing a compound or composition, regardless of its form. For example, the methods disclosed herein include administering an effective amount of a compound or composition to achieve a desired or prescribed effect.

[0635] As used herein, the terms "treat," "treated," or "therapy" refer to partial or complete alleviation, inhibition, amelioration, or alleviation of a disease or condition suffered by a subject. This means any manner in which one or more symptoms of a disease or condition (e.g., cancer) are improved or otherwise beneficially altered. As used herein, improvement of symptoms of a particular condition (e.g., cancer) refers to any alleviation, whether permanent or temporary, lasting or transient, attributable to or associated with treatment with the bivalent compounds, compositions, and methods of the invention. In some embodiments, treatment may promote or result in, for example, a decrease in the number of tumor cells (e.g., in a subject) relative to the number of tumor cells prior to treatment; a decrease in the viability (e.g., average / mean viability) of tumor cells (e.g., in a subject) relative to the viability of tumor cells prior to treatment; a decrease in tumor cell growth rate; a decrease in the rate of local or distant tumor metastasis; a reduction in one or more symptoms associated with one or more tumors compared to the symptoms of the subject prior to treatment.

[0636] As used herein, the terms "prevention," "preventing," and "prophylaxis" shall refer to a reduction in the occurrence of a disease in a subject or a reduction in the risk of developing a disease or its associated symptoms. Prevention can be complete, e.g., the complete absence of disease or pathological cells in a subject. Prevention can also be partial, such that the occurrence of a disease or pathological cells in a subject is less, occurs later, or develops more slowly than in the absence of the present invention. In certain embodiments, a subject is at increased risk of developing one or more CBP / P300-mediated diseases.Exemplary CBP / P300-mediated diseases that can be treated with the bivalent compounds include, for example, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative change), embryonal carcinoma, endometrial carcinoma, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, estrogen receptor-positive breast cancer, parenchymal thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, mucin Sarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, Wilms' tumor, Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease disease), bullous skin diseases, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, cholangitis, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock, thyroiditis, type I diabetes mellitus, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

[0637] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, disorder or symptom, the patient's predisposition to the disease, disorder or symptom, and the judgment of the treating physician.

[0638] The effective amount can be administered in one or more administrations, one or more applications, or one or more doses. The therapeutically effective amount (i.e., effective dose) of the therapeutic compound depends on the selected therapeutic compound. In addition, treating a subject with a therapeutically effective amount of a compound or composition as described herein may include a single treatment or a series of treatments. For example, an effective amount may be administered at least once. The composition may be administered once or more per day to once or more per week; including once every other day. The skilled person will appreciate that certain factors may affect the dose and time required to effectively treat the subject, including but not limited to the severity of the disease or condition, previous treatment, the general health or age of the subject, and other diseases present.

[0639] After administration, the subject can be evaluated to detect, evaluate or determine their disease level. In some cases, treatment can continue until a change (such as reduction) in the subject's disease level is detected. After the patient's condition improves (for example, the subject's disease level changes (for example, decreases)), if necessary, a maintenance dose of a compound or composition disclosed herein can be administered. Subsequently, the dosage or frequency of administration or both can be reduced (for example, as a function of symptoms) to a level that maintains the improved condition. However, once any disease symptoms recur, the patient may need long-term intermittent treatment.

[0640] The present disclosure is further described and demonstrated by the following examples. However, the use of these and other examples anywhere in the specification is illustrative only and in no way limits the scope and meaning of the present invention or any exemplary term. Likewise, the present invention is not limited to any particular preferred embodiment or aspect described herein. In fact, after reading this specification, many modifications and changes will be apparent to those skilled in the art, and such changes can be made without departing from the spirit or scope of the present invention. Therefore, the present invention is limited only by the terms of the appended claims and the full scope of equivalents to which those claims are entitled. Example

[0641] Synthesis of degradation tags with linkers for divalent compounds

[0642] Example 1: 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 1)

[0643]

[0644] In a microwave reactor, a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.66 g, 6.0 mmol), tert-butyl (2-aminoethyl)carbamate (1.25 g, 6.6 mmol) and N,N-diisopropylethylamine (2.32 g, 18 mmmol) in DMF (12 mL) was heated to 85 ° C for 50 min. The three batches were combined and diluted with EtOAc (200 mL). The reaction was washed with water and brine. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluted with hexane / EtOAc=1:1) to give tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)carbamate (1.3 g, yield 16%) as a yellow solid. MS (ESI) m / z=317.1 [M-100+H] + . A solution of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)carbamate (2.0 g, 4.5 mmol) in DCM (10 mL) and TFA (5 mL) was stirred at room temperature for 2 h. The reaction was concentrated and triturated with EtOAc. The solid precipitate was filtered. The solid was washed with MTBE and dried to give 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione as a yellow solid (connector 1) (1.3 g, yield 98%). 1 HNMR (400 MHz, DMSO-d 6 )δ11.14(s,1H),7.85(s,3H),7.45(t,J=7.2Hz,1H),7.19(d,J=7.2Hz,1H),7.10(d,J=7.2Hz,1H),6.84(t,J=6.4Hz,1H),5.07(dd,J=5 .2,12.8Hz,1H),3.58(q,J=6.4Hz,2H),3.00(s,2H),2.94-2.85(m,1H),2.62-2.50(m,2H),2.05-2.00(m,1H).MS(ESI)m / z=317.1[M+H] + .

[0645] Example 2: 4-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 2)

[0646]

[0647] Linker 2 was synthesized following the same procedure as Linker 1 described in Example 1. (1.2 g, yield: 11%, two steps). 1 H NMR (400MHz, DMSO-d6)11.11(s,1H),7.74(s,3H),7.62-7.58(m,1H),7.15(d,J=8.4Hz,1H),7.05(d,J=7.2Hz,1H),6.78-6.75(m,1H),5. 08-5.04(m,1H),3.43-3.36(m,2H),2.90-2.86(m,3H),2.62-2.51(m,2H),2.08-2.01(m,1H),1.86-1.80(m,2H).MS(ESI)m / z=331.1[M+H] +

[0648] Example 3: 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 3)

[0649]

[0650] The same procedure as described for connector 1 in Example 1 was followed to synthesize connector 3. (1.4 g, yield: 15%, two steps). 1H NMR (400 MHz, DMSO-d6) 11.11 (s, 1H), 7.84 (s, 3H), 7.62-7.57 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.62 (s, 1H), 5.08-5.04 (m, 1H), 3.34 (s, 2H), 2.90-2.83 (m, 3H), 2.62-2.51 (m, 2H), 2.06-2.01 (m, 1H), 1.65-1.60 (m, 4H). MS (ESI) m / z = 345.1 [M+H]+

[0651] Example 4: 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 4)

[0652]

[0653] Linker 4 was synthesized following the same procedure as Linker 1 described in Example 1. (2.3 g, yield: 26%, two steps). 1 H NMR (400 MHz, DMSO-d 6)δ11.14(s,1H),7.72(s,3H),7.61-7.57(m,1H),7.10(d,J=8.4Hz,1H),7.03(d,J=7.2Hz,1H),6.56-6.53(m,1H),5.07-5.03(m,1H),3.3 2-3.28(m,2H),2.90-2.78(m,3H),2.62-2.51(m,2H),2.05-1.90(m,1H),1.62-1.54(m,4H),1.41-1.37(m,2H).MS(ESI)m / z=359.1[M+H] +

[0654] Example 5: 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 5)

[0655]

[0656] Linker 5 was synthesized following the same procedure as Linker 1 described in Example 1. (1.8 g, yield: 20%, two steps). 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.76(s,3H),7.58(t,J=7.2Hz,1H),7 .10(d,J=8.4Hz,1H),7.03(d,J=7.2Hz,1H),6.54(t,J=6.0Hz,1H),5.07-5. 03(m,1H),3.37-3.27(m,2H),2.88-2.78(m,3H),2.61-2.50(m,2H),2.04-2 .01(m,1H),1.57-1.52(m,4H),,1.40-1.30(m,4H).MS(ESI)m / z=373.1[M+H] +

[0657] Example 6: 4-((7-aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 6)

[0658]

[0659] Linker 6 was synthesized following the same procedure as Linker 1 described in Example 1. (2.0 g, yield: 25%, two steps). 1H NMR(400MHz, DMSO-d6)δ11.05(br,1H),7.94-7.56(m,4H),7.10-7.02(m,2H),6.52(t,J=6.0Hz,1H),5.07-5.02(m,1H),3.32-3.27(m,2H), 2.88-2.77(m,1H),2.75-2.61(m,2H),2.60-2.50(m,2H),2.04-2.02(m,1H),1.59-1.50(m,4H),1.35-1.30(m,6H).MS(ESI)m / z=387.2[M+H] +

[0660] Example 7: 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 7)

[0661]

[0662] Linker 7 was synthesized following the same procedure as Linker 1 described in Example 1. (1.1 g, yield: 18%, two steps). 1 H NMR (400 MHz, DMSO-d 6 )δ11.10(s,1H),7.69-7.56(m,4H),7.09(d,J=8.4Hz,1H),7.03(d,J=6.8Hz,1H),6.52(t,J=6.0Hz,1H),5.07-5.03(m,1H),3.34-3.26( m,2H),2.89-2.85(m,1H),2.76(s,2H),2.61-2.56(m,2H),2.04-2.00(m,1H),1.59-1.49(m,4H),1.35-1.27(m,8H).MS(ESI)m / z=401.2

[0663] [M+H] +

[0664] Example 8: 4-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 8)

[0665]

[0666] Linker 8 was synthesized following the same procedure as Linker 1 described in Example 1. (2.0 g, yield: 23%, two steps). 1 H NMR (400 MHz, DMSO-d 6)δ10.10(s,1H),7.88(s,3H),7.60(t,J=8.0Hz,1H),7.17(d,J=8.4Hz,1H),7.06(d,J=6.8Hz,1H),6.40(d,J=5.6Hz,1H),5.05(dd,J=5.2,12.8H z,1H),3.67-3.62(m,4H),3.54-3.50(m,2H),3.00(s,2H),2.90-2.85(m ,1H),2.62-2.50(m,2H),2.03(t,J=7.6Hz,1H).MS(ESI)m / z=361.1[M+H] +

[0667] Example 9: 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 9)

[0668]

[0669] Linker 9 was synthesized following the same procedure as Linker 1 described in Example 1. (1.1 g, yield: 17%, two steps). 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.84(s,3H),7.62-7.58(m,1H),7.15(d,J=8.8Hz,1H),7.05(d,J=6.8Hz,1H),6.62-6.59(m,1H),5. 08-5.04(m,1H),3.65-3.59(m,8H),3.50-3.46(m,2H),2.97-2.86(m,3H),2.62-2.51(m,2H),2.05-1.99(m,1H).MS(ESI)m / z=405.2[M+H] +

[0670] Example 10: 4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 10)

[0671]

[0672] Linker 10 was synthesized following the same procedure as Linker 1 described in Example 1. (1.3 g, yield: 17%, two steps). 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.83(s,3H),7.61-7.57(m,1H),7.15(d,J=8.8Hz,1H),7.05(d,J=6.8Hz,1H),6.62-6.59( m,1H),5.08-5.04(m,1H),3.64-3.45(m,14H),2.97-2.86(m,3H),2.62-2.51(m,2H),2.08-2.01(m,1H).MS(ESI)m / z=449.2[M+H] +

[0673] Example 11: 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 11)

[0674]

[0675] Linker 11 was synthesized following the same procedure as Linker 1 described in Example 1. (1.2 g, yield: 16%, two steps). 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.84(s,3H),7.61-7.57(m,1H),7.15(d,J=8.8Hz,1H),7.05(d,J=6.8Hz,1H),6.61(s,1 H),5.08-5.04(m,1H),3.64-3.47(m,18H),2.99-2.86(m,3H),2.62-2.51(m,2H),2.08-2.01(m,1H).MS(ESI)m / z=493.2[M+H] +

[0676] Example 12: 4-((17-amino-3,6,9,12,15-pentaoxaheptadecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 12)

[0677]

[0678] Linker 12 was synthesized following the same procedure as Linker 1 described in Example 1. (1.2 g, yield: 15%, two steps). 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.82(s,3H),7.61-7.57(m,1H),7.15(d,J=8.4Hz,1H),7.05(d,J=7.2Hz,1H),6.61-6.59( m,1H),5.08-5.03(m,1H),3.64-3.47(m,22H),3.00-2.86(m,3H),2.62-2.51(m,2H),2.05-2.02(m,1H).MS(ESI)m / z=537.2[M+H] +

[0679] Example 13: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (Linker 13)

[0680]

[0681] Linker 13 was synthesized following the same procedure as Linker 1 described in Example 1 (840 mg, yield: 16%, two steps). 1 HNMR(400MHz,DMSO-d6)δ11.07(s,1H),7.52(t,J=7.6Hz,1H),6.99-6.88(m,3H),5.04(dd,J=5.2,12.8H z,1H),3.73(s,2H),2.93-2.83(m,1H),2.61-2.50(m,2H),2.02(t,J=5.6Hz,1H).MS(ESI)m / z=330.1[MH] -

[0682] Example 14: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoic acid (Linker 14)

[0683]

[0684] Linker 14 was synthesized following the same procedure as Linker 1 described in Example 1. (1.42 g, yield: 24%, two steps). 1 HNMR (400 MHz, DMSO-d 6)δ11.61(br,1H),11.08(s,1H),7.58(dd,J=7.2,8.8Hz,1H),7.15(d,J=8.8Hz,1H),7.04(d,J=7.2Hz,1H),6.64(s,1H),5.05(d d,J=5.2,12.8Hz,1H),3.53(t,J=6.4Hz,2H),2.92-2.83(m,1H),2.61-2.50(m,4H),2.05-2.00(m,1H).MS(ESI)m / z=346.1[M+H] +

[0685] Example 15: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyric acid (Linker 15)

[0686]

[0687] Linker 15 was synthesized following the same procedure as Linker 1 described in Example 1. (1.27 g, yield: 13%, two steps). 1 HNMR(400MHz,DMSO-d6)δ12.12(br,1H),11.08(s,1H),7.58(dd,J=7.2,8.8Hz,1H ),7.13(d,J=8.8Hz,1H),7.03(d,J=7.2Hz,1H),6.64(t,J=6.0Hz,1H),5.05(dd,J= 5.6,12.8Hz,1H),3.33(q,J=6.8Hz,2H),2.93-2.83(m,1H),2.61-2.50(m,2H),2.3 1(t,J=6.8Hz,2H),2.07-2.00(m,1H),1.83-1.75(m,2H).MS(ESI)m / z=360.1[M+H] +

[0688] Example 16: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid (Linker 16)

[0689]

[0690] Linker 16 was synthesized following the same procedure as Linker 1 described in Example 1. (1.4 g, yield: 15%, two steps). 1 H NMR (400 MHz, DMSO-d 6)δ12.02(br,1H),11.08(s,1H),7.58(dd,J=8.8,7.2Hz,1H),7.10(d,J=8.4Hz,1H),7.02(d,J=7.2Hz,1H),6.64(t,J=5.6Hz,1H),5.07-5.03(m, 1H),3.32-3.02(m,2H),2.93-2.84(m,1H),2.61-2.54(m,2H),2.28-2.2 5(m,2H),2.05-2.01(m,1H),1.60-1.51(m,4H).MS(ESI)m / z=374.1[M+H] +

[0691] Example 17: 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoic acid (Linker 17)

[0692]

[0693] Linker 17 was synthesized following the same procedure as Linker 1 described in Example 1. (1.43 g, yield: 18%, two steps). 1 HNMR (400 MHz, DMSO-d 6 )δ11.97(s,1H),11.08(s,1H),7.57(dd,J=7.2,8.8Hz,1H),7.08(d,J=8.8Hz,1H ),7.02(d,J=7.2Hz,1H),6.52(t,J=6.0Hz,1H),5.05(dd,J=5.6,12.8Hz,1H),3.3 0(q,J=6.8Hz,2H),2.93-2.83(m,1H),2.61-2.50(m,2H),2.32(t,J=7.2Hz,2H),2 .07-2.00(m,1H),1.61-1.50(m,4H),1.39-1.33(m,2H).MS(ESI)m / z=388.1[M+H] +

[0694] Example 18: 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoic acid (Linker 18)

[0695]

[0696] Linker 18 was synthesized following the same procedure as Linker 1 described in Example 1. (2.3 g, yield: 24%, two steps). 1H NMR (400MHz, DMSO-d6) δ11.92(br,1H),11.08(s,1H),7.57(t,J=8.0Hz,1H),7.13(d, J=8.8Hz,1H),7.03(d,J=6.8Hz,1H),6.52(t,J=5.6Hz,1H),5.05(dd,J=5.6,12.8Hz, 1H),3.30(q,J=6.4Hz,2H),2.93-2.83(m,1H),2.61-2.50(m,2H),2.31(t,J=7.2Hz,2 H),2.07-2.00(m,1H),1.58-1.48(m,4H),1.34-1.31(m,4H).MS(ESI)m / z=402.1[M+H] +

[0697] Example 19: 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoic acid (Linker 19)

[0698]

[0699] Linker 19 was synthesized following the same procedure as Linker 1 described in Example 1. (1.14 g, yield: 35%, two steps). 1 HNMR(400MHz,DMSO-d6)δ11.94(s,1H),11.08(s,1H),7.57(t,J=8.0Hz,1H),7.08(d ,J=8.4Hz,1H),7.02(d,J=6.8Hz,1H),6.52(t,J=5.6Hz,1H),5.05(dd,J=5.6,12.8Hz ,1H),3.31-3.26(m,2H),2.93-2.83(m,1H),2.61-2.50(m,2H),2.19(t,J=7.2Hz,2H ),2.05-2.00(m,1H),1.58-1.47(m,4H),1.35-1.25(s,6H).MS(ESI)m / z=416.1[M+H] +

[0700] Example 20: 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid (Linker 20)

[0701]

[0702] Linker 20 was synthesized following the same procedure as Linker 1 described in Example 1. (3.5 g, yield: 18%, two steps).1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.8Hz,1H),7.13(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.58(t,J=5.6Hz 1H),5.05(dd,J=6.4Hz,12.8Hz,1H),3.67-3.58(m,4H),3.47-3.43(m,2H),2.9 3-2.84(m,1H),2.61-2.45(m,4H),2.07-2.01(m,1H).MS(ESI)m / z=390.1[M+H] +

[0703] Example 21: 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (Linker 21)

[0704]

[0705] Linker 21 was synthesized following the same procedure as Linker 1 described in Example 1. (2.0 g, yield: 24%, two steps). 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.4Hz,1H),7.14(d,J=8.4Hz,1H),7.04(d,J=6.8Hz,1H),6.60(t,J=6.0Hz 1H),5.05(dd,J=5.2Hz,12.4Hz,1H),3.63-3.44(m,10H),2.88-2.85(m,1H),2. 61-2.49(m,2H),2.44-2.41(m,2H),2.04-2.01(m,1H).MS(ESI)m / z=434.1[M+H] +

[0706] Example 22: 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (Linker 22)

[0707]

[0708] Linker 22 was synthesized following the same procedure as Linker 1 described in Example 1. (3.2 g, yield: 42%, two steps). 1H NMR (400MHz, DMSO-d6) δ12.14(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.4H z,1H),7.14(d,J=8.8Hz,1H),7.04(d,J=6.8Hz,1H),6.60(t,J=6.0Hz,1H),5 .05(dd,J=5.2Hz,12.8Hz,1H),3.63-3.45(m,14H),2.88-2.85(m,1H),2.61- 2.49(m,2H),2.44-2.40(m,2H),2.04-2.01(m,1H).MS(ESI)m / z=478.2[M+H] +

[0709] Example 23: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)3,6,9,12-tetraoxapentadeca-15-oic acid (Linker 23)

[0710]

[0711] Linker 23 was synthesized following the same procedure as Linker 1 described in Example 1. (2.3 g, yield: 31%, two steps). 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),11.08(s,1H),7.58(dd,J=7.2Hz,8.8H z,1H),7.14(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.60(t,J=6.0Hz,1H),5 .05(dd,J=5.2Hz,12.8Hz,1H),3.63-3.48(m,18H),2.898-2.85(m,1H),2.61 -2.49(m,2H),2.44-2.41(m,2H),2.04-2.01(m,1H).MS(ESI)m / z=522.2[M+H] +

[0712] Example 24: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)3,6,9,12,15-pentaoxaoctadecane-18-oic acid (Linker 24)

[0713]

[0714] Linker 24 was synthesized following the same procedure as Linker 1 described in Example 1. (2.4 g, yield: 36%, two steps). 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),7.58(dd,J=7.2,8.4Hz,1H),7.13(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.60(t,J=5.6Hz,1H),5.05(dd, J=5.6,12.8Hz,1H),3.64-3.46(m,22H),2.93-2.83(m,1H),2.61-2.50(m ,2H),2.44-2.40(m,2H),2.02(t,J=6.4Hz,1H).MS(ESI)m / z=566.2[M+H] +

[0715] Example 25: (2S,4R)-1-((S)-2-(2-aminoacetylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 25)

[0716]

[0717] Step 1:

[0718] 0 o To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2.00 g, 4.67 mmol), 2-((tert-butoxycarbonyl)amino)acetic acid (900 mg, 5.14 mmol) and triethylamine (TEA) (3.2 mL, 23.35 mmol) in DCM / DMF (225 mL / 11 mL) was added EDCI (1.07 g, 5.60 mmol) and HOBt (756 mg, 5.60 mmol) at RT. The mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with DCM. The combined organic layers were concentrated and the residue was purified by chromatography on a silica gel column (DCM / MeOH=20 / 1, v / v) to give the desired product (tert-butyl (2-(((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)-2-oxoethyl)carbamate (1.5 g, yield: 55%). MS (ESI) m / z=588.2 [M+H] +

[0719] Step 2:

[0720] To a solution of tert-butyl (2-(((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)-2-oxoethyl)carbamate (1.50 g, 2.56 mmol) in ethyl acetate (EA) (30 mL) was added HCl / EA (100 mL). The mixture was stirred at room temperature for 3 hours and filtered to obtain the desired product, which was dissolved in water (100 mL) and lyophilized to obtain (2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (Linker 25) (1.07 g, yield: 80%). 1 H NMR (400 MHz, DMSO-d 6 )9.29(s,1H),8.72(s,1H),8.56(d,J=9.2Hz,1H),8.26(s,3H),7.38-7.47(m,4H),4.61(d,J=9.2Hz,1H),4.36-4.47(m,3H),4 .20-4.25(m,1H),3.60-3.70(m,4H),2.46(s,3H),2.10-2.05(m,1H),1.97-1.89(m,1H),0.95(s,9H).MS(ESI)m / z=488.3[M+H] +

[0721] Example 26: (2S,4R)-1-((S)-2-(3-aminopropionylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 26)

[0722]

[0723] Linker 26 was synthesized following the same procedure of linker 25 described in Example 25. (1.38 g, yield: 37%, two steps). 1 H NMR (400 MHz, DMSO-d 6)9.36(s,1H),8.68(s,1H),8.26(d,J=9.2Hz,1H),8.16(s,3H),7.49-7.3 9(m,4H),4.53(d,J=9.2Hz,1H),4.47-4.35(m,3H),4.24-4.19(m,1H),3.6 9-3.60(m,2H),2.94-2.93(m,2H),2.64(t,J=7.2Hz,2H),2.48(s,3H),2. 06-2.01(m,1H),1.92-1.85(m,1H),0.95(s,9H).MS(ESI)m / z=502.3[M+H] +

[0724] Example 27: (2S,4R)-1-((S)-2-(4-aminobutyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 27)

[0725]

[0726] Linker 27 was synthesized following the same procedure as linker 25 described in Example 25. (1.38 g, yield: 46%, two steps). 1 H NMR (400 MHz, DMSO-d 6 )9.66(s,1H),8.74(t,J=6.0,1H),8.25(s,3H),8.03(d,J=9.2Hz,1H),7.49 -7.41(m,4H),4.53(d,J=9.2Hz,1H),4.51-4.36-4.35(m,3H),4.29-4.24(m, 1H),3.71-3.65(m,2H),2.79-2.77(m,2H),2.52(s,3H),2.45-2.27(m,2H), 2.12-2.07(m,1H),1.94-1.80(m,3H),0.94(s,9H).MS(ESI)m / z=516.0[M+H] + .

[0727] Example 28: (2S,4R)-1-((S)-2-(5-aminopentanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 28)

[0728]

[0729] Linker 28 was synthesized following the same procedure of linker 25 described in Example 25. (1.50 g, yield: 57%, two steps). 1 H NMR (400 MHz, DMSO-d 6 )9.52(s,1H),8.73(t,J=11.6Hz,1H),8.20(s,3H),7.95(d,J=9.6Hz,1H),7.43-7.50 (m,4H),4.55(d,J=9.2Hz,1H),4.38-4.50(m,3H),4.23-4.29(m,1H),3.64-3.71(m,2H ),2.74-2.78(m,2H),2.51(s,3H),2.30-2.35(m,1H),2.18-2.23(m,1H),2.07-2.12(m ,1H),1.88-1.95(m,1H),1.58(d,J=4.4Hz,4H),0.96(s,9H).MS(ESI)m / z=530.1[M+H] +

[0730] Example 29: (2S,4R)-1-((S)-2-(6-aminohexanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 29)

[0731]

[0732] Linker 29 was synthesized following the same procedure as linker 25 described in Example 25. (2.70 g, yield: 87%, two steps). 1 H NMR(400MHz, DMSO-d6):9.36(s,1H),8.69(t,J=6.4Hz,1H),8.12(brs,3H),7.92(d,J=9.6Hz,1H),7.44(dd ,J=13.6,8.4Hz,4H),4.54(d,J=9.6Hz,1H),4.48-4.39(m,2H),4.36(brs,1H),4.28-4.19(m,1H),3.72-3.6 0(m,2H),2.79-2.67(m,2H),2.49(s,3H),2.31-2.21(m,1H),2.20-2.12(m,1H),2.10-2.01(m,1H),1.94-1 .85(m,1H),1.62-1.54(m,2H),1.53-1.44(m,2H),1.34-1.22(m,2H),0.94(s,9H).MS(ESI)m / z=544.3[M+H] +.

[0733] Example 30: (2S,4R)-1-((S)-2-(7-aminoheptanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 30)

[0734]

[0735] Linker 30 was synthesized following the same procedure of linker 25 described in Example 25. (2.13 g, yield: 76%, two steps). 1 H NMR(400MHz, DMSO-d6):9.45(s,1H),8.70(t,J=6.0Hz,1H),8.14(brs,3H),7.86(d,J=9.2Hz,1H),7.4 4(dd,J=12.8,8.4Hz,4H),4.54(d,J=9.2Hz,1H),4.49-4.40(m,2H),4.36(brs,1H),4.29-4.20(m,1H), 3.71-3.61(m,2H),2.78-2.67(m,2H),2.50(s,3H),2.31-2.22(m,1H),2.21-2.13(m,1H),2.11-2.03( m,1H),1.95-1.85(m,1H),1.60-1.44(m,4H),1.35-1.18(m,4H),0.94(s,9H).MS(ESI)m / z=558.3[M+H] + .

[0736] Example 31: (2S,4R)-1-((S)-2-(8-aminooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 31)

[0737]

[0738] Linker 31 was synthesized following the same procedure of linker 25 described in Example 25. (1.81 g, yield: 65%, two steps). 1H NMR(400MHz, DMSO-d6):9.35(s,1H),8.69(t,J=6.0Hz,1H),8.11(brs,3H),7.88(d,J=9.2Hz,1H),7.4 4(dd,J=14.0,8.4Hz,4H),4.54(d,J=9.6Hz,1H),4.48-4.39(m,2H),4.36(brs,1H),4.27-4.20(m,1H), 3.71-3.60(m,2H),2.78-2.68(m,2H),2.49(s,3H),2.31-2.22(m,1H),2.18-2.11(m,1H),2.09-2.01( m,1H),1.94-1.85(m,1H),1.58-1.44(m,4H),1.32-1.19(m,6H),0.94(s,9H).MS(ESI)m / z=572.3[M+H] + .

[0739] Example 32: (2S,4R)-1-((S)-2-(9-aminononanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 32)

[0740]

[0741] Linker 32 was synthesized following the same procedure of linker 25 described in Example 25. (2.32 g, yield: 80%, two steps). 1 H NMR (400MHz, DMSO-d6):9.30(s,1H),8.67(t,J=6.4Hz,1H),8.10(brs,3H),7.88(d,J=9.2Hz,1H),7 .43(dd,J=14.0,8.8Hz,4H),4.55(d,J=9.2Hz,1H),4.48-4.39(m,2H),4.35(brs,1H),4.28-4.19(m, 1H),3.71-3.60(m,2H),2.77-2.67(m,2H),2.48(s,3H),2.31-2.22(m,1H),2.17-2.10(m,1H),2.09- 2.01(m,1H),1.94-1.85(m,1H),1.60-1.40(m,4H),1.33-1.19(m,8H),0.94(s,9H).m / z=586.3[M+H] + .

[0742] Example 33: (2S,4R)-1-((S)-2-(10-aminodecanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 33)

[0743]

[0744] Linker 33 was synthesized following the same procedure of linker 25 described in Example 25. (2.29 g, yield: 77%, two steps). 1 H NMR(400MHz, DMSO-d6):9.41(s,1H),8.67(t,J=6.0Hz,1H),8.14(brs,3H),7.85(d,J=8.8Hz,1H),7.4 4(dd,J=13.6,8.8Hz,4H),4.54(d,J=8.8Hz,1H),4.48-4.39(m,2H),4.36(brs,1H),4.29-4.20(m,1H), 3.71-3.60(m,2H),2.78-2.67(m,2H),2.49(s,3H),2.32-2.22(m,1H),2.17-2.11(m,1H),2.10-2.01(m ,1H),1.95-1.86(m,1H),1.62-1.40(m,4H),1.34-1.16(m,10H),0.94(s,9H).MS(ESI)m / z=600.4[M+H] + .

[0745] Example 34: (2S,4R)-1-((S)-2-(11-aminoundecanoylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 34)

[0746]

[0747] Linker 34 was synthesized following the same procedure of linker 25 described in Example 25. (1.10 g, yield: 37%, two steps). 1H NMR (400MHz, DMSO-d6): 8.99 (s, 1H), 8.61 (t, J = 6.4Hz, 1H), 7.87 (d, J = 8.8Hz, 1H), 7.41 (dd, J = 17.6, 8. 0Hz,4H),4.55(d,J=9.6Hz,1H),4.49-4.40(m,2H),4.36(brs,1H),4.26-4.17(m,1H),3.70-3.64(m,2H) ,2.59-2.52(m,2H),2.45(s,3H),2.31-2.22(m,1H),2.16-2.08(m,1H),2.06-1.99(m,1H),1.96-1.86( m,1H),1.56-1.42(m,2H),1.39-1.30(m,2H),1.28-1.19(m,12H),0.94(s,9H).MS(ESI)m / z=614.4[M+H] + .

[0748] Example 35: (2S,4R)-1-((S)-2-(2-aminoethoxy)acetylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 35)

[0749]

[0750] Linker 35 was synthesized following the same procedure of linker 25 described in Example 25. (1.35 g, yield: 55%, two steps). 1 H NMR (400 MHz, DMSO-d 6 )9.23(s,1H),8.70(t,J=6.0Hz,1H),8.35-8.14(m,3H),7.78(d,J=9.6Hz,1H ),7.47-7.38(m,4H),4.61(d,J=9.6Hz,1H),4.49-4.34(m,3H),4.30-4.21(m ,1H),4.09-3.99(m,2H),3.75-3.58(m,4H),3.06-2.94(m,2H),2.48(s,3H), 2.13-2.03(m,1H),1.95-1.85(m,1H),0.95(s,9H).MS(ESI)m / z=532.0[M+H] +

[0751] Example 36: (2S,4R)-1-((S)-2-(3-(2-aminoethoxy)propionylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 36)

[0752]

[0753] Linker 36 was synthesized following the same procedure of linker 25 described in Example 25. (1.32 g, yield: 49%, two steps). 1 H NMR (400 MHz, DMSO-d 6 )8.99(s,1H),8.57(t,J=6.0Hz,1H),8.03(d,J=8Hz,1H),7.85(s,3H),7.43 -7.37(m,4H),4.57(d,J=9.2Hz,1H),4.46-4.31(m,3H),4.26-4.20(m,1H),3 .69-3.55(m,6H),3.99-2.95(m,2H),2.60-2.56(m,1H),2.46-2.42(m,4H), 2.05-2.03(m,1H),1.93-1.92(m,1H),0.95(s,9H).MS(ESI)m / z=546.0[M+H] + .

[0754] Example 37: (2S,4R)-1-((S)-2-(2-(2-(2-aminoethoxy)ethoxy)acetylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 37)

[0755]

[0756] Linker 37 was synthesized following the same procedure of linker 25 described in Example 25. (1.2 g, yield: 49%, two steps). 1HNMR(400MHz,DMSO-d6)δ9.38(s,1H),8.78(t,J=6.0Hz,1H),8.18(s,3H),7 .59–7.37(m,5H),4.58(d,J=9.6Hz,1H),4.49(t,J=8.2Hz,1H),4.42–4.26(m ,3H),4.09–3.95(m,2H),3.72–3.55(m,8H),2.99–2.92(m,2H),2.49(s,3H), 2.15–2.04(m,1H),1.95–1.85(m,1H),0.95(s,9H).MS(ESI)m / z=576.1[M+H] +

[0757] Example 38: (2S,4R)-1-((S)-2-(3-(2-(2-aminoethoxy)ethoxy)propionylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 38)

[0758]

[0759] Linker 38 was synthesized following the same procedure as linker 25 described in Example 25. (1.34 g, yield: 49%, two steps). 1 HNMR (400 MHz, DMSO-d 6 )9.02(s,1H),8.58(t,J=6.0Hz,1H),7.94(d,J=8Hz,1H),7.82(s,3H),7.42-7. 30(m,4H),4.58(d,J=9.2Hz,1H),4.60-4.37(m,3H),4.25-4.31(m,1H),3.70-3. 50(m,10H),3.00-2.96(m,2H),2.57-2.55(m,1H),2.45(s,3H),2.41-2.38(m,1 H),2.06-2.04(m,1H),1.95-1.93(m,1H),0.95(s,9H).MS(ESI)m / z=590.1[M+H] +

[0760] Example 39: (2S,4R)-1-((S)-14-amino-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 39)

[0761]

[0762] Linker 39 was synthesized following the same procedure of linker 25 described in Example 25. (1.53 g, yield: 56%, two steps). 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.59(t,J=6.0Hz,1H),7.81(s,3H),7.48-7.41(m,5H),4.58(d,J=9.6Hz,1H),4.47-4.26(m,4H),3.9 9(s,2H),3.70-3.58(m,12H),3.0-2.96(m,2H),2.46(s,3H),2.11–2.06(m,1H),1.95-1.88(m,1H),0.96(s,9H).MS(ESI)m / z=621.1[M+H] +

[0763] Example 40: (2S,4R)-1-((S)-1-amino-14-(tert-butyl)-12-oxo-3,6,9-trioxa-13-azapentadeca-15-yl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 40)

[0764]

[0765] Linker 40 was synthesized following the same procedure of linker 25 described in Example 25. (1.52 g, yield: 51%, two steps). 1 H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 8.57 (t, J = 6.0Hz, 1H), 7.91 (d, J = 9.2Hz, 1H), 7. 81(s,3H),7.44-7.38(m,4H),4.58-4.55(m,1H),4.45-4.36(m,3H),4.25-4.21(m,1H ),3.70-3.48(m,14H),3.00-2.97(m,2H),2.59-2.52(m,1H),2.46(s,3H),2.39-2.34 (m,1H),2.08-2.03(m,1H),1.95-1.88(m,1H),0.94(s,9H).MS(ESI)m / z=633.8[M+H] +

[0766] Example 41: (2S,4R)-1-((S)-1-amino-17-(tert-butyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-yl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 41)

[0767]

[0768] Linker 41 was synthesized following the same procedure as linker 25 described in Example 25. (1.12 g, yield: 37%, two steps). 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.58(t,J=5.6Hz,1H),7.92(d,J=9.2Hz,1H),7.44-7.38(m,4 H),4.56(d,J=9.2Hz,1H),4.47-4.41(m,2H),4.38-4.34(m,1H),4.26-4.19(m,1H),3.70-3.55(m,5 H),3.53-3.45(m,14H),3.35(t,J=5.6Hz,2H),2.64(t,J=5.6Hz,2H),2.58-2.50(m,1H),2.45(s,3 H),2.40-2.35(m,1H),2.08-2.00(m,1H),1.94-1.91(m,1H),0.94(s,9H).MS(ESI)m / z=678.1[M+H] +

[0769] Example 42: (2S, 4R)-1-((S)-1-amino-20-(tert-butyl)-18-oxo-3,6,9,12,15-pentaoxa-19-azahexa-21-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 42)

[0770]

[0771] Linker 42 was synthesized following the same procedure as linker 25 described in Example 25. (1.1 g, 1.52 mmol, yield 82%: 32% in two steps). 1 HNMR (400 MHz, DMSO-d 6)9.38(s,1H),8.67(t,J=16Hz,1H),8.14(br,3H),7.91(d,J=9.2Hz,1H),7.39-7.48( m,4H),4.53(d,J=9.2Hz,1H),4.39-4.46(m,2H),4.36-4.34(m,1H),4.20-4.25(m,1H ),3.45-3.68(m,22H),2.91-2.95(m,2H),2.52-2.58(m,1H),2.47(s,3H),2.32-2.39 (m,1H),2.03-2.08(m,1H),1.85-1.92(m,1H),0.92(s,9H).MS(ESI)m / z=722.4[M+H] +

[0772] Example 43: 4-(((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)-4-oxobutanoic acid (Linker 43)

[0773]

[0774] A mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (1.0 g, 2.3 mmol) and succinic anhydride (465 mg, 4.65 mmol) in pyridine (5 mL) was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by flash chromatography (reverse phase, MeCN / H 2 O) to obtain the title compound connector 43 (1.05 g, yield: 86%). 1 HNMR (400 MHz, DMSO-d 6 ): δ12.02(s,1H),8.99(s,1H),8.58(t,J=6.0Hz,1H),7.96(d,J=9.2Hz,1H), 7.43-7.37(m,4H),5.13(d,J=3.6Hz,1H),4.53(d,J=9.2Hz,1H),4.46-4.40( m,2H),4.34(s,1H),4.21(dd,J=16.0,5.2Hz,1H),3.69-3.60(m,2H),2.45(s ,3H),2.44-2.33(m,4H),2.06-2.01(m,1H),1.93-1.87(m,1H),0.93(s,9H). 13C NMR (100MHz, DMSO-d6): δ173.83,171.92,170.86,169.56,151.41,147.70,139.48,131.15,129.63,128.62,1 27.41,68.87,58.70,56.44,56.34,41.65,37.91,35.35,29.74,29.25,26.35,15.92.MS(ESI)m / z=531.2[M+H] +

[0775] Example 44: 5-(((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)-5-oxopentanoic acid (Linker 44)

[0776]

[0777] Linker 44 was synthesized following the same procedure as linker 43 described in Example 43. (1.5 g, yield: 79%). 1 H NMR (400 MHz, DMSO-d 6 ): δ8.99(s,1H),8.59(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1H),7.44-7.37(m ,4H),5.16(brs,1H),4.54(d,J=9.2Hz,1H),4.47-4.42(m,2H),4.36(s,1H) ,4.21(dd,J=16.0,5.2Hz,1H),3.7-3.64(m,2H),2.45(s,3H),2.31-2.14(m ,4H),2.07-2.02(m,1H),1.94-1.81(m,1H),1.74-1.68(m,2H),0.94(s,9H). 13 C NMR (100 MHz, DMSO-d 6 ): δ174.18,171.94,171.63,169.66,151.41,147.70,139.46,131.15,129.61,128.62,127.41,68. 86,58.69,56.38,41.65,37.91,35.16,34.03,33.10,26.35,20.89,15.92.MS(ESI)m / z=543.2[MH] -

[0778] Example 45: 6-(((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)-6-oxohexanoic acid (Linker 45)

[0779]

[0780] Linker 45 was synthesized following the same procedure as linker 25 described in Example 25. (1.2 g, yield: 55%, two steps). 1 HNMR (400MHz, CDCl 3 )8.68(s,1H),7.75(s,1H),7.32-7.27(m,5H),4.64-4.57(m,3H),4.56-4.50(m,1H),4.28-4.25(m,1H),4.02-3.99( m,1H),3.71-3.68(m,1H),2.47(s,3H),2.24-2.18(m,6H),1.59-1.48(m,4H),0.96(s,9H).MS(ESI)m / z=559.3[M+H] +

[0781] Example 46: 7-(((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)-7-oxoheptanoic acid (Linker 46)

[0782]

[0783] Linker 46 was synthesized following the same procedure as linker 45 described in Example 45. (1.1 g, yield: 33%, two steps). 1 HNMR (400MHz, CDCl 3 )8.67(s,1H),7.56-7.55(m,1H),7.34-7.30(m,5H),4.68-4.59(m,3H),4.59-4.51(m,1H),4.25(dd,J=4.8Hz,15.2Hz,1H),4.06-4.03( m,1H),3.70-3.68(m,1H),2.46(s,3H),2.31-2.11(m,6H),1.55-1.51(m,4H),1.29-1.24(m,2H),0.94(s,9H).MS(ESI)m / z=573.1[M+H] +

[0784] Example 47: 8-(((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)-8-oxooctanoic acid (Linker 47)

[0785]

[0786] Linker 47 was synthesized following the same procedure of linker 45 described in Example 45. (1.08 g, yield: 52%, two steps). 1 H NMR (400MHz, DMSO-d6)8.99(s,1H),8.55(t,J=2.4Hz,1H),7.83(d,J=9.2Hz ,1H),7.44-7.38(m,4H),4.55(d,J=9.6Hz,1H),4.52-4.41(m,2H),4.36(s, 1H),4.25-4.21(m,1H),3.67-3.66(m,2H),2.45(s,3H),2.30-1.91(m,6H), 1.49-1.47(m,4H),1.26-1.24(m,4H),0.92(s,9H).MS(ESI)m / z=587.3[M+H] +

[0787] Example 48: 9-(((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)-9-oxononanoic acid (Linker 48)

[0788]

[0789] Linker 48 was synthesized following the same procedure of linker 45 described in Example 45. (1.16 g, yield: 44%, two steps). 1 H NMR (400 MHz, CDCl 3 )8.70(s,1H),7.55(s,1H),7.33-7.27(m,4H),7.08(d,J=8.0Hz,1H),4.68-4.52(m,4H),4.31-4.27(m,1H),4.08-4.05(m,1H), 3.69-3.67(m,1H),2.48(s,3H),2.33-2.11(m,6H),1.60-1.47(m,4H),1.29-1.20(m,6H),0.96(s,9H).MS(ESI)m / z=601.1[M+H]+

[0790] Example 49: 10-(((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)-10-oxodecanoic acid (Linker 49)

[0791]

[0792] Linker 49 was synthesized following the same procedure as linker 45 described in Example 45. (1.1 g, yield: 35%). 1 H NMR (400 MHz, DMSO-d 6 ): δ8.99(s,1H),8.58(t,J=6.0Hz,1H),7.85(d,J=9.2Hz,1H),7.43-7.37 (m,4H),4.54(d,J=9.2Hz,1H),4.47-4.41(m,2H),4.35(s,1H),4.21(dd,J =16.0,5.6Hz,1H),3.69-3.63(m,2H),2.45(s,3H),2.29-2.09(m,4H),2.0 3-2.01(m,1H),1.94-1.88(m,1H),1.47(m,4H),1.24(b,8H),0.94(s,9H). 13 C NMR (100 MHz, DMSO-d 6 ): δ172.07,171.92,169.69,151.41,147.70,139.48,131.14,129.62,128.61,127.40,68.84,58.6 7,56.32,56.26,41.64,37.93,35.18,34.85,28.62,26.36,25.39,15.93.MS(ESI)m / z=615.3[M+H] +

[0793] Example 50: 11-(((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)-11-oxoundecanoic acid (Linker 50)

[0794]

[0795] Linker 50 was synthesized following the same procedure as linker 45 described in Example 45. (1.1 g, yield: 50%). 1 H NMR (400 MHz, DMSO-d 6 ): δ8.99(s,1H),8.58(t,J=6.0Hz,1H),7.85(t,J=9.2Hz,1H),7.37-7.43(m,4H),4.56-4.19(m,5H) ,3.70-3.60(m,2H),2.45(s,3H),2.27-1.90(m,6H),1.49-1.45(m,4H),1.23(m,10H),0.93(s,9H). 13 C NMR (100 MHz, DMSO-d 6 ): δ174.59,172.07,171.92,169.69,151.42,147.70,139.49,131.14,129.62,128.61,127.41,68.84,58.67,56.32,56.25, 41.64,37.93,35.19,34.85,33.80,28.82,28.70,28.68,28.62,28.55,26.37,25.42,24.55,15.93.MS(ESI)m / z=629.4[M+H] +

[0796] Example 51: 3-(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)propanoic acid (Linker 51)

[0797]

[0798] Linker 51 was synthesized following the same procedure as linker 45 described in Example 45. (1.1 g, yield: 42%). 1H NMR(400MHz, DMSO-d6)8.98(s,1H),8.55(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1H) ,7.43-7.37(m,4H),4.55-4.53(m,1H),4.45-4.40(m,2H),4.35(s,1H),4.24-4. 19(m,1H),3.68-3.52(m,6H),2.54-2.56(m,1H),2.45-2.37(m,5H),2.34-2.30( m,1H),2.05-2.00(m,1H),1.93-1.86(m,1H),0.93(s,9H).MS(ESI)m / z=575[M+H] +

[0799] Example 52: 2-(2-(((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)-2-oxoethoxy)acetic acid (Linker 52)

[0800]

[0801] Linker 52 was synthesized following the same procedure as linker 43 described in Example 43. (1.2 g, yield: 63%). 1 H NMR(400MHz,DMSO-d6)12.81(br s,1H),8.98(s,1H),8.58(t,J=6.0Hz,1H),7.60(d,J=9.6Hz,1H),7.45- 7.35(m,4H),5.14(br,1H),4.58-4.55(m,1H),4.46-4.36(m,3H),4.28-4 .26(m,1H),4.14(s,2H),4.04(s,2H),3.69-3.60(m,2H),2.44(s,3H),2 .08-2.03(m,1H),1.93-1.87(m,1H),0.95(s,9H).MS(ESI)m / z=547[M+H] +

[0802] Example 53: 3-(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)ethoxy)propanoic acid (Linker 53)

[0803]

[0804] Linker 53 was synthesized following the same procedure as linker 45 described in Example 45. (1.4 g, 23% yield, two steps). 1 HNMR (400 MHz, DMSO-d 6 ):8.98(s,1H),8.56(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1H),7.43-7.37(m,4H),4.55 (d,J=9.6Hz,1H),4.46-4.41(m,2H),4.35(s,1H),4.29-4.20(m,1H),3.70-3.57(m,7 H),3.50-3.45(m,5H),2.57-2.55(m,1H),2.45(s,3H),2.43-2.41(m,1H),2.37-2.32 (m,1H),2.09-2.01(m,1H),1.94-1.87(m,1H),0.94(s,9H).MS(ESI)m / z=619.3[M+H] +

[0805] Example 54: 2-(2-(2-(((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)-2-oxoethoxy)ethoxy)acetic acid (Linker 54)

[0806]

[0807] Linker 54 was synthesized following the same procedure as linker 53 described in Example 53. (1.13 g, 20% yield, two steps). 1 HNMR (400 MHz, DMSO-d 6 ):8.98(s,1H),8.60(t,J=6.0Hz,1H),7.49(d,J=9.2Hz,1H),7.40(s,4H),4.57(d,J=9.2Hz,1H),4.47-4.36(m,3H),4.28-4.23(m,1 H),4.05-3.93(m,4H),3.69-3.61(m,6H),2.45(s,3H),2.08-2.03(m,1H),1.94-1.87(m,1H),0.94(s,9H).MS(ESI)m / z=591.2[M+H] +

[0808] Example 55: (S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecanoic acid (Linker 55)

[0809]

[0810] The same procedure as described for linker 45 in Example 45 was followed to synthesize linker 55 (1.7 g, yield 37%). 1 HNMR (400 MHz, DMSO-d 6 ):8.99(s,1H),8.56(t,J=6.0Hz,1H),7.91(d,J=9.6Hz,1H),7.44-7.38(m,4H),4 .56(d,J=9.2Hz,1H),4.47-4.42(m,2H),4.36(s,1H),4.25-4.20(m,1H),3.70-3.5 5(m,6H),3.50-3.46(m,8H),2.58-2.51(m,3H),2.45-2.42(m,5H),2.40-2.33(m, 1H),2.07-2.02(m,1H),1.94-1.88(m,1H),0.94(s,9H).LCMS(ESI)m / z=661.0[MH] -

[0811] Example 56: (S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecanoic acid (Linker 56)

[0812]

[0813] Linker 56 was synthesized following the same procedure as linker 45 described in Example 45. (1.21 g, 31% yield, two steps). 1 HNMR (400MHz, CDCl 3): δ8.68(s,1H),7.80-7.71(m,11H),7.41-7.33(m,5H),4.71-7.65(m,1H),4.61-4.50(m,3H),4.37-4.33(m,1H),4.07-3. 94(m,5H),3.77-3.58(m,10H),2.51(s,3H),2.38-2.30(m,1H),2.24-2.19(m,1H),0.98(s,9H).LCMS(ESI)m / z=635.0[M+H] +

[0814] Example 57: (S)-18-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-19,19-dimethyl-16-oxo-4,7,10,13-tetraoxa-17-azaeicosanoic acid (Linker 57)

[0815]

[0816] The same procedure as described for linker 45 in Example 45 was followed to synthesize linker 57 (1.6 g, yield 43%). 1 HNMR (400MHz, CDCl 3 ): δ8.69(s,1H),7.55-7.52(m,1H),7.47-7.45(m,1H),7.36(s,4H),4.70-4.66(m,1H),4.62-4.57(m,2H),4.50(s,1H),4.34-4.29(m,1H ),4.12-4.09(m,1H),3.75-3.48(m,18H),2.56-2.47(m,7H),2.40-2.33(m,1H),2.23-2.18(m,1H),0.96(s,9H).MS(ESI)m / z=707.1[M+H] +

[0817] Example 58: (S)-21-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20-azatricosanoic acid (Linker 58)

[0818]

[0819] Linker 58 was synthesized following the same procedure of linker 45 described in Example 45. (1.2 g, yield: 23%).1 H NMR (400MHz, DMSO-d6)8.98(s,1H),8.57(t,J=6.0Hz,1H),7.91(d,J=9.6Hz,1H) ,7.43-7.31(m,4H),4.56-4.53(m,1H),4.45-4.35(m,3H),4.24-4.19(m,1H),3.6 9-3.55(m,6H),3.49-3.47(m,16H),2.57-2.53(m,1H),2.45(s,3H),2.39-2.32( m,3H),2.06-2.01(m,1H),1.93-1.86(m,1H),0.95(s,9H).MS(ESI)m / z=751[M+H] +

[0820] Example 59: (S)-19-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-20,20-dimethyl-17-oxo-3,6,9,12,15-pentaoxa-18-azaheneicosanoic acid (Linker 59)

[0821]

[0822] Linker 59 was synthesized following the same procedure as linker 45 described in Example 45. (1.3 g, yield: 39%). 1 H NMR (400MHz, DMSO-d6)8.98(s,1H),8.69(t,J=6.0Hz,1H),7.45(d,J=9.6H z,1H),7.43-7.37(m,4H),4.57-4.55(m,1H),4.47-4.34(m,3H),4.27-4.2 2(m,1H),3.97(s,2H),3.68-3.65(m,2H),3.61-3.48(m,18H),2.45(s,3H) ,2.09-2.04(m,1H),1.92-1.86(m,1H),0.94(s,9H).MS(ESI)m / z=723[M+H] +

[0823] Example 60: 5-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 60)

[0824]

[0825] 5-Fluoroisobenzofuran-1,3-dione (87 g, 524 mmol), 3-aminopiperidine-2,6-dione (85.7 g, 524 mmol) and CH 3 COONa (85.9 g, 1050 mmol) CH 3 The mixture of COOH (500 mL) was stirred at 130°C overnight. After cooling to room temperature, the mixture was concentrated. The residue was poured into ice water and filtered. The filter cake was washed with water (500 mL x 2), EtOH (500 mL x 2), MeOH (500 mL) and DCM (500 mL) to give a solid, which was dried in vacuo to give 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (120 g, yield: 83%) as a yellow solid. MS (ESI) m / z = 277.1 [M+H] +

[0826] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (6.9 g, 25.0 mmol), tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (5.6 g, 27.5 mmol) and DIEA (9.7 g, 75 mmol) in NMP (75 mL) was stirred at 130 °C in a microwave reactor for 50 min. After cooling to room temperature, the mixture was poured into EtOAc (200 mL), washed with water (200 mL x 2) and brine (200 mL). The organic phase was purified by anhydrous Na 2 SO 4 Drying, filtration and concentration gave the crude product, which was chromatographed on silica (petroleum ether / EtOAc=2:1 to 1:2) to give tert-butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)carbamate (2.4 g, yield: 21%) as a yellow oil. MS (ESI) m / z=361.1 [M+H] +

[0827] To a solution of tert-butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)carbamate (2.4 g, 5.2 mmol) in DCM (10 mL) was added TFA (5 mL) in one portion. The reaction mixture was stirred at room temperature for 2 h and concentrated to dryness. The residue was dissolved in water (20 mL) and washed with EtOAc (40 mL) and methyl tert-butyl ether (MTBE) (40 mL). The aqueous phase was lyophilized to give 5-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (1.9 g, yield: 77%) as a yellow solid. MS (ESI) m / z=361.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.06(s,1H),8.01(s,3H),7.58(d,J=8.4Hz,1H),7.12(br,s,1H),7.02(d,J=2.0Hz,1H),6.91(dd,J=2.0Hz,8.8Hz,1H),5.04(dd,J=5 .6Hz,13.2Hz,1H),3.64(t,J=5.6Hz,4H),3.40(t,J=5.2Hz,2H),3.01(br,2H),2.89–2.83(m,1H),2.60–2.50(m,2H),2.03–1.97(m,1H).

[0828] Example 61: 5-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 61)

[0829]

[0830] The same procedure as that of the connector 60 described in Example 60 was followed to synthesize the connector 61. (1.4 g, yield: 71%). MS (ESI) m / z = 405.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.05(s,1H),7.94(br,3H),7.56(d,J=8.4Hz,1H),7.01(s,1H),6.90(d,J=8.0Hz,1H),5.03(dd,J=5.2Hz,12. 8Hz,1H),3.58(br,8H),3.36(s,2H),2.97–2.92(m,2H),2.91–2.83(m,1H),2.60–2.50(m,2H),2.01–1.99(m,1H).

[0831] Example 62: 5-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 62)

[0832]

[0833] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 62. (1.19 g, yield: 59%). MS (ESI) m / z = 449.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),7.79(br,3H),7.57(d,J=8.4Hz,1H),7.15(br,s,1H),7.00(d,J=2.0Hz,1H),6.90(dd,J=2.0Hz,8.4Hz,1H),5.03(dd,J=5 .6Hz,12.8Hz,1H),3.61–3.55(m,12H),3.36(t,J=5.6Hz,2H),2.99–2.94(m,2H),2.88–2.84(m,1H),2.60–2.52(m,2H)2.01–1.98(m,1H).

[0834] Example 63: 5-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 63)

[0835]

[0836] The same procedure as that of the connector 60 described in Example 60 was followed to synthesize the connector 63. (1.2 g, yield: 73%). MS (ESI) m / z = 493.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.05(s,1H),7.79(br,J=1.6Hz,3H),7.56(d,J=8.4Hz,1H),7.14(br,s,1H),7.01(d,J=2.0Hz,1H),6.90(dd,J=2.0Hz,8.4Hz,1H),5.03(dd ,J=5.6Hz,13.2Hz,1H),3.61–3.56(m,16H),3.36(t,J=5.2Hz,2H),2.9 9–2.95(m,2H),2.89–2.83(m,1H),2.60–2.53(m,2H)2.01–1.97(m,1H).

[0837] Example 64: 5-((17-amino-3,6,9,12,15-pentaoxaheptadecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 64)

[0838]

[0839] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 64. (1.73 g, yield: 88%). MS (ESI) m / z = 537.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),7.79(s,3H),7.55(d,J=8.4Hz,1H),7.18(br,s,1H),7.01(s,1H),6.90(d,J=8.4Hz,1H),5.03(dd,J=5.2 Hz,12.8Hz,1H),3.61–3.54(m,20H),3.35(s,2H),2.98(s,2H),2.92–2.83(m,1H),2.61–2.54(m,2H),2.02–1.98(m,1H).

[0840] Example 65: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine (Linker 65)

[0841]

[0842] The same procedure as that of the connector 60 described in Example 60 was followed to synthesize the connector 65. (1.0 g, yield: 84%). MS (ESI) m / z = 332.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ12.80(br,1H),11.06(s,1H),7.59(d,J=8.4Hz,1H),7.32(br,s,1H),6.98(d,J=1.2Hz,1H),6.89(dd,J=2.0Hz, 8.4Hz, 1H), 5.04 (dd, J = 5.6Hz, 13.2Hz, 1H), 4.03 (s, 2H), 2.92–2.83 (m, 1H), 2.60–2.52 (m, 2H), 2.03–1.98 (m, 1H).

[0843] Example 66: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanoic acid (Linker 66)

[0844]

[0845] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 66. (1.24 g, yield: 60%). MS (ESI) m / z = 346.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),7.57(d,J=8.4Hz,1H),6.97(d,J=2.0Hz,1H),6.87(dd,J=2.0Hz,8.4Hz,1H),5.02(dd, J=5.2Hz,12.8Hz,1H),3.41(t,J=6.8Hz,2H),2.89–2.83(m,1H),2.60–2.52(m,4H),2.02–1.97(m,1H).

[0846] Example 67: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyric acid (Linker 67)

[0847]

[0848] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 67. (0.52 g, yield: 25%). MS (ESI) m / z = 360.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ12.12(s,1H),11.05(s,1H),7.55(d,J=8.4Hz,1H),7.14(t,J=4.8Hz,1H),6.95(d,J=2.0Hz,1H),6.85(dd,J=2.0Hz,8.4Hz,1H),5.02(dd, J=5.6Hz,12.8Hz,1H),3.21–3.16(m,2H),2.91–2.83(m,1H),2.60–2.51(m,2H),2.34(t,J=7.2Hz,2H),2.01–1.97(m,1H),1.82–1.75(m,2H).

[0849] Example 68: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoic acid (Linker 68)

[0850]

[0851] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 68. (0.66 g, yield: 51%). MS (ESI) m / z = 374.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.03(br,1H),11.05(s,1H),7.55(d,J=8.4Hz,1H),7.10(t,J=5.2Hz,1H),6.94(s,1H),6.83(dd,J=1.6Hz,8.4Hz,1H),5.02(dd,J= 5.6Hz,12.8Hz,1H),3.17–3.16(m,2H),2.92–2.83(m,1H),2.60–2.53(m,2H),2.26–2.25(m,2H),2.01–1.98(m,1H),1.60–1.59(m,4H).

[0852] Example 69: 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoic acid (Linker 69)

[0853]

[0854] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 69. (1.33 g, yield: 66%). MS (ESI) m / z = 388.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.98(s,1H),11.05(s,1H),7.55(d,J=8.4Hz,1H),7.08(t,J=5.2Hz,1H),6.95(s,1H),6.83(dd,J=1.2Hz,8.4Hz,1H),5.03(dd,J=5.2Hz,12.8 Hz,1H),3.17–3.12(m,2H),2.92–2.83(m,1H),2.60–2.53(m,2H),2.22(t ,J=7.2Hz,2H),2.01–1.98(m,1H),1.61–1.51(m,4H),1.41–1.33(m,2H).

[0855] Example 70: 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoic acid (Linker 70)

[0856]

[0857] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 70. (1.06 g, yield: 39%). MS (ESI) m / z = 402.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.94(s,1H),11.04(s,1H),7.55(d,J=8.4Hz,1H),7.09(t,J=5.6Hz,1H ),6.94(d,J=2.0Hz,1H),6.84(dd,J=2.0Hz,8.4Hz,1H),5.02(dd,J=5.6Hz, 13.2Hz,1H),3.17–3.12(m,2H),2.88–2.83(m,1H),2.60–2.53(m,2H),2.21 (t,J=7.2Hz,2H),2.01–1.97(m,1H),1.58–1.48(m,4H),1.39–1.29(m,4H).

[0858] Example 71: 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoic acid (Linker 71)

[0859]

[0860] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 71. (1.66 g, yield: 51%). MS (ESI) m / z = 416.1 [M+H] + .1 H NMR (400 MHz, DMSO-d 6 )δ11.95(s,1H),11.05(s,1H),7.55(d,J=8.4Hz,1H),7.09(t,J=5.6Hz,1H ),6.94(d,J=2.0Hz,1H),6.84(dd,J=2.0Hz,8.4Hz,1H),5.02(dd,J=5.6Hz, 13.2Hz,1H),3.17–3.12(m,2H),2.88–2.83(m,1H),2.60–2.53(m,2H),2.19 (t,J=7.2Hz,2H),2.02–1.98(m,1H),1.58–1.47(m,4H),1.36–1.29(m,6H).

[0861] Example 72: 5-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 72)

[0862]

[0863] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 72. (1.74 g, yield: 80%). MS (ESI) m / z = 317.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.08(s,1H),8.10(s,3H),7.62(d,J=8.4Hz,1H),7.33(t,J=5.2Hz,1H),7.05(s,1H),6.94(d,J=8.0Hz,1H),5.07(dd, J=5.2Hz,12.8Hz,1H),3.50–3.49(m,2H),3.03(t,J=6.0Hz,2H),2.95–2.86(m,1H),2.63–2.57(m,2H),2.05–2.02(m,1H).

[0864] Example 73: 5-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 73)

[0865]

[0866] The same procedure as that of the connector 60 described in Example 60 was followed to synthesize the connector 73. (1.3 g, yield: 57%). MS (ESI) m / z = 331.1 [M+H] + .1 H NMR (400 MHz, DMSO-d 6 )δ11.07(s,1H),7.85(br,3H),7.59(d,J=8.4Hz,1H),7.22(t,J=5.2Hz,1H),6.98(d,J=2.0Hz,1H),6.88(dd,J=2.0Hz,8.4Hz,1H) ,5.04(dd,J=5.6Hz,13.2Hz,1H),3.29–3.25(m,2H),2.91–2.85(m,3H),2.60–2.53(m,2H),2.02–1.98(m,1H),1.87–1.81(m,2H).

[0867] Example 74: 5-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 74)

[0868]

[0869] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 74. (2.9 g, yield: 85%). MS (ESI) m / z = 345.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.08(s,1H),7.97(br,3H),7.58(d,J=8.4Hz,1H),7.22(br,s,1H),6.99(s,1H),6.89(d,J=8.0Hz,1H),5.05 (dd,J=5.2Hz,12.8Hz,1H),3.22(s,2H),2.93-2.84(m,3H),2.63–2.53(m,2H),2.04–2.00(m,1H),1.66(s,4H).

[0870] Example 75: 5-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 75)

[0871]

[0872] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 75. (1.8 g, yield: 78%). MS (ESI) m / z = 359.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.09(s,1H),7.89(br,3H),7.57(d,J=6.8Hz,1H),7.17(br,s,1H),6.96(s,1H),6.86(d,J=6.0Hz,1H),5.05(d,J=7.2H z,1H),3.19-3.15(m,2H),2.89-2.70(m,3H),2.61-2.51(m,2H),2.01-1.90(m,1H),1.62-1.56(m,4H),1.45-1.40(m,2H).

[0873] Example 76: 5-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 76)

[0874]

[0875] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 76. (1.8 g, yield: 62%). MS (ESI) m / z = 373.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),7.71(br,3H),7.57(d,J=8.4Hz,1H),7.12(t,J=5.2Hz,1H),6.94(d,J=2.0Hz,1H),6.85(dd,J=2.0Hz,8.4Hz,1H),5.03(dd .

[0876] Example 77: 5-((7-aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 77)

[0877]

[0878] The same procedure as that of the connector 60 described in Example 60 was followed to synthesize the connector 77. (1.3 g, yield: 70%). MS (ESI) m / z = 387.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.05(s,1H),7.72(br,3H),7.56(d,J=8.4Hz,1H),7.12(t,J=5.6Hz,1H),6.94(d,J=2.0Hz,1H),6.85(dd,J=2.4Hz,8.8Hz,1H),5.03(dd .

[0879] Example 78: 5-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 78)

[0880]

[0881] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 78. (1.6 g, yield: 62%). MS (ESI) m / z = 401.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),7.73(br,3H),7.56(d,J=8.4Hz,1H),7.14(br,1H),6.94(d,J=1.6Hz,1H),6.85(dd,J=2.0Hz,8.8Hz,1H),5.03(dd,J=5.6Hz,12.8 Hz,1H),3.15(t,J=7.2Hz,2H),2.89–2.83(m,1H),2.80–2.75(m,2H),2.6 0–2.54(m,2H),2.02–1.98(m,1H),1.59–1.51(m,4H),1.37–1.30(m,8H).

[0882] Example 79: 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid (Linker 79)

[0883]

[0884] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 79. (1.7 g, yield: 60%). MS (ESI) m / z = 390.1 [M+H] + . 1H NMR (400 MHz, DMSO-d 6 )δ12.19(br,1H),11.06(s,1H),7.57(d,J=8.4Hz,1H),7.09(br,1H),7.01(d,J=2.0Hz,1H),6.90(dd,J=2.0Hz,8.4Hz,1H),5.04(dd,J=5.6Hz,13.2Hz ,1H),3.66(t,J=6.4Hz,2H),3.59(t,J=5.6Hz,2H),3.35(t,J=5.2Hz,2H),2 .93–2.84(m,1H),2.62–2.56(m,2H),2.52–2.47(m,2H),2.03–1.99(m,1H).

[0885] Example 80: 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoic acid (Linker 80)

[0886]

[0887] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 80. (2.3 g, yield: 78%). MS (ESI) m / z = 434.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.06(s,1H),7.57(d,J=8.4Hz,1H),7.02(d,J=2.0Hz,1H),6.90(dd,J=2.0Hz,8.4Hz,1H),5.04(dd,J=5.6Hz,13.2Hz,1H),3.63–3 .59(m,4H),3.57–3.51(m,4H),3.36(t,J=5.6Hz,2H),2.90–2.84(m,1H),2.61–2.55(m,2H),2.44(t,J=6.4Hz,2H),2.04–1.99(m,1H).

[0888] Example 81: 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (Linker 81)

[0889]

[0890] The same procedure as that of the connector 60 described in Example 60 was followed to synthesize the connector 81. (1.2 g, yield: 52%). MS (ESI) m / z = 478.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.59(d,J=11.2Hz,1H),7.23(t,J=6.8Hz,1H),7.04(d,J=1.6Hz,1H),7.04(dd,J=2.4Hz,11.2Hz,1H),5.06(dd,J=7.2Hz,16.8Hz,1H) ,3.64-3.57(m,8H),3.54-3.48(m,4H),3.40-3.38(m,2H),2.92–2.89(m,1H),2.64–2.54(m,2H),2.42–2.38(m,2H),2.05–2.01(m,1H).

[0891] Example 82: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)3,6,9,12-tetraoxapentadeca-15-oic acid (Linker 82)

[0892]

[0893] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 82. (1.3 g, yield: 55%). MS (ESI) m / z = 522.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.17(br,1H),11.07(s,1H),7.56(d,J=8.4Hz,1H),7.17(t,J=5.6Hz,1H),7.01(d,J=1.2Hz,1H),6.90(dd,J=1.6Hz,8.4Hz,1H), 5.03(dd,J=5.6Hz,12.8Hz,1H),3.61-3.48(m,18H),2.92-2.83(m,1H),2.60-2.54(m,2H),2.43(t,J=6.4Hz,2H),2.03-1.98(m,1H).

[0894] Example 83: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)3,6,9,12,15-pentaoxaoctadecane-18-oic acid (Linker 83)

[0895]

[0896] The same procedure as that of the connector 60 described in Example 60 was followed to synthesize the connector 83. (1.0 g, yield: 50%). MS (ESI) m / z = 566.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.17(br,s,1H),11.07(s,1H),7.56(d,J=8.0Hz,1H),7.17(t,J=5.6Hz,1H),7.01(s,1H),6.90(dd,J=1.6Hz,8.4Hz,1H),5.0 3(dd,J=5.6Hz,13.2Hz,1H),3.60-3.48(m,22H),2.89-2.83(m,1H),2.60-2.54(m,2H),2.43(t,J=6.4Hz,2H),2.01-1.98(m,1H).

[0897] Synthesis steps of the P300 binding head of P300 PROTAC

[0898] Example 84 Synthesis of 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P300 combined with head 1)

[0899]

[0900] Step 1: Synthesis of quinoline-7-carboxaldehyde

[0901]

[0902] At 160°C, SeO 2 (220g, 1.97mol), after 25min. The mixture was stirred at 160°C for 8h. After cooling to room temperature, DCM (2000mL) was added and the mixture was filtered through a diatom pad. The organic layer was concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum ether / EtOAc=10:1) to give quinoline-7-carboxaldehyde (100g, yield: 38%) as a yellow solid.

[0903] Step 2: Synthesis of 7-(difluoromethyl)quinoline

[0904]

[0905] To a cooled (0°C) solution of quinoline-7-carboxaldehyde (35.0 g, 223 mmol) in DCM (400 mL) was added diethylaminosulfur trifluoride (162.0 g, 1150 mmol) dropwise over 30 min. The mixture was stirred at room temperature for 16 h and then poured into saturated NaHCO at 0°C. 3 The aqueous solution (2 L) was extracted with DCM (400 mL x 2). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=5:1) to give 7-(difluoromethyl)quinoline (26.0 g, yield: 65%) as a yellow oil.

[0906] Step 3: Synthesis of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline

[0907]

[0908] To cooled (0 °C) 7-(difluoromethyl)quinoline (26.0 g, 72.6 mmol) and NaBH 3 Boron trifluoride etherate (41.2 g, 290 mmol) was added dropwise to a solution of CN (46.1 g, 726 mmol) in MeOH (300 mL) over 20 min. The mixture was heated to 90 °C for 24 h. After cooling to room temperature, the mixture was poured into saturated NaHCO at 0 °C. 3 The aqueous solution (2 L) was extracted with DCM (500 mL x 2). The combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=20:1) to give 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (13.0 g, yield: 49%) as a brown oil.

[0909] Step 4: Synthesis of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline

[0910]

[0911] N-bromosuccinimide (6.90 g, 38.3 mmol) was added to a solution of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (29.0 g, 158.5 mmol) in DCM (600 mL) at 0°C in portions over 20 minutes. The mixture was stirred at room temperature for 16 h, then poured into water (100 L) and extracted with DCM (400 mL x 2). The combined organic layers were purified by Na 2 SO 4Dry, filter and concentrate in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=300:1) to give 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (22.0 g, yield: 52.8%) as a white solid. 1 HNMR (400MHz, CDCl 3 )δ7.12(s,1H),6.77(t,J=55.2Hz,1H),6.77(s,1H),4.01(s,1H),3.30(t,J=6.4Hz,2H),2.74(t,J=6.0Hz,2H),1.94-1.88(m,2H).

[0912] Step 5: Synthesis of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline

[0913]

[0914] To a solution of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (2 g, 7.66 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.59 g, 7.66 mmol) in 1,4-dioxane (50 mL) was added Pd(dppf)Cl 2 (1.6 g, 2.3 mmol), K 2 CO 3 (2.11 g, 15.32 mmol). The reaction mixture was heated to 95°C overnight, then diluted with ethyl acetate, washed with water and brine. The organic layer was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (1.4 g, yield: 69%) as a white solid. MS (ESI) m / z: 264.4 [M+H] + .

[0915] Step 6: Synthesis of tert-butyl 3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0916]

[0917] To a solution of tert-butyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (10 g, 44.84 mmol) in DMF (100 mL) was added 1 2(22.76 g, 89.68 mmol) and KOH (10.04 g, 179.36 mmol). The resulting mixture was stirred at 50 °C overnight. The reaction was heated with Na 2 SO 3 The aqueous solution was quenched and extracted with EtOAc. The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=3:1) to obtain the desired product (8.0 g, yield: 51%) as a colorless oil. MS (ESI) m / z: 350.2 [M+H] + .

[0918] Step 7: Synthesis of tert-butyl 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0919]

[0920] To a solution of tert-butyl 3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (6 g, 17.19 mmol) in DMF (50 mL) were added benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (8.07 g, 25.79 mmol) and K 2 CO 3 (4.74 g, 34.38 mmol). The resulting mixture was stirred at 100°C overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=1:1) to obtain the desired product (4.0 g, yield: 41%) as a white solid. MS (ESI) m / z: 567.4 [M+H] + .

[0921] Step 8: Synthesis of tert-butyl 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0922]

[0923] To a solution of tert-butyl 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (132 mg, 0.233 mmol) and 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (74 mg, 0.280 mmol) in dioxane (3 mL) was added RuPhos Pd G1 (22.8 mg, 0.028 mmol), RuPhos (13.0 mg, 0.028 mmol) and t BuONa (78.3 mg, 0.816 mmol). The resulting mixture was stirred under reflux overnight. The reaction mixture was purified by reverse phase flash chromatography to obtain the desired product (80 mg, yield: 49%) as a white solid. MS (ESI) m / z: 703.1 [M+H] + .

[0924] Step 9: Synthesis of benzyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate

[0925]

[0926] A mixture of tert-butyl 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (189 mg, 0.27 mmol) in DCM:TFA=1:1 (10 ml) was stirred at room temperature for 3 h and then concentrated. The residue was used directly in the next step.

[0927] Step 10: Synthesis of benzyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-5-(methylcarbamoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate

[0928]

[0929] To a solution of benzyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (crude product from the previous reaction) in DCM (10 ml) was added benzyl 2,5-dioxopyrrolidin-1-ylmethylcarbamate (141 mg, 0.81 mmol) and TEA (82 mg, 0.81 mmol). The resulting mixture was stirred at room temperature for 5 h, before the reaction mixture was purified by reverse phase chromatography to give the desired product (105 mg, yield: 59%) as a white solid. MS (ESI) m / z: 659.9 [M+H] + .

[0930] Step 11: Synthesis of 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P300 binding head 1)

[0931]

[0932] A mixture of benzyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-5-(methylcarbamoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (105 mg, 0.16 mmol) and Pd / C (10%, 100 mg) in MeOH (10 ml) was stirred at 4 ℃ for 1 h. 2 The reaction mixture was filtered through celite and the filtrate was concentrated to give the desired product (56 mg, yield: 67%) as a white solid. MS (ESI) m / z: 525.8 [M+H] + .

[0933] Example 85 Synthesis of 2-(4-(7-(difluoromethyl)-1-(5-(methylcarbamoyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetic acid (P300 combined with head 2)

[0934]

[0935] Step 1: Synthesis of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate

[0936]

[0937] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 10.31 mmol), tert-butyl 2-bromoacetate (2.21 g, 11.34 mmol) and K 2 CO 3 A mixture of 1.71 g, 12.37 mmol) in acetone (20 ml) was stirred at 65 °C overnight. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel chromatography (PE / EA=5:1) to obtain the desired product (1.7 g, yield: 54%) as an oil. MS (ESI) m / z: 309.2 [M+H] + .

[0938] Step 2: Synthesis of tert-butyl 2-(4-(7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetate

[0939]

[0940] To a solution of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (1.44 g, 5.52 mmol) and tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate (1.7 g, 5.52 mmol) in 1,4-dioxane (50 mL) was added Pd(dppf)Cl 2 (1.15 g, 1.66 mmol), K 2 CO 3 (1.52 g, 11.03 mmol). The reaction mixture was heated to 95 °C overnight, then diluted with ethyl acetate, washed with water and brine. The organic layer was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the desired product (0.9 g, yield: 45%) as a white solid. MS (ESI) m / z: 364.6 [M+H] + .

[0941] Step 3:Synthesis of tert-butyl 3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0942]

[0943] To a solution of tert-butyl 3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (6 g, 17.19 mmol) in DMF (50 mL) were added tetrahydro-2H-pyran-4-yl methanesulfonate (4.64 g, 25.79 mmol) and K 2 CO 3 (4.74 g, 34.38 mmol). The resulting mixture was stirred at 100°C overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EA. The combined organic phases were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel chromatography (PE / EA=1:1) to obtain the desired product (5.0 g, yield: 67%) as a white solid. MS (ESI) m / z: 434.6 [M+H] + .

[0944] Step 4: Synthesis of 2-(4-(1-(5-(tert-butoxycarbonyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetic acid

[0945]

[0946] To a solution of tert-butyl 3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (258 mg, 0.60 mmol) and tert-butyl 2-(4-(7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetate (262 mg, 0.72 mmol) in dioxane (10 mL) was added RuPhos Pd G1 (58.6 mg, 0.072 mmol), RuPhos (33.4 mg, 0.072 mmol) and t BuONa (201.3 mg, 2.098 mmol). The resulting mixture was stirred under reflux overnight. The reaction mixture was purified by reverse phase flash chromatography to obtain the desired product (108 mg, yield: 29%) as a white solid. MS (ESI) m / z: 613.7 [M+H] + .

[0947] Step 5: Synthesis of 2-(4-(7-(difluoromethyl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetic acid

[0948]

[0949] A solution of 2-(4-(1-(5-(tert-butoxycarbonyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetic acid (108 mg, 0.176 mmol) in DCM / TFA=1:1 (6 ml) was stirred at room temperature for 3 h, then it was concentrated and the residue was used directly in the next step.

[0950] Step 6: Synthesis of 2-(4-(7-(difluoromethyl)-1-(5-(methylcarbamoyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetic acid (P300 combined with head 2)

[0951]

[0952] To a solution of 2-(4-(7-(difluoromethyl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetic acid (crude product from the previous reaction) in DCM (10 ml) was added 2,5-dioxodiopyrrolidin-1-ylmethylcarbamate (91.9 mg, 0.528 mmol) and TEA (53.5 mg, 0.528 mmol). The resulting mixture was stirred at room temperature for 5 h, and then the reaction mixture was purified by reverse phase chromatography to give the desired product (81 mg, yield: 81%) as a white solid. MS (ESI) m / z: 570.4 [M+H] + .

[0953] Synthesis steps of P300 PROTAC

[0954] Example 86-259 Synthesis of Compounds P-001 to P-174 (see Table 1B below)

[0955] Compounds P-001 to P-174 (see Table 1B below) can be prepared according to the method described in PCT / CN2020 / 076648.

[0956] Certain compounds disclosed herein have the structures shown in Table 1B.

[0957] Table 1B

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030] Example 260 4-(3-(1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-187)

[1031]

[1032] P-187 (7.5 mg, 46% yield) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 932.5 [M+H] + .

[1033] Example 261 4-((2-(1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-188)

[1034]

[1035] P-188 (7.8 mg, 48% yield) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 920.6 [M+H] + .

[1036] Example 262 4-((4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)morpholin-2-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-189)

[1037]

[1038] P-189 (6.9 mg, 43% yield) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 909.6 [M+H] + .

[1039] Example 263 4-(2-(1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-190)

[1040]

[1041] Step 1: Synthesis of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)ethynyl)piperidine-1-carboxylate

[1042]

[1043] To a solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.0 g, 3.0 mmol) in DMF (10 mL) were added tert-butyl 4-ethynylpiperidine-1-carboxylate (621 mg, 3.0 mmol), Pd(dppf)Cl 2 (110 mg, 0.15 mmol), CuI (57 mg, 0.3 mmol) and TEA (3.0 g, 30 mmol). Then, the mixture was stirred at 85 ° C for 12 h in an Ar atmosphere. The reaction mixture was purified by reverse phase chromatography to obtain the title product (1.07 g, yield 78%) as a white solid. MS (ESI) m / z: 410.2 [M+H-56] + .

[1044] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-ylethynyl)isoindoline-1,3-dione

[1045]

[1046] A mixture of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)ethynyl)piperidine-1-carboxylate (50 mg, 107.41 umol) and TFA (1.5 mL) in DCM (3 mL) was stirred at 25 °C for 1 h. The mixture was concentrated to give the title compound (45 mg, yield 87%) as a colorless oil, which was used directly in the next step without further purification. MS (ESI) m / z: 366.4 [M+H] + .

[1047] Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(2-(piperidin-4-yl)ethynyl)isoindoline-1,3-dione

[1048]

[1049] In a hydrogen atmosphere, a mixture of 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-ylethynyl)isoindoline-1,3-dione (45 mg, 93.87 umol) and Pd / C (10 mg, 2.6 umol) in THF / MeOH (3 mL) was stirred at 25°C for 12 h. After filtration, the filtrate was concentrated to give the title compound (32 mg, yield 71%) as a white solid. MS (ESI) m / z: 370.4 [M+H] + .

[1050] Step 4: Synthesis of 1-(1-(1-(3-chloropropyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

[1051]

[1052] A mixture of 1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (100 mg, 0.354 mmol), 1-chloro-3-iodo-propane (48.14 mg, 235.48 umol) and DIEA (75.94 mg, 588.71 umol) in DMSO (3 mL) was stirred at 25 °C for 12 h. The reaction mixture was purified by reverse phase to give the title product (83 mg, yield 78%) as a white solid. MS (ESI) m / z: 586.5 [M+H] + .

[1053] Step 5: Synthesis of 4-(2-(1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1054]

[1055] 1-(1-(1-(3-chloropropyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (20 mg, 34.12 umol), DIEA (13.21 mg, 102.37 umol), NaI (7.67 mg, 51.18 umol) and 2-(2,6-dioxopiperidin-3-yl)-4-(2-(piperidin-4-yl)ethyl)isoindoline-1,3-dione (18.15 mg, 37.54 umol) in CH 3 The mixture in CN (2.0 mL) was stirred at 75 ° C for 4 h. The mixture was purified by silica gel column (DCM / MeOH=10:1) to give the title product (23.8 mg, yield 76%) as a brown solid. MS (ESI) m / z: 919.9 [M+H] + .

[1056] Example 264 4-(4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-191)

[1057]

[1058] P-191 (6.5 mg, 42% yield) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 878.8 [M+H] + .

[1059] Example 265 4-(4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-192)

[1060]

[1061] P-192 (39.8 mg, yield 77%) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 877.7 [M+H] + .

[1062] Example 266 4-(((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-193)

[1063]

[1064] P-193 (33 mg, yield 87%) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 920.9 [M+H] + .

[1065] Example 267 3-(7-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-194)

[1066]

[1067] P-194 (4.1 mg, 41% yield) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 872.8 [M+H] + .

[1068] Example 268 4-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-195)

[1069]

[1070] P-195 (13 mg, 58% yield) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 886.9 [M+H] + .

[1071] Example 269 3-(4-(((5-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)pyridin-2-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-196)

[1072]

[1073] P-196 (10 mg, yield 29%) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 872.7 [M+H] + .

[1074] Example 270 4-((4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperazin-2-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-197)

[1075]

[1076] Step 1: Synthesis of tert-butyl 4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)-2-(((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)methyl)piperazine-1-carboxylate

[1077]

[1078] The title compound (9.0 mg, yield 51%) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 1008.6 [M+H] + .

[1079] Step 2: Synthesis of 4-((4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperazin-2-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1080]

[1081] To a solution of tert-butyl 4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)-2-(((2,6-dipiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)methyl)piperazine-1-carboxylate (9.0 mg, 0.0089 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 2 h, after which the mixture was concentrated. The residue was purified by preparative TLC to give the title compound (6.02 mg, yield: 74.5%) as a white solid. MS (ESI) m / z: 908.6 [M+H] + .

[1082] Example 271 3-(7-(((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)pyridin-2-yl)ethyl)morpholin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-198)

[1083]

[1084] P-198 (12.9 mg, yield 82.5%) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 894.7 [M+H] + .

[1085] Example 272 3-(4-(((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)pyridin-2-yl)ethyl)morpholin-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-199)

[1086]

[1087] P-199 (3.2 mg, yield 16.1%) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 894.7 [M+H] + .

[1088] Example 273 3-(4-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-200)

[1089]

[1090] P-200 (8.8 mg, yield 40.2%) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 871.7 [M+H] + .

[1091] Example 274 4-(3-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)butyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-201)

[1092]

[1093] P-201 (2.7 mg, 16.4% yield) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 877.7 [M+H] + .

[1094] Example 275 3-(4-((3-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-202)

[1095]

[1096] P-202 (3.5 mg, yield 39.3%) was synthesized according to the standard procedure for preparing P-190. MS (ESI) m / z: 872.8 [M+H] + .

[1097] Example 276 3-(5-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperidin-4-yl)methoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-203)

[1098]

[1099] Step 1: Synthesis of tert-butyl 4-(((1-(2,6-dioxopiperidin-3-yl)3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)methyl)piperidine-1-carboxylate

[1100]

[1101] To a solution of 3-(5-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (44.7 mg, 0.164 mmol) in DMSO (3 mL) were added tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate (60 mg, 0.163 mmol), sodium iodide (36.67 mg, 0.245 mmol) and potassium carbonate (56.30 mg, 0.408 mmol). The mixture was then heated at 60 ° C for 2 h. After the mixture was purified by C18 column, the title compound (34 mg, yield 44.2%) was obtained as a white solid. MS (ESI) m / z: 473.3 [M+H] + .

[1102] Step 2: Synthesis of 3-(3-methyl-2-oxo-5-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[1103]

[1104] To a solution of tert-butyl 4-(((1-(2,6-dioxopiperidin-3-yl)3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)methyl)piperidine-1-carboxylate (34 mg, 0.072 mmol) in DCM (1 mL) was added TFA (1 mL). After the reaction was stirred at room temperature for 1 h, the mixture was concentrated to give the title compound (26 mg, yield 99.9%) as a white solid. MS (ESI) m / z: 373.2 [M+H] + .

[1105] Step 3: Synthesis of tert-butyl 3-(4-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)methyl)piperidin-1-yl)propanoate

[1106]

[1107] To a solution of 3-(3-methyl-2-oxo-5-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (26 mg, 0.069 mmol) in DMSO (2 mL) was added DIEA (36.35 mg, 0.284 mmol). The solution was heated at 60 °C, at which temperature 5 drops of tert-butyl 3-bromopropionate (144.26 mg, 0.69 mmol) were added within 1 h. The reaction was then stirred at the same temperature for 1 h. The mixture was purified by C18 column to give the title compound (15 mg, yield 43.5%) as a white solid. MS (ESI) m / z: 501.5 [M+H] + .

[1108] Step 4: Synthesis of 3-(4-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)methyl)piperidin-1-yl)propanoic acid

[1109]

[1110] To a solution of tert-butyl 3-(4-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)methyl)piperidin-1-yl)propanoate (15 mg, 0.03 mmol) in DCM (0.5 mL) was added TFA (0.5 mL). After the reaction was stirred at room temperature for 2 h, the mixture was concentrated to give the crude product (13.35 mg, yield 99.9%) as a white solid, which was used directly in the next step without further purification. MS (ESI) m / z: 445.2 [M+H] + .

[1111] Step 5: Synthesis of 3-(5-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperidin-4-yl)methoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[1112]

[1113] 3-(4-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)methyl)piperidin-1-yl)propanoic acid (12 mg, 0.027 mmol), 1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(piperidin-4 A mixture of 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (13.73 mg, 0.027 mmol), HOAT (5.5 mg, 0.041 mmol), EDCI (7.87 mg, 0.041 mmol) and 4-methylmorpholine (13.64 mg, 0.135 mmol) in DMSO was stirred at room temperature for 12 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were concentrated and the residue was purified by preparative TLC to give the title compound (20 mg, yield 79.2%) as a white solid. MS (ESI) m / z: 936.8 [M+H] + .

[1114] Example 277 3-(3-((1-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-204)

[1115]

[1116] Step 1: Synthesis of tert-butyl 4-(((2-nitrophenyl)amino)methyl)piperidine-1-carboxylate

[1117]

[1118] To a solution of 1-fluoro-2-nitrobenzene (329.44 mg, 2.34 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (500 mg, 2.34 mmol) in DMF (10 mL) was added K 2 CO 3 (968.76 mg, 7.02 mmol). After the mixture was heated at 80°C for 3 h, the resulting mixture was treated with H 2 O (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were purified by Na 2 SO 4 Drying, filtration and evaporation gave a residue which was purified by silica gel column chromatography to give the title compound (650 mg, yield 83%) as a white solid. MS (ESI) m / z: 336.0 [M+H] + .

[1119] Step 2: Synthesis of tert-butyl 4-(((2-aminophenyl)amino)methyl)piperidine-1-carboxylate

[1120]

[1121] To a solution of tert-butyl 4-(((2-nitrophenyl)amino)methyl)piperidine-1-carboxylate (650 mg, 1.94 mmol) in 20 mL of THF was added Pd / C (0.5 g, 10%). The reaction was stirred under balloon pressure of hydrogen overnight. After filtration, the filtrate was evaporated to dryness and used directly in the next step without further purification (580 mg, 91% yield).

[1122] Step 3: Synthesis of tert-butyl 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate

[1123]

[1124] To a 50 mL round-bottom flask was added tert-butyl 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate (580 mg, 1.76 mmol), N,N'-carbonyldiimidazole (428.08 mg, 2.64 mmol) and THF (15 mL). The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to remove the solvent. The residue was recrystallized from methanol and n-hexane to give the title compound (400 mg, yield: 69%) as a white solid. MS (ESI) m / z: 332.2 [M+H] + .

[1125] Step 4: Synthesis of tert-butyl 4-((3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate

[1126]

[1127] To a stirred solution of tert-butyl 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate (400 mg, 1.21 mmol) in DMF (2 mL) was added NaH (96.8 mg, 2.42 mmol, 60% w / w dispersion in mineral oil) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 20 min. A solution of 3-bromopiperidine-2,6-dione (161.94 mg, 0.84 mmol) in DMF (1 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for another 3 h and then treated with H 2 O quenched, extracted with EtOAc. The combined organic layers were washed with brine and washed with Na 2 SO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography to obtain the title compound (170 mg, yield: 32%) as a white solid. MS (ESI) m / z: 443.2 [M+H] + .

[1128] Step 5: Synthesis of 3-(2-oxo-3-(piperidin-4-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[1129]

[1130] To a solution of tert-butyl 4-((3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate (170 mg, 0.38 mmol) in DCM (2 mL) was added TFA (2 mL). After the reaction was stirred at room temperature for 2 h, the mixture was concentrated in vacuo to give the crude product (179.36 mg, yield: 99.9%) as a white solid. MS (ESI) m / z: 343.2 [M+H] + .

[1131] Step 6: Synthesis of tert-butyl 4-(4-((3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)butanoate

[1132]

[1133] To a solution of 3-(2-oxo-3-(piperidin-4-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (70 mg, 0.42 mmol) and tert-butyl 4-bromobutyrate (91 mg, 0.42 mmol) in DMSO (2 mL) was added DIEA (107.52 mg, 0.84 mmol). The reaction was then stirred at 60 °C overnight and the mixture was purified by C18 column to give the title compound (100 mg, yield: 98%) as a white solid. MS (ESI) m / z: 485.6 [M+H] + .

[1134] Step 7: Synthesis of 4-(4-((3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)butanoic acid

[1135]

[1136] To a solution of tert-butyl 4-(4-((3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)butanoate (100 mg, 0.21 mmol) in DCM (2 mL) was added TFA (2 mL). After the reaction was stirred at room temperature for 2 h, the mixture was concentrated in vacuo to give the crude product (88 mg, yield 99.9%) as a brown solid, which was used directly in the next step without further purification. MS (ESI) m / z: 429.4 [M+H] + .

[1137] Step 8: Synthesis of 3-(3-((1-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[1138]

[1139] To 4-(4-((3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)butanoic acid (10 mg, 0.023 mmol), 1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl) To a mixture of 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (11.89 mg, 0.023 mmol), HOAT (4.66 mg, 0.035 mmol) and EDCI (6.62 mg, 0.035 mmol) in DMSO (0.5 mL) was added NMM (11.6 mg, 0.115 mmol). After the reaction was stirred at room temperature for 2 h, the resulting mixture was purified by silica gel column to obtain the title compound (17.9 mg, yield: 84.6%) as a white solid. MS (ESI) m / z: 920.8 [M+H] + .

[1140] Example 278 3-(3-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperidin-4-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-205)

[1141] P-205 (82 mg, yield: 81.6%) was synthesized according to the similar procedure of preparing P-204. MS (ESI) m / z: 906.7 [M+H] + .

[1142] Example 279 3-(5-((1-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)methoxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione P-206)

[1143]

[1144] P-206 (32 mg, yield: 38.9%) was synthesized according to the similar procedure of preparing P-203. MS (ESI) m / z: 950.9 [M+H] + .

[1145] Example 280 3-(4-((4-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperazin-1-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-207)

[1146]

[1147] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-nitrobenzyl)amino)piperazine-1-carboxylate

[1148]

[1149] At room temperature, 2-fluoro-4-methyl-1-nitro-benzene (10 g, 64.46 mmol) was added to CCl 4 BPO (398.51 mg, 6.45 mmol) and NBS (12.62 g, 70.91 mmol) were added to the (100 mL) solution. The mixture was heated at 80 °C for 16 hours and then concentrated to give a crude product. 3 K was added to CN (150 mL) solution 2 CO 3(17.79 g, 128.93 mmol) and tert-butyl piperazine-1-carboxylate (12.01 g, 64.46 mmol). After stirring the mixture for 4 hours, it was concentrated and purified by silica gel chromatography (petroleum ether: EtOAc = 10:1 to 0:1) to obtain the title compound (5.8 g, 46.56 mmol, yield 72.22%) as a yellow oil. MS (ESI) m / z: 340.4 [M+H] + .

[1150] Step 2: Synthesis of tert-butyl 4-(3-(methylamino)-4-nitrobenzyl)piperazine-1-carboxylate

[1151]

[1152] TEA (19.08 g, 188.59 mmol) was added to a solution of tert-butyl 4-[(3-fluoro-4-nitrophenyl)methyl]piperazine-1-carboxylate (16 g, 47.15 mmol) and methylamine hydrochloride (4.77 g, 70.72 mmol) in EtOH (200 mL). After the resulting mixture was stirred at 80 ° C overnight, the reaction mixture was concentrated and purified by silica gel chromatography (petroleum ether: EtOAc = 10: 1 to 1: 1) to obtain the title compound (13 g, yield 78.69%). MS (ESI) m / z: 351.4 [M+H] + .

[1153] Step 3: Synthesis of tert-butyl 4-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazine-1-carboxylate

[1154]

[1155] To a solution of tert-butyl 4-[[3-(methylamino)-4-nitro-phenyl]methyl]piperazine-1-carboxylate (6.00 g, 17.12 mmol) in THF (150 mL) was added Pd / C (600.00 mg, 4.94 mmol). 2 The reaction mixture was stirred at room temperature for 16 h and then filtered. CDI (14.79 g, 102.74 mmol) was added to the filtrate, and the resulting mixture was stirred at room temperature for 8 hours, then concentrated and purified by silica gel chromatography (petroleum ether: EtOAc = 2:1 to 1:1) to obtain the title compound (5.5 g, yield 92.7%) as a white solid. MS (ESI) m / z: 347.5 [M+H] + .

[1156] Step 4: Synthesis of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazine-1-carboxylate

[1157]

[1158] At 0°C, NaH (431.36 mg, 11.26 mmol) was added to a solution of tert-butyl 4-[(3-methyl-2-oxo-1H-benzimidazol-5-yl)methyl]piperazine-1-carboxylate (3.00 g, 8.66 mmol) in DMF (100 mL). After the reaction mixture was stirred at 0°C for 0.5 h, 3-bromopiperidine-2,6-dione (1.33 g, 6.93 mmol) was added. The resulting mixture was slowly warmed to room temperature and stirred for 16 h. The reaction was concentrated and purified by silica gel chromatography (petroleum ether: EtOAc = 2: 1 to 0: 1) to give the title compound (280 mg, yield 7.1%). MS (ESI) m / z: 458.6 [M+H] + .

[1159] Step 5: Synthesis of 3-(3-methyl-2-oxo-5-(piperazin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[1160]

[1161] At room temperature, TFA (3 mL) was added to a solution of tert-butyl 4-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]piperazine-1-carboxylate (280 mg, 611.99 umol) in DCM (10 mL). After the reaction mixture was stirred at room temperature for 2 h, it was concentrated to give the title compound (300 mg, yield 99%), which was used directly in the next step without further purification. MS (ESI) m / z: 358.6 [M+H] + .

[1162] Step 6: Synthesis of tert-butyl 4-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methylpiperazin-1-yl)butanoate

[1163]

[1164] At room temperature, DIPEA (179.29 mg, 1.39 mmol), NaI (69.31 mg, 462.42 umol) and tert-butyl 4-bromobutyrate (77.38 mg, 346.82 umol) were added to a solution of 3-[3-methyl-2-oxo-5-(piperazine-1-ylmethyl)benzimidazol-1-yl]piperidine-2,6-dione (109 mg, 231.21 umol) in DMSO (10 mL). After the...

Claims

1. A divalent compound or a pharmaceutically acceptable salt thereof, characterized in that: The divalent compound is selected from the following group: 4-(3-(1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, i.e., P-187; 4-((2-(1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, i.e., P-188; 4-(4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, i.e., P-192; 4-(((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, i.e., P-193; 3-(7-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, i.e., P-194; 3-(4-(((5-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)pyridin-2-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, i.e., P-196; 3-(7-(((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)morpholin-2-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, i.e., P-198; 3-(4-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, i.e., P-200; 4-(3-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)butyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, i.e., P-201; 3-(4-((3-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, i.e., P-202; 3-(5-((1-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-211; 3-(5-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-212; 3-(5-(2-(1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-221; 3-(5-(2-(1-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-222; 3-(4-(3-(4-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperazin-1-yl)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-224; 3-(4-((1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-227; 3-(4-(2-(1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-228; 3-(4-((1-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-229; 3-(4-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-231; 3-(5-(3-(4-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropyl)piperazin-1-yl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-234; 5-((7-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-7-oxoheptyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide, i.e., P-240; 5-((5-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-5-oxoheptyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide, i.e., P-241; 5-((6-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide, i.e., P-242; 3-(5-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-243; 3-(5-(2-(1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-244; 4-(4-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, i.e., P-249; 3-(4-((1-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)propyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-250; 3-(4-((1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-251; 3-(4-(2-(1-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)ethyl)piperidin-4-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, i.e., P-252; 5-((4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-4-oxobutyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide, i.e., P-253; 5-((2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)amino)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide, i.e., P-254; and 5-(4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)quinoline-8-carboxamide, i.e., P-256.

2. A pharmaceutical composition comprising the divalent compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. Use of the divalent compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating CBP / P300-mediated cancer, wherein the CBP / P300-mediated cancer is prostate cancer.

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