Cyclic amp reaction element binding protein (CBP) and / or 300kda adenovirus e1a binding protein (P300) degrading compounds and methods of use

Abstract

The divalent compound compositions include one or more divalent compounds. The divalent compounds comprise a cyclic AMP reactive element binding protein (CBP) and / or a 300 kDa adenovirus EIA binding protein (P300) ligand (CBP / P300 ligand) that binds to a degradation tag. Methods of using the divalent compounds are to treat certain diseases in a subject in need thereof. Methods of identifying such divalent compounds are disclosed.

Description

[0001] This application is a divisional application of the invention patent application with the application date of February 25, 2020, application number 202080017498.6, and invention name “Cyclic AMP response element binding protein (CBP) and / or 300KDA adenovirus E1A binding protein (P300) degradation compounds and use methods”. Background of the Invention

[0002] The present invention relates to bivalent compounds (eg, bifunctional small molecule compounds), compositions containing one or more bivalent compounds, and methods of using the same for treating certain diseases in subjects in need thereof. The present invention also relates to methods for identifying such bivalent compounds. Summary of the Invention

[0003] 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.

[0004] 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.

[0005] In one embodiment, the CBP / P300 ligand is a CBP / P300 inhibitor or a portion of a CBP / P300 inhibitor.

[0006] In another embodiment, the CBP / P300 ligand is selected from the group consisting of 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, CPD 27, C646, A-485, naphthol-AS-E, MYBMIM, CCS1477, HBS1, OHM1, KCN1, ICG-001, YH249, YH250, and analogs thereof.

[0007] 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.

[0008] In other embodiments, the ubiquitin ligase is an E3 ligase.

[0009] 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.

[0010] 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.

[0011] In other embodiments, the CBP / P300 ligand is conjugated to the degradation tag via a linker moiety.

[0012] In other embodiments, the CBP / P300 ligand comprises a moiety of Formula 1:

[0013]

[0014] in,

[0015] The linker portion of the divalent compound is bound to R 2 ;

[0016] X 1 and X 3 Independently selected from: C and N, with the proviso 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;

[0017] X 2 Selected from: CR', O and NR', wherein

[0018] R' is selected from the group consisting of: H, optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclyl;

[0019] A is selected from: None, CR 4 R 5 , CO, O, S, SO, SO2 and NR 4,in

[0020] R 4 and R 5 independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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;

[0021] Ar and R 4 , Ar and R 5 , and / or R 4 and R 5 together with the atoms to which they are attached, form an optionally substituted 3-20 membered cycloalkyl or heterocyclyl ring;

[0022] 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, NO2, OR 6 SR 6 NR 6 R 7 , OCOR 6 、OCO2R 6 、OCONR 6 R 7 、COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 NR 8 CO2R 6 NR 8 COR 6 NR 8 C(O)NR 6 R 7 NR 8 SOR 6 NR 8 SO2R 6 NR 8 SO2NR 6 R7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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

[0023] R 6 、R 7 and R 8 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0024] R 6 and R 7 、R 6 and R 8 together with the atoms to which they are attached, form a 4-20 membered heterocyclyl ring;

[0025] R 1 Selected from: hydrogen, halogen, CN, NO2, OR 9 SR 9 NR 9 R 10 , OCOR 9 、OCO2R 9 、OCONR 9 R 10 、COR 9 、CO2R 9 、CONR 9 R 10 、SOR 9 、SO2R 9 、SO2NR 9 R 10 NR 11 CO2R 9 NR 11 COR 9 NR 11 C(O)NR 9 R 10 NR 11 SOR 9 NR 11SO2R 9 NR 11 SO2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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

[0026] R 9 、R 10 and R 11 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0027] 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;

[0028] R 2 The "linker" portion connected to the divalent compound and selected from: none, R ” O, R”S, R”NR 12 、R”OC(O),R”OC(O)O、R ” OCONR 12 ,R”C(O),R”C(O)O,R”CONR 12 ,R”S(O),R”S(O)2,R”SO2NR 12 、R”NR 13 C(O)O、R”NR 13 C(O), R ” NR 13 C(O)NR 12 、R”NR 13 S(O), R”NR 13 S(O)2、R”NR 13 S(O)2NR 12, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0029] R" is none or a divalent moiety selected from the following: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0030] R 12 and R 13 independently selected from: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0031] 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

[0032] R 3 Selected from: hydrogen, COR 14 、CO2R 14 、CONR 14 R 15 、SOR14 、SO2R 14 、SO2NR 14 R 15 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0033] R 14 and R 15 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0034] R 14 and R 15 Together with the atoms to which they are attached, they form a 4-20 membered heterocyclyl ring.

[0035] In another embodiment, X 1 is C; and X 2 and X 3 is N. Formula I is Formula 1A:

[0036]

[0037] in,

[0038] A, Ar, R 1 、R 2 and R 3 Same as in formula 1.

[0039] In another embodiment, A-Ar-R 1 For the A1 part:

[0040]

[0041] in,

[0042] A and R 1 Same as in formula 1.

[0043] X is selected from: CR"' and N, where

[0044] R'' and is selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, 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

[0045] 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 OCO2R 16 、R b OCONR 16 R 17 、R b COR 16 、R b CO2R 16 、R b CONR 16 R 17 、R b SOR 16 、R b SO2R 16 、R b SO2NR 16 R 17 、R b NR 18 CO2R 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 SO2R 16 、R b NR 18 SO2NR 16 R 17, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynyl, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0046] R b is none, or a divalent or trivalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0047] R 16 、R 17 and R 18 R is independently selected from: none, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 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;

[0048] In other embodiments, A is none.

[0049] 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:

[0050]

[0051] in,

[0052] R 1 Same as in formula 1.

[0053] In another embodiment, A is NR 4 ,in,

[0054] R 4is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0055] In another embodiment, A is NR 4 ; and A-Ar-R 1 For the formula A4, A5 or A6 part:

[0056]

[0057] in,

[0058] R 1 Same as in formula 1.

[0059] 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.

[0060] In another embodiment, R 1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.

[0061] In another embodiment, R 1 is selected from the group consisting of optionally substituted pyrazole and optionally substituted pyridinyl.

[0062] In another embodiment, R 2 is selected from the group consisting of an optionally substituted C1-C8 alkylene group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-8 membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group.

[0063] In another embodiment, R 3 Selected from: COR 14 and CONR 14 R 15 .

[0064] In another embodiment, R 3 Selected from: COMe and CONHMe.

[0065] In other embodiments, the CBP / P300 ligand comprises a moiety of Formula 2:

[0066]

[0067] in,

[0068] The linker portion of the divalent compound is bound to R 1 ;as well as

[0069] X 1 and X 3 Independently selected from: C and N, with the proviso 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;

[0070] X 2 Selected from: CR', O and NR', wherein

[0071] R' is selected from the group consisting of: H, optionally substituted C1-C8 alkyl, and optionally substituted 3-10 membered carbocyclic ring;

[0072] A is selected from: None, CR 4 R 5 , CO, O, S, SO, SO2 and NR 4 ,in

[0073] R 4 and R 5 independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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;

[0074] Ar and R 4 , Ar and R 5 , and / or R 4 and R 5 together with the atoms to which they are attached, form an optionally substituted 3-20 membered cycloalkyl ring or a 4-20 membered heterocyclyl ring;

[0075] 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, NO2, OR 6 SR 6 NR 6 R 7 , OCOR 6 、OCO2R 6、OCONR 6 R 7 、COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 NR 8 CO2R 6 NR 8 COR 6 NR 8 C(O)NR 6 R 7 NR 8 SOR 6 NR 8 SO2R 6 NR 8 SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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

[0076] R 6 、R 7 and R 8 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0077] R 6 and R 7 、R 6 and R 8 together with the atoms to which they are attached, form a 4-20 membered heterocyclyl ring; and

[0078] R 1 The "linker" portion connected to the divalent compound and selected from: none, R"O, R"S, R"NR 9,R”OC(O),R”OC(O)O,R”OCONR 9 ,R”C(O),R”C(O)O,R”CONR 9 ,R”S(O),R”S(O)2,R”SO2NR 9 、R”NR 10 C(O)O、R”NR 10 C(O), R”NR 10 C(O)NR 9 、R”NR 10 S(O), R”NR 10 S(O)2、R”NR 10 S(O)2NR 9 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0079] R" is none or a divalent moiety selected from the following: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0080] R 9 and R 10 independently selected from: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0081] R 9 and R 10 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

[0082] R 2 Selected from: hydrogen, halogen, CN, NO2, OR 11 SR 11 NR 11 R 12 , OCOR 11 、OCO2R 11 、OCONR 11 R 12 、COR 11 、CO2R 11 、CONR 11 R 12 、SOR 11 、SO2R 11 、SO2NR 11 R 12 NR 13 CO2R 11 NR 13 COR 11 NR 13 C(O)NR 11 R 12 NR 13 SOR 11 NR 13 SO2R 11 NR 13 SO2NR 11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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

[0083] R 11 、R 12 and R 13 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0084] R 11 and R 12 、R11 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

[0085] R 3 Selected from: hydrogen, COR 14 、CO2R 14 、CONR 14 R 15 、SOR 14 、SO2R 14 、SO2NR 14 R 15 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, wherein

[0086] R 14 and R 15 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, and optionally substituted 4-6 membered heterocyclyl, or

[0087] R 14 and R 15 Together with the atoms to which they are attached, they form a 4-6 membered heterocyclyl ring.

[0088] In another embodiment, X 1 is C; and X 2 and X 3 is N. Formula 2 is Formula 2A:

[0089]

[0090] in,

[0091] A, Ar, R 1 、R 2 and R 3 Same as in formula 2.

[0092] In another embodiment, A-Ar-R 1 For the formula B1 part:

[0093]

[0094] in,

[0095] * indicates the connection to the linker portion of the divalent compound;

[0096] A and R 1 Same as in formula 2;

[0097] X is selected from: CR"' and N, where

[0098] R'' and are selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 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

[0099] 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 OCO2R 16 、R b OCONR 16 R 17 、R b COR 16 、R b CO2R 16 、R b CONR 16 R 17 、R b SOR 16 、R b SO2R 16 、R b SO2NR 16 R 17 、R b NR 18 CO2R 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 SO2R 16 、R bNR 18 SO2NR 16 R 17 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0100] R b is none, or a divalent or trivalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0101] R 16 、R 17 and R 18 is independently selected from: none, a bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0102] 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.

[0103] In other embodiments, A is none.

[0104] 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:

[0105]

[0106] in,

[0107] * indicates the connection to the linker portion of the divalent compound; and

[0108] R1 Same as in formula 2.

[0109] In another embodiment, A is NR 4 ,in

[0110] R 4 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0111] In another embodiment, A is NR 4 ; and A-Ar-R 1 For the formula B4, B5 or B6 part:

[0112]

[0113] in,

[0114] * indicates the connection to the linker portion of the divalent compound; and

[0115] R 1 Same as in formula 2.

[0116] 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.

[0117] In another embodiment, R 1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.

[0118] In another embodiment, R 1 is selected from the group consisting of optionally substituted pyrazole and optionally substituted pyridinyl.

[0119] In another embodiment, R 2 is selected from the group consisting of an optionally substituted C1-C8 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-10 membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group.

[0120] In another embodiment, R 3 Selected from: COR 14 and CONR 14 R 15 .

[0121] In another embodiment, R 3Selected from: COMe and CONHMe.

[0122] In other embodiments, the CBP / P300 ligand is derived from any of the following:

[0123]

[0124] In other embodiments, the CBP / P300 ligand is derived from the following CBP / P300 inhibitors: C646, naphthol-AS-E, compounds 1-10, MYBMIM, CCS1477, ICG-001, YH249, YH250, HBS1, OHM1, and KCN1.

[0125] In another embodiment, the CBP / P300 ligand is selected from the group consisting of:

[0126]

[0127] In other embodiments, the degradation tag is a moiety selected from the group consisting of Formulas 5A, 5B, 5C, and 5D

[0128]

[0129] in,

[0130] V, W and X are each independently selected from CR 2 and N;

[0131] Y is selected from: CO, CR 3 R 4 、N=CR 3 and N = N;

[0132] Z is selected from: None, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 Alkyne, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; preferably, Z is selected from: none, CH2, CH=CH, C≡C, NH and O;

[0133] R 1 and R 2 independently selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl;

[0134] R 3 and R 4 R is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6-membered carbocyclyl, and optionally substituted 4 to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl; and

[0135] R 5 and R 6 R is independently selected from the group consisting of: none, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or 5 and R 6 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclic group or a 4-6 membered heterocyclic group.

[0136] In other embodiments, the degradation tag is a moiety selected from the group consisting of Formulas 5A, 5B, 5C, and 5D

[0137]

[0138] in,

[0139] V, W and X are independently selected from: CR 2 and N;

[0140] Y is selected from the group consisting of: CO, CH2 and N=N;

[0141] Z is selected from the group consisting of: CH2, NH and O; and

[0142] R 1 and R 2 Independently selected from the group consisting of: hydrogen, halogen, cyano, nitro and C1-C5 alkyl.

[0143] In other embodiments, the degradation tag is a moiety selected from the group consisting of Formula 5E, 5F, 5G, 5H, and 5I

[0144]

[0145] in,

[0146] U, V, W and X are independently selected from: CR 2 and N;

[0147] Y is selected from: CR 3 R 4 NR 3 and O; preferably, Y is selected from: CH2, NH, NCH3 and O;

[0148] Z is selected from: None, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 Alkyne, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; preferably, Z is selected from: none, CH2, CH=CH, C≡C, NH and O;

[0149] R 1 and R 2 independently selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl;

[0150] R 3 and R 4 R is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6-membered carbocyclyl, and optionally substituted 4 to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl; and

[0151] R 5 and R 6 R is independently selected from the group consisting of: none, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or 5 and R 6Together with the atoms to which they are attached, they form a 3-6 membered carbocyclic group or a 4-6 membered heterocyclic group.

[0152] In one embodiment, the degradation tag is a moiety selected from the group consisting of Formula 5J, 5K, 5L, 5M, 5N, 5O, 5P, and 5Q

[0153] in,

[0154]

[0155] U, V, W, Y, X, Z, R 1 and R 2 As defined in Formula 5E, 5F, 5G, 5H or 5I;

[0156] Y', Y" and Y'" are each independently selected from: CR 3 R 4 ;

[0157] X' is independently selected from: CR 2 and N;

[0158] R' is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl.

[0159] In one embodiment, the degradation tag is a moiety of formula 6A:

[0160]

[0161] in,

[0162] R 1 and R 2 Independently selected from: hydrogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 4-10 membered heterocyclyl.

[0163] R 3Selected from: hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O) (3-10 membered carbocyclyl), optionally substituted C(O) (4 -10 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted Substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2 and optionally substituted P(O)(OC1-C8 aryl)2.

[0164] In other embodiments, the degradation tags are moieties of formula 6B, 6C, and 6D:

[0165]

[0166] in,

[0167] R 1 and R 2 independently selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

[0168] R 3 Selected from: hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O) (3-10 membered carbocyclyl), optionally substituted C(O) (4 -10 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC1-C8 C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted optionally substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2 and optionally substituted P(O)(OC1-C8 aryl)2, and

[0169] R 4 Selected from: NR 7 R 8 、 optionally substituted C1-C8 alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0170] R 7is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkyl-CO, optionally substituted C1-C8 cycloalkyl-CO, optionally substituted C1-C8 cycloalkyl-C1-C8 alkyl-CO, optionally substituted 4-10 membered heterocyclyl-CO, optionally substituted 4-10 membered heterocyclyl-C1-C8 alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-C1-C8 alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-C1-C8 alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;

[0171] R 8 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, and optionally substituted C1-C8 cycloalkyl;

[0172] R 9 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 heterocycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 cycloalkoxy, halosubstituted C1-C8 alkyl, halosubstituted C1-C8 cycloalkyl, halosubstituted C1-C8 alkoxy, halosubstituted C1-C8 cycloalkoxy, and halosubstituted C1-C8 heterocycloalkyl;

[0173] X is selected from the group consisting of: CH and N; and

[0174] n is 0, 1, 2, 3 or 4;

[0175] R 6 is selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkoxy, and optionally substituted C1-C8 cycloalkoxy, optionally substituted C1-C8 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.

[0176] In another embodiment, the degradation tag is a moiety of formula 7A:

[0177]

[0178] in,

[0179] V, W, X and Z are each independently selected from CR 4 and N; and

[0180] R 1 、R 2 、R3 and R 4 Independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted 3-10 membered carbocyclyl and optionally substituted 4-10 membered heterocyclyl.

[0181] In another embodiment, the degradation tag is a moiety of formula 7B:

[0182]

[0183] in,

[0184] R 1 、R 2 and R 3 each independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl;

[0185] R 4 and R 5 Independently selected from: hydrogen, COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted aryl-C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0186] R 6 and R 7 are independently selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0187] R 6 and R 7 Together with the atoms to which they are attached, they form a 4-8 membered cycloalkyl ring or heterocyclyl ring.

[0188] In other embodiments, the degradation tag is a moiety of Formula 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, and 5I.

[0189] In additional embodiments, the degradation tag is a moiety of Formula 5A, 5B, 5C, 5D, 5E, and 5F.

[0190] In other embodiments, the degradation tag is derived from any of the following:

[0191]

[0192] In other embodiments, 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 and CRBN-11.

[0193] In other embodiments, the degradation tag is selected from the group consisting of:

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] 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, and 8BN, 8BO, 8BP, 8BQ, 8BR, 8BS, 8CB, 8CC, 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, 8 DY, 8DZ, 8EA, 8EB, 8EC, 8ED, 8EE, 8EF, 8EG, 8EH, 8EI, 8EJ, 8EK, 8EL, 8EM, 8EN, 8EO, 8EP, 8EO, 8GU, 8GV, 8GW, 8GX, 8GY, 8 GZ, 8HA, 8HB, 8HC, 8HD, 8HE, 8HF, 8HG, 8HH, 8HI, 8HJ, 8HK, 8HL, 8HM, 8HN, 8HO, 8HP, 8HQ, 8HR, 8HS, 8HT, 8HU, 8HV, 8HW, 8H X, 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, 8IX, 8IY, 8IZ, 8JA, 8JB, 8JC, 8JD, 8JE, 8JF, 8JG, 8JH, 8JI, 8JJ, 8JK, 8JL, 8JM, 8JN, 8JO, 8JP, 8JQ, 8JR, 8JS and 8JT.

[0201] In some embodiments, the connector portion is as shown in Formula 9:

[0202]

[0203] in,

[0204] A, W and B, at each occurrence, are independently selected from: none, or a divalent moiety selected from the following: R'-R", R'COR", R'CO2R", R'C(O)N(R 1)R”、R'C(S)N(R 1 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 1 )R”、R'N(R 1 )R”、R”N(R 1 )COR”、R'N(R 1 )CON(R 2 )R”、R'N(R 1 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0205] R' and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkyl) or a moiety comprising optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0206] R r Selected from: optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0207] R 1 and R 2 each independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0208] R' and R", R 1 and R 2 , R' and R 1 , R' and R 2 , R” and R 1 , R” and R 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

[0209] m is 0 to 15.

[0210] In another embodiment, W and m are as defined above; and A and B, at each occurrence, are each independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2)0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, -CO-NH, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 - and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0211] In another embodiment, R r Selected from: formulae C1a, C2a, C3a, C4a and C5a as defined hereinafter.

[0212] In another embodiment, R r Selected from: formulae C1, C2, C3, C4 and C5 as defined hereinafter.

[0213] In another embodiment, R r is selected from Group G, and Group G consists of:

[0214]

[0215]

[0216] In one embodiment, the linker portion is as shown in Formula 9A:

[0217]

[0218] in,

[0219] R 1 、R 2 、R 3 and R 4 , is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0220] R 1 and R 2 、R 3 and R 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;

[0221] A, W and B, at each occurrence, are independently selected from: none, or a divalent moiety selected from the following: R'-R", R'COR", R'CO2R", R'C(O)N(R 5 )R”、R'C(S)N(R 5 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 5 )R”、R'N(R 5 )R”、R'N(R 5 )COR”、R'N(R 5 )CON(R 6 )R”、R'N(R 5 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C13 spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0222] R' and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene) or a moiety comprising optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0223] R r Selected from: optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0224] R 5 and R 6each independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0225] R' and R", R 5 and R 6 , R' and R 5 , R' and R 6 , R” and R 5 , R” and R 6 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

[0226] m is 0 to 15;

[0227] n, at each occurrence, is 0 to 15; and

[0228] o is 0 to 15.

[0229] In another embodiment, A, W and B, at each occurrence, are each independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, -CO-NH, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3-、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 - and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0230] In another embodiment, R r Selected from: formulae C1a, C2a, C3a, C4a and C5a as defined hereinafter.

[0231] In another embodiment, R r Selected from: formulae C1, C2, C3, C4 and C5 as defined hereinafter.

[0232] In another embodiment, R r is selected from group R, and group R is defined as in Formula 9.

[0233] In one embodiment, the CBP / P300 ligand of the bivalent compound is bound to A in Formula 9A.

[0234] In other embodiments, A (when A is attached to a CBP / P300 ligand) is selected from the group consisting of: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 0-8 -NH-(CH2) 0-8 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2)0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -,in

[0235] R r is selected from Group R, and Group R is as defined in Formula 9; and

[0236] W and B are None.

[0237] In one embodiment, the linker portion is as shown in Formula 9A:

[0238] in,

[0239] R 1 、R 2 、R 3 and R 4 , at each occurrence, are independently selected from: hydrogen, optionally substituted C1-C8 alkyl (preferably, C1-C4 alkyl), or

[0240] R 1 and R 2 、R 3 and R 4 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl (preferably, a 3-5 membered cycloalkyl) ring or a 4-20 membered heterocyclyl ring.

[0241] A is as defined above; and W and B are none;

[0242] m is 0 to 15 (preferably, m is 0, 1 or 2);

[0243] n, at each occurrence, is from 1 to 15 (preferably, n is 1); and

[0244] o is 1 to 15 (preferably, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13).

[0245] In other embodiments, A is independently selected from: none, or a divalent moiety selected from: R'-R", R'COR", R'CO2R", R'C(O)N(R 5 )R”、R'C(S)N(R 5 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 5 )R”、R'N(R 5 )R”、R'N(R 5 )COR”、R'N(R 5 )CON(R 6 )R”、R'N(R 5 )C(S)R”; R′ and R” are as defined above.

[0246] In other embodiments, R' and R" are independently selected from: none, optionally (C1-C8 alkyl)-R r (Preferably, CH2-R r ), or an optionally substituted C1-C8 alkyl group (preferably, an optionally substituted C1-C2 alkyl group).

[0247] In another embodiment, the linker portion is as shown in Formula 9B:

[0248]

[0249] in,

[0250] R 1 and R 2 , is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, C1-C8 alkylaminoC1-C8 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, or

[0251] R 1 and R 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;

[0252] A and B, at each occurrence, are independently selected from: none, or a divalent moiety selected from the following: R'-R", R'COR", R'CO2R", R'C(O)N(R 3)R”、R'C(S)N(R 3 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 3 )R”、R'N(R 3 )R”、R'N(R 3 )COR”、R'N(R 3 )CON(R 4 )R”、R'N(R 3 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0253] R' and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene) or a moiety comprising optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0254] R r Selected from: optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0255] R 3 and R 4 each independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0256] R' and R", R 3 and R 4 , R' and R 3 , R' and R 4 , R” and R 3 , R” and R 4 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

[0257] each m is 0 to 15; and

[0258] n is 0 to 15.

[0259] In another embodiment, A and B, at each occurrence, are each independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8-CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0260] In another embodiment, R r Selected from: formulae C1a, C2a, C3a, C4a and C5a as defined hereinafter.

[0261] In another embodiment, R r Selected from: formulae C1, C2, C3, C4 and C5 as defined hereinafter.

[0262] In another embodiment, R r is selected from group R, and group R is defined as in Formula 9.

[0263] In another embodiment, the linker portion is as shown in Formula 9C:

[0264]

[0265] in,

[0266] X is selected from O, NH and NR 7;

[0267] R 1 、R 2 、R 3 、R 4 、R 5 and R 6 , is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0268] A and B are independently selected from: none, or a divalent moiety selected from the following: R'-R", R'COR", R'CO2R", R'C(O)N(R 8 )R”、R'C(S)N(R 8 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 8 )R”、R'N(R 8 )R”、R'N(R 8 )COR”、R'N(R 8 )CON(R 9 )R”、R'N(R 8 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0269] R' and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-Rr (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene) or a moiety comprising optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0270] R r Selected from: optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0271] R 7 、R 8 and R 9independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0272] R' and R", R 8 and R 9 , R' and R 8 , R' and R 9 , R” and R 8 , R” and R 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;

[0273] m, at each occurrence, is 0 to 15;

[0274] n, at each occurrence, is 0 to 15;

[0275] o is 0 to 15; and

[0276] p is 0 to 15.

[0277] In another embodiment, A and B, at each occurrence, are each independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, -CO-NH, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3-R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 - and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0278] In another embodiment, R r Selected from: formulae C1a, C2a, C3a, C4a and C5a as defined hereinafter.

[0279] In another embodiment, R r Selected from: formulae C1, C2, C3, C4 and C5 as defined hereinafter.

[0280] In another embodiment, R r is selected from group R, and group R is defined as in Formula 9.

[0281] In another embodiment, A and B, at each occurrence, are each independently selected from: none, CO, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2.

[0282] In another embodiment, o is 0-5.

[0283] 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.

[0284] In another embodiment, the linker moiety degradation tag comprises one or more rings selected from the group consisting of formula C1a, C2a, C3a, C4a, and C5a.

[0285]

[0286] in,

[0287] X' and Y' are independently selected from: N, CR b ;

[0288] A 1 、B 1 、C 1 and D 1 , at each occurrence, is independently selected from: none, O, CO, SO, SO2, NR b , CR b R c ;

[0289] A 2 、B 2 、C 2 and D 2 , at each occurrence, is independently selected from: N, CR b ;

[0290] A 3 、B 3 、C 3 、D 3 and E 3 , at each occurrence, is independently selected from: N, O, S, NR b , CR b ;

[0291] R b and R c , is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0292] m 1 、n 1 、o 1 and p 1 Independently selected from: 0, 1, 2, 3, 4 and 5.

[0293] In another embodiment, the linker moiety degradation tag comprises one or more rings selected from the group consisting of formula C1, C2, C3, C4, and C5.

[0294]

[0295] In another embodiment, the linker portion is as shown in Formula 9A.

[0296] In another embodiment, A, W and B, at each occurrence, are independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 - and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -;

[0297] In another embodiment, R r Selected from: formula C1a, C2a, C3a, C4a and C5a as defined above.

[0298] In another embodiment, R r Selected from: formula C1, C2, C3, C4 and C5 as defined above.

[0299] In another embodiment, R r is selected from group R, and group R is defined as in Formula 9.

[0300] In another embodiment, in Formula 9A, A and B are independently as defined above, and W is none.

[0301] In other embodiments, the linker is 0 to 40 chain atoms in length.

[0302] In other embodiments, the linker is 3 to 20 chain atoms in length.

[0303] In other embodiments, the linker is 5 to 15 chain atoms in length.

[0304] In other embodiments, when the CBP / P300 ligand of the bivalent compound is attached to A, A is selected from: -(CO)-, -(CH2) 1-2 (CO)-NH-, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 ,in

[0305] R r is selected from group R, and group R is defined as in Formula 9.

[0306] In another embodiment, the linker is -(CO)-(CH2) 3-7 -.

[0307] In another embodiment, the linker is -(CH2) 1-2 (CO)-NH-(CH2) 3-7 -.

[0308] In another embodiment, the linker is -(CH2) 0-11 -or-(CH2) 0-3 -CO-(CH2) 0-10 -.

[0309] In another embodiment, the linker is -(CH2) 0-3 -R r -(CH2) 0-3 -or-(CH2) 0-3 -(CO)-(CH2) 0-3-R r -(CH2) 0-3 -, where R r is selected from group R, and group R is defined as in Formula 9.

[0310] In some embodiments, the bivalent compound is selected from the group consisting of P-001 to P-141 and CPD-1139 to CPD-1179, or a pharmaceutically acceptable salt or analog thereof.

[0311] In some embodiments, the divalent compound is selected from the group consisting of P-004, P-005, P-006, P-007, P-015, P-020, P-026, P-027, P-033, P-034, P-035, P-036, P-041, P-043, P-085, P-088, P-090, P-091, P-093, P-096, P-097, P-100, P-104, P-106, P-109, P-110, P-111, P-112, P-113, P-115, P-116, P-119, P-120, P-129, P-130, P-131, P-133, P-135, P-142, P-143, P-146, P-147, P-148, P-149, P-151, P-153, P-155, P-157, P-159, P-160, P-161, P-162, P-163, P-164, P-166, P-173, P-174 and pharmaceutically acceptable salts thereof or their analogs.

[0312] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-004).

[0313] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-005).

[0314] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-006).

[0315] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-007).

[0316] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-015).

[0317] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-020).

[0318] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-(2-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-026).

[0319] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-(2-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-027).

[0320] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-033).

[0321] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-034).

[0322] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-035).

[0323] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-036).

[0324] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-041).

[0325] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-(2-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-043).

[0326] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-085).

[0327] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-088).

[0328] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-090).

[0329] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-091).

[0330] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-093).

[0331] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-096).

[0332] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-097).

[0333] In one embodiment, the divalent compound is 4-((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)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-100).

[0334] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)ethyl)piperidin-1-yl)acetyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-104).

[0335] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)heptanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-106).

[0336] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-109).

[0337] In one embodiment, the divalent compound is 3-(4-((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)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-110).

[0338] In one embodiment, the divalent compound is 3-(4-((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)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-111).

[0339] In one embodiment, the divalent compound is 4-((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)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-112).

[0340] In one embodiment, the divalent compound is 4-((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)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-113).

[0341] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-115).

[0342] In one embodiment, the divalent compound is 3-(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)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-116).

[0343] In one embodiment, the divalent compound is 5-((8-(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)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-119).

[0344] 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)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-120).

[0345] In one embodiment, the divalent compound is 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)heptanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-129).

[0346] In one embodiment, the divalent compound is 3-(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)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-130).

[0347] 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)-2-oxoethyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-131).

[0348] In one embodiment, the divalent compound is 2-(4-(1-(5-acetyl-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)-N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)acetamide (P-133).

[0349] In one embodiment, the divalent compound is 3-(3-(8-(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)-8-oxooctyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-135).

[0350] 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)-2-oxoethyl)morpholin-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-142).

[0351] In one embodiment, the divalent compound is 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)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-143).

[0352] 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)-4-oxobutyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-146).

[0353] 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)-2-oxoethyl)piperidin-4-yl)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-147).

[0354] In one embodiment, the divalent compound is 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)-3-oxopropyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-148).

[0355] 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)methyl)piperidin-1-yl)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-149).

[0356] In one embodiment, the divalent compound is 3-(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)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2,6-dione (P-151).

[0357] In one embodiment, the divalent compound is 3-(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)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2,6-dione (P-153).

[0358] In one embodiment, the divalent compound is 3-(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)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2,6-dione (P-155).

[0359] 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)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-157).

[0360] In one embodiment, the divalent compound is 3-(4-((8-(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)-8-oxooctyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-159).

[0361] In one embodiment, the divalent compound is 3-(4-((9-(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)-9-oxononyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-160).

[0362] In one embodiment, the divalent compound is 3-(5-((8-(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)-8-oxooctyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-161).

[0363] In one embodiment, the divalent compound is 3-(5-((9-(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)-9-oxononyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-162).

[0364] In one embodiment, the divalent compound is 3-(3-(9-(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)-9-oxononyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-163).

[0365] In one embodiment, the divalent compound is 3-(3-(10-(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)-10-oxodecanyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-164).

[0366] 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)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-166).

[0367] In one embodiment, the divalent compound is 3-(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)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-173).

[0368] 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)phenethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-174).

[0369] 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.

[0370] 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.

[0371] In one embodiment, the CBP / P300-mediated disease is caused by CBP / P300 expression, mutation, deletion or fusion.

[0372] In one embodiment, a subject suffering from a CBP / P300 mediated disease has elevated CBP / P300 function relative to a healthy subject not suffering from the CBP / P300 mediated disease.

[0373] In one embodiment, the divalent compound is selected from the group consisting of P-001 to P-174 and CPD-1139 to CPD-1179, or an analog thereof.

[0374] In one embodiment, the bivalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

[0375] 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.

[0376] In one embodiment, the additional treatment regimen is selected from surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.

[0377] 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, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative change), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, 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 tumors, 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, 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.

[0378] 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.

[0379] 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 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, diabetes mellitus, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

[0380] In one embodiment, the CBP / P300-mediated disease is recurrent cancer.

[0381] In one embodiment, the CBP / P300-mediated disease is refractory to one or more prior therapies.

[0382] According to one aspect of the present invention, a method for identifying a bivalent compound that mediates the degradation or reduction of CBP / P300 is disclosed. The method comprises:

[0383] providing a heterobifunctional test compound comprising a CBP / P300 ligand conjugated to a degradation tag via a linker;

[0384] contacting the heterobifunctional test compound with cells containing a ubiquitin ligase and CBP / P300;

[0385] determining whether CBP / P300 levels in the cells are reduced; and

[0386] Heterobifunctional test compounds that mediate degradation or reduction of CBP / P300 are identified as bivalent compounds.

[0387] In one embodiment, the cell is a cancer cell.

[0388] In one embodiment, the cancer cell is a CBP / P300-dependent cancer cell.

[0389] Incorporation by reference

[0390] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0391] The novel features of the present invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention may be gained by reference to the following detailed description which sets forth an illustrative embodiment in which the principles of the invention are utilized, and the accompanying drawings which illustrate:

[0392] 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.

[0393] 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.

[0394] Figure 3 Shown are immunoblots 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.

[0395] Figure 4 Shown is a graph of LNCaP cell viability versus GNE-781, P-001, P-002, and P-019 concentrations.

[0396] Figure 5 Shown are immunoblots of P300 and CBP proteins expressed by LNCaP cells after treatment 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.

[0397] Figure 6 Shown are immunoblots of P300 protein expressed by LNCaP cells after treatment with the indicated concentrations of P-084 to P-093, P-096, P-097, P-100, P-102, or P-104 to P-108.

[0398] Figure 7 A shows immunoblot of P300 protein expressed in LNCaP cells after treatment with the indicated concentrations of heterobifunctional compound P-034 or P-034-neg.

[0399] Figure 7 B shows immunoblot of P300 protein expressed in 22RV1 cells after treatment with the indicated concentrations of heterobifunctional compound P-034 or P-034-negative.

[0400] 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.

[0401] Figure 9 Shown are immunoblots for P300 and CBP protein expression 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).

[0402] Figure 10 Shown are the changes in LNCaP cells ( Figure 10 AB) or 22RV1 cells ( Figure 10 CE) Immunoblotting of expressed P300 and CBP proteins.

[0403] Figure 11 Shown are the changes in LNCaP cells ( Figure 11 BE) or 22RV1 cells ( Figure 11 A) Immunoblotting of expressed P300 and CBP proteins.

[0404] Figure 12 Shown are immunoblots of CBP protein expressed in lung tissue of ICR mice following treatment with a single dose of 40 mg / kg of the indicated heterobifunctional compounds by oral gavage (po). Detailed Description of the Invention

[0405] Post-translational modifications of proteins, such as phosphorylation, acetylation, methylation, and ubiquitination, contribute significantly to protein diversity and regulation. P300 (encoded by EP300) and the closely related CBP (encoded by CREBBP) are two extensively studied lysine acetyltransferases (HATs) that catalyze the transfer of acetyl groups to lysine residues on proteins. The most well-characterized substrates of P300 and CBP are histones. Histone acetylation regulates chromatin conformation and often leads to transcriptional activation. Recruitment of P300 and / or CBP is crucial for many transcription factors and other transcriptional regulators to effectively promote regional transcription (Dancy and Cole, 2015). P300 and CBP substrates also include numerous 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 numerous signaling pathways (Bedford et al., 2010). By regulating the acetylation of multiple substrates and ligating various binding partners, P300 and CBP are widely involved in biological processes such as cell proliferation, differentiation, development, DNA repair, inflammation, metabolism and memory.

[0406] 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 linked to a variety of human diseases. Germline mutations that inactivate one of the CREBBP alleles cause Rubinstein-Taybi syndrome (Petrij et al., 1995), likely due to impaired activation of Hedgehog family transcription factors. Both P300 and CBP are known to promote hematopoiesis through interactions with hematopoietic transcription factors such as GATA-1 (Blobel, 2000). The tumor suppressor role of P300 and CBP is well 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 distinct 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). Fusions of CBP and, less commonly, P300 with MLL have also been found in chemoresistant leukemias (Sobulo et al., 1997). Accumulating evidence indicates that most oncogenic transcription factors, such as MYC (Faiola et al., 2005; Vervoorts et al., 2003), NF-κB (VandenBerghe 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. Furthermore, P300 has been reported to regulate immune cell function (Liu et al., 2013). Furthermore, 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 could be used to modulate immune system activity and crosstalk between immune cells and cancer cells (Liu et al., 2013). Finally, there is a well-documented association between histone acetylation and neurodegenerative diseases (Saha and Pahan, 2006; Valor et al., 2013).In summary, the development of novel therapeutics targeting P300 and CBP represents new opportunities for the treatment of cancer, inflammatory diseases, neurological indications, and other indications.

[0407] P300 and CBP share nearly 75% similarity and 63% identity in their protein sequences. Even greater homology is found in functional domains that are highly conserved throughout 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 less amenable to 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 have been found to interfere with the TAZ1 / HIF-1α protein interaction. ICG-001 (Emami et al., 2004) has been reported to be a selective inhibitor of the CBP NRID / β-catenin interaction. Furthermore, YH249 and YH250 (Yusuke et al., 2016) have been 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 bromodomain. The HAT domain catalyzes the transfer of acetyl groups, while the bromodomain binds to 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 11 (Denny et al., 2017), CPD 41 (Denny et al., 2017), CPD30 (Lai et al., 2018), CPD 5 (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 the CBP HAT domain-targeting P300 / CBP inhibitors, C646 (Oike et al., 2014) and A-485 (Lasko et al., 2017), have been reported. 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, the use of these small-molecule inhibitors to modulate the activities of P300 and CBP presents several significant caveats. First, P300 and CBP possess multiple functional domains. Blockade of the HAT domain or bromodomain results in only partial inhibition of their activity. These small-molecule inhibitors are unable to effectively modulate the scaffolding functions of P300 and CBP. Second, the HAT domain and bromodomain of P300 and CBP share significant homology, making most small-molecule compounds unable to effectively distinguish between these two targets. Instead, P300 and CBP exhibit distinct tissue-type-dependent effects.For example, in prostate cancer, P300 is the primary coactivator of the androgen receptor, while CBP has a limited effect (Ianculescu et al., 2012). Therefore, simultaneous targeting of P300 and CBP is not always necessary and may result in more significant side effects than selectively targeting one of them. Furthermore, many P300 / CBP inhibitors have unclear off-target effects. To improve the selectivity and activity of anti-P300 / CBP therapies, approaches that selectively degrade the target protein are expected to have substantial advantages.

[0408] 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 that degrade CBP / P300, CBP / P300 fusion proteins, and / or CBP / P300 muteins (“Proteolysis Targeting Chimeras” / “PROTACs” and “Specific and Non-Inheritable IAP-Dependent Protein Erasers” / “SNIPERs”) 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).

[0409] 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 in which one part binds to the E3 ubiquitin ligase and the other part binds 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); and (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 the degradation of various 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). Furthermore, a hydrophobic tagging approach utilizing bulky and hydrophobic adamantyl groups 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.

[0410] 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 (Utta rkar 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).

[0411] In the present disclosure, a new approach is adopted: developing compounds that not only directly and selectively regulate the protein-protein interaction and acetyltransferase activity of CBP / P300, but also regulate their protein levels. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, simulating protein misfolding with hydrophobic tags, and inhibiting molecular chaperones. 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 for more flexible regulation of protein levels in vitro and in vivo. Unlike 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.

[0412] Divalent compounds

[0413] In some aspects, the present disclosure provides bivalent compounds comprising a CBP / P300 ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof. The CBP / P300 ligand can be bound to the degradation tag directly or through a linker moiety. In certain embodiments, the CBP / P300 ligand can be bound to the degradation tag directly. In certain embodiments, the CBP / P300 ligand can be bound to the degradation tag through a linker moiety.

[0414] 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 encompassing any molecule ranging from small molecules to large proteins that associates 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 (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.

[0415] CBP / P300 ligand

[0416] 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., 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), and analogs thereof), which 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.

[0417] In certain embodiments, the CBP / P300 ligand is derived from a CBP / P300 inhibitor comprising:

[0418]

[0419] 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 (Ut Tarkar 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).

[0420] In other embodiments, the CBP / P300 ligand comprises a moiety of Formula 1:

[0421]

[0422] in,

[0423] The linker portion of the divalent compound is bound to R 2 ;

[0424] X 1 and X 3 Independently selected from: C and N, with the proviso 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;

[0425] X 2 Selected from: CR', O and NR', wherein

[0426] R' is selected from the group consisting of: H, optionally substituted C1-C8 alkyl, and optionally substituted 3-10 membered carbocyclic ring;

[0427] A is selected from: None, CR 4 R 5 , CO, O, S, SO, SO2 and NR 4 ,in

[0428] R 4 and R 5 each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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;

[0429] Ar and R 4 , Ar and R 5 , and / or R 4 and R 5 together with the atoms to which they are attached, form an optionally substituted 3-20 membered cycloalkyl or heterocyclyl ring;

[0430] 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, NO2, OR 6 SR 6 NR 6 R 7 , OCOR 6 、OCO2R 6 、OCONR 6 R 7 、COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 NR 8 CO2R 6 NR 8 COR 6 NR 8 C(O)NR 6 R 7 NR 8 SOR 6 NR 8 SO2R 6 NR 8 SO2NR 6 R 7, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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

[0431] R 6 、R 7 and R 8 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0432] 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;

[0433] R 1 Selected from: hydrogen, halogen, CN, NO2, OR 9 SR 9 NR 9 R 10 , OCOR 9 、OCO2R 9 、OCONR 9 R 10 、COR 9 、CO2R 9 、CONR 9 R 10 、SOR 9 、SO2R 9 、SO2NR 9 R 10 NR 11 CO2R 9 NR 11 COR 9 NR 11 C(O)NR 9 R 10 NR 11 SOR 9 NR 11 SO2R9 NR 11 SO2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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

[0434] R 9 、R 10 and R 11 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0435] 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;

[0436] R 2 The "linker" portion connected to the divalent compound and selected from: none, R"O, R"S, R"NR 12 ,R”OC(O),R”OC(O)O,R”OCONR 12 ,R”C(O),R”C(O)O,R”CONR 12 ,R”S(O),R”S(O)2,R”SO2NR 12 、R”NR 13 C(O)O、R”NR 13 C(O), R”NR 13 C(O)NR 12 、R”NR 13 S(O), R”NR 13 S(O)2、R”NR 13 S(O)2NR 12, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0437] R" is none or a divalent moiety selected from the following: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0438] R 12 and R 13 each independently selected from: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0439] 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

[0440] R 3 Selected from: hydrogen, COR 14 、CO2R 14 、CONR 14 R 15、SOR 14 、SO2R 14 、SO2NR 14 R 15 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0441] R 14 and R 15 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0442] R 14 and R 15 Together with the atoms to which they are attached, they form a 4-20 membered heterocyclyl ring.

[0443] In another embodiment, X 1 is C; and X 2 and X 3 is N. Formula I is Formula 1A:

[0444]

[0445] in,

[0446] A, Ar, R 1 、R 2 and R 3 Same as in formula 1.

[0447] In another embodiment, A-Ar-R 1 For the A1 part:

[0448]

[0449] in,

[0450] A and R 1 Same as in formula 1.

[0451] X is selected from: CR"' and N, where

[0452] R'' and is selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, 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

[0453] 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 OCO2R 16 、R b OCONR 16 R 17 、R b COR 16 、R b CO2R 16 、R b CONR 16 R 17 、R b SOR 16 、R b SO2R 16 、R b SO2NR 16 R 17 、R b NR 18 CO2R 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 SO2R 16 、R b NR 18 SO2NR 16 R 17, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynyl, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0454] R b is none, or a divalent or trivalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0455] R 16 、R 17 and R 18 R is independently selected from: none, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 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;

[0456] In other embodiments, A is none.

[0457] 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:

[0458]

[0459] in,

[0460] R 1 Same as in formula 1.

[0461] In another embodiment, A is NR 4 ,in

[0462] R 4is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0463] In another embodiment, A is NR 4 ; and A-Ar-R 1 For the formula A4, A5 or A6 part:

[0464]

[0465] in,

[0466] R 1 Same as in formula 1.

[0467] 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.

[0468] In another embodiment, R 1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.

[0469] In another embodiment, R 1 is selected from the group consisting of optionally substituted pyrazole and optionally substituted pyridinyl.

[0470] In another embodiment, R 2 is selected from the group consisting of an optionally substituted C1-C8 alkylene group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-8 membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group.

[0471] In another embodiment, R 3 Selected from: COR 14 and CONR 14 R 15 .

[0472] In another embodiment, R 3 Selected from: COMe and CONHMe.

[0473] In other embodiments, the CBP / P300 ligand comprises a moiety of Formula 2:

[0474]

[0475] in,

[0476] The linker portion of the divalent compound is bound to R 1 ;as well as

[0477] X 1 and X 3 Independently selected from: C and N, with the proviso 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;

[0478] X 2 Selected from: CR', O and NR', wherein

[0479] R' is selected from the group consisting of: H, optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclyl;

[0480] A is selected from: None, CR 4 R 5 , CO, O, S, SO, SO2 and NR 4 ,in

[0481] R 4 and R 5 independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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;

[0482] 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 ring or a 4-20 membered heterocyclyl ring;

[0483] 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, NO2, OR 6 SR 6 NR 6 R 7 , OCOR 6 、OCO2R 6、OCONR 6 R 7 、COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 NR 8 CO2R 6 NR 8 COR 6 NR 8 C(O)NR 6 R 7 NR 8 SOR 6 NR 8 SO2R 6 NR 8 SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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

[0484] R 6 、R 7 and R 8 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0485] 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

[0486] R 1 The "linker" portion connected to the divalent compound and selected from: none, R"O, R"S, R"NR 9,R”OC(O),R”OC(O)O,R”OCONR 9 ,R”C(O),R”C(O)O,R”CONR 9 ,R”S(O),R”S(O)2,R”SO2NR 9 、R”NR 10 C(O)O、R”NR 10 C(O), R”NR 10 C(O)NR 9 、R”NR 10 S(O), R”NR 10 S(O)2、R”NR 10 S(O)2NR 9 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein,

[0487] R" is none or a divalent moiety selected from the following: optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0488] R 9 and R 10 independently selected from: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0489] R 9 and R 10 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

[0490] R 2 Selected from: hydrogen, halogen, CN, NO2, OR 11 SR 11 NR 11 R 12 , OCOR 11 、OCO2R 11 、OCONR 11 R 12 、COR 11 、CO2R 11 、CONR 11 R 12 、SOR 11 、SO2R 11 、SO2NR 11 R 12 NR 13 CO2R 11 NR 13 COR 11 NR 13 C(O)NR 11 R 12 NR 13 SOR 11 NR 13 SO2R 11 NR 13 SO2NR 11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 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

[0491] R 11 、R 12 and R 13 is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0492] R 11 and R 12 、R11 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

[0493] R 3 Selected from: hydrogen, COR 14 、CO2R 14 、CONR 14 R 15 、SOR 14 、SO2R 14 、SO2NR 14 R 15 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, wherein

[0494] R 14 and R 15 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl and optionally substituted 4-6 membered heterocyclyl, or

[0495] R 14 and R 15 Together with the atoms to which they are attached, they form a 4-6 membered heterocyclyl ring.

[0496] In another embodiment, X 1 is C; and X 2 and X 3 is N. Formula 2 is Formula 2A:

[0497]

[0498] in,

[0499] A, Ar, R 1 、R 2 and R 3 Same as in formula 2.

[0500] In another embodiment, A-Ar-R 1 For the formula B1 part:

[0501]

[0502] in,

[0503] * indicates the connection to the linker portion of the divalent compound;

[0504] A and R 1 Same as in formula 2;

[0505] X is selected from: CR"' and N, where

[0506] R'' and are selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, 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

[0507] 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 OCO2R 16 、R b OCONR 16 R 17 、R b COR 16 、R b CO2R 16 、R b CONR 16 R 17 、R b SOR 16 、R b SO2R 16 、R b SO2NR 16 R 17 、R b NR 18 CO2R 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 SO2R 16 、R b NR18 SO2NR 16 R 17 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynyl, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

[0508] R b is none, or a divalent or trivalent moiety selected from optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0509] R 16 、R 17 and R 18 is independently selected from: none, a bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0510] 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.

[0511] In other embodiments, A is none.

[0512] 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:

[0513]

[0514] in,

[0515] * indicates the connection to the linker portion of the divalent compound; and

[0516] R 1Same as in formula 2.

[0517] In another embodiment, A is NR 4 ,in

[0518] R 4 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

[0519] In another embodiment, A is NR 4 ; and A-Ar-R 1 For the formula B4, B5 or B6 part:

[0520]

[0521] in,

[0522] * indicates the connection to the linker portion of the divalent compound; and

[0523] R 1 Same as in formula 2.

[0524] 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.

[0525] In another embodiment, R 1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.

[0526] In another embodiment, R 1 is selected from the group consisting of optionally substituted pyrazole and optionally substituted pyridinyl.

[0527] In another embodiment, R 2 is selected from the group consisting of an optionally substituted C1-C8 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-10 membered heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group.

[0528] In another embodiment, R 3 Selected from: COR 14 and CONR 14 R 15 .

[0529] In another embodiment, R 3 Selected from: COMe and CONHMe.

[0530] In other embodiments, the CBP / P300 ligand is derived from any of the following:

[0531]

[0532] In other embodiments, the CBP / P300 ligand is derived from the following CBP / P300 inhibitors: C646, naphthol-AS-E, compounds 1-10, MYBMIM, CCS1477, ICG-001, YH249, YH250, HBS1, OHM1, and KCN1.

[0533] In another embodiment, the CBP / P300 ligand is selected from the group consisting of:

[0534]

[0535] Degradable labels

[0536] 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.

[0537] In some embodiments, the degradation tag is a moiety selected from the group consisting of Formulas 5A, 5B, 5C, and 5D:

[0538]

[0539] in,

[0540] V, W and X are each independently selected from: CR 2 and N;

[0541] Y is selected from: CO, CR 3 R 4 、N=CR 3 and N = N;

[0542] Z is selected from: None, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 Alkyne, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; preferably, Z is selected from: none, CH2, CH=CH, C≡C, NH and O;

[0543] R 1 and R 2 independently selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl;

[0544] R 3 and R 4 R is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6-membered carbocyclyl, and optionally substituted 4 to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl; and

[0545] R 5 and R 6 R is independently selected from the group consisting of: none, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or 5 and R 6 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclic group or a 4-6 membered heterocyclic group.

[0546] In some embodiments, the degradation tag is a moiety selected from the group consisting of Formulas 5A, 5B, 5C, and 5D:

[0547]

[0548] in,

[0549] V, W and X are independently selected from: CR 2 and N;

[0550] Y is selected from the group consisting of: CO, CH2 and N=N;

[0551] Z is selected from the group consisting of: CH2, NH and O; and

[0552] R 1 and R 2 Independently selected from the group consisting of: hydrogen, halogen, cyano, nitro and C1-C5 alkyl.

[0553] In some embodiments, the degradation tag is a moiety selected from the group consisting of Formula 5J, 5K, 5L, 5M, 5N, 5O, 5P, and 5Q:

[0554]

[0555]

[0556] in,

[0557] U, V, W, X and X' are independently selected from: CR 2 and N;

[0558] Y is selected from: CR 3 R 4 NR 3 and O; preferably, Y is selected from: CH2, NH, NCH3 and O;

[0559] Y', Y" and Y'" are each independently selected from: CR 3 R 4 ;

[0560] Z is selected from: None, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 Alkyne, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from: none, CH2, CH=CH, C≡C, NH and O;

[0561] R 1 and R 2 independently selected from the group consisting of hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl;

[0562] R 3 and R 4R is independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6-membered carbocyclyl, and optionally substituted 4 to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl; and

[0563] R 5 and R 6 R is independently selected from the group consisting of: none, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; or 5 and R 6 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl; and

[0564] R' is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl.

[0565] In one embodiment, the degradation tag is a moiety of formula 6A:

[0566]

[0567] in,

[0568] R 1 and R 2 independently selected from: hydrogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl; optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 4-10 membered heterocyclyl; and

[0569] R 3Selected from: hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O) (3-10 membered carbocyclyl), optionally substituted C(O) (4 -10 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted Substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC1-C8 aryl)2.

[0570] In some embodiments, the degradation tag is a moiety of Formula 6B, 6C, and 6D:

[0571]

[0572] in,

[0573] R 1 and R 2 Independently selected from: hydrogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl; optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 4-10 membered heterocyclyl;

[0574] R 3 Selected from: hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O) (3-10 membered carbocyclyl), optionally substituted C(O) (4 -10 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC1-C8 (O)O (3-10 membered carbocyclyl), optionally substituted C(O)O (4-10 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC1-C8 aryl)2, and

[0575] R 4 Selected from: NR 7 R 8 、 optionally substituted C1-C8 alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0576] R 7is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkyl-CO, optionally substituted C1-C8 cycloalkyl-CO, optionally substituted C1-C8 cycloalkyl-C1-C8 alkyl-CO, optionally substituted 4-10 membered heterocyclyl-CO, optionally substituted 4-10 membered heterocyclyl-C1-C8 alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-C1-C8 alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-C1-C8 alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;

[0577] R 8 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, and optionally substituted C1-C8 cycloalkyl;

[0578] R 9 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 heterocycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 cycloalkoxy, halosubstituted C1-C8 alkyl, halosubstituted C1-C8 cycloalkyl, halosubstituted C1-C8 alkoxy, halosubstituted C1-C8 cycloalkoxy, and halosubstituted C1-C8 heterocycloalkyl;

[0579] X is selected from the group consisting of: CH and N; and

[0580] n is 0, 1, 2, 3 or 4;

[0581] R 6 is selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkoxy, and optionally substituted C1-C8 cycloalkoxy, optionally substituted C1-C8 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.

[0582] In another embodiment, the degradation tag is a moiety of formula 7A:

[0583]

[0584] in,

[0585] V, W, X and Z are independently selected from: CR 4 and N; and

[0586] R 1 、R 2 、R3 and R 4 Independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 4-10 membered heterocyclyl.

[0587] In another embodiment, the degradation tag is a moiety of formula 7B:

[0588]

[0589] in,

[0590] R 1 、R 2 and R 3 each independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl;

[0591] R 4 and R 5 Independently selected from: hydrogen, COR 6 、CO2R 6 、CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted aryl-C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0592] R 6 and R 7independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or

[0593] R 6 and R 7 Together with the atoms to which they are attached, they form a 4-8 membered cycloalkyl ring or heterocyclyl ring.

[0594] In other embodiments, the degradation tag is a moiety of Formula 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, and 5I.

[0595] In additional embodiments, the degradation tag is a moiety of Formula 5A, 5B, 5C, 5D, 5E, and 5F.

[0596] In other embodiments, the degradation tag is derived from any of the following:

[0597]

[0598]

[0599] In other embodiments, 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 and CRBN-11.

[0600] In other embodiments, the degradation tag is selected from the group consisting of:

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607] 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, and 8BN, 8BO, 8BP, 8BQ, 8BR, 8BS, 8CB, 8CC, 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, 8 DY, 8DZ, 8EA, 8EB, 8EC, 8ED, 8EE, 8EF, 8EG, 8EH, 8EI, 8EJ, 8EK, 8EL, 8EM, 8EN, 8EO, 8EP, 8EO, 8GU, 8GV, 8GW, 8GX, 8GY, 8 GZ, 8HA, 8HB, 8HC, 8HD, 8HE, 8HF, 8HG, 8HH, 8HI, 8HJ, 8HK, 8HL, 8HM, 8HN, 8HO, 8HP, 8HQ, 8HR, 8HS, 8HT, 8HU, 8HV, 8HW, 8H X, 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, 8IX, 8IY, 8IZ, 8JA, 8JB, 8JC, 8JD, 8JE, 8JF, 8JG, 8JH, 8JI, 8JJ, 8JK, 8JL, 8JM, 8JN, 8JO, 8JP, 8JQ, 8JR, 8JS and 8JT.

[0608] Connector part

[0609] As used herein, a "linker" or "linker moiety" is a bond, molecule, or group of molecules that binds two separate entities to each other. The linker provides optimal spacing between the 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 attachment of a linker, provided that the linker, once attached 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).

[0610] The length of the linker 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 through the hydrophobic tag. In certain embodiments, the linker comprises an acyclic or cyclic saturated or unsaturated carbon, glycol, amide, ammonia, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic or carbonyl group. In some embodiments, the length of the linker 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.

[0611] In some embodiments, the connector portion is as shown in Formula 9:

[0612]

[0613] in,

[0614] A, W and B, at each occurrence, are independently selected from: none, or a divalent moiety selected from the following: R'-R", R'COR", R'CO2R", R'C(O)N(R 1 )R”、R'C(S)N(R 1 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 1 )R”、R'N(R 1 )R”、R'N(R 1 )COR”、R'N(R 1 )CON(R 2 )R”、R'N(R 1 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0615] R' and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene) or a moiety comprising optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0616] R r Selected from: optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0617] R 1 and R 2 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0618] R' and R", R 1 and R 2 , R' and R 1 , R' and R 2 , R” and R 1 , R” and R 2 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and

[0619] m is 0 to 15.

[0620] In another embodiment, W and m are as defined above; and A and B, at each occurrence, are independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, -CO-NH, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3-(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 -, and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0621] In another embodiment, W and m are as defined above; and A and B, at each occurrence, are independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 1-2 -NH-CO, (CH2) 1-2 -CO-NH, NH-CO-(CH2) 1-2 、CO-NH-(CH2) 1-2 、(CH2) 1-2 -NH-(CH2) 1-2 -CO-NH, (CH2) 1-2 -NH-(CH2) 1-2 -NH-CO, -CO-NH, CO-NH-(CH2) 1-2 -NH-(CH2) 1-2 、(CH2) 1-2 -NH-(CH2) 1-2 、-(CH2) 0-2 -R r -(CH2) 0-2 、-(CH2) 0-2 -(CO)-(CH2) 0-3 -R r -(CH2) 0-2 -、-(CH2) 0-2 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-2 -、-(CH2) 0-2 -(NH-CO)-(CH2) 0-3-R r -(CH2) 0-2 -、-(CH2) 0-2 -(NH)-(CH2) 0-3 -R r -(CH2) 0-2 -.

[0622] In another embodiment, R r Selected from: formulae C1a, C2a, C3a, C4a, C5a, C1, C2, C3, C4 and C5 as defined hereinafter.

[0623] In another embodiment, R r is selected from group R, and group R consists of:

[0624]

[0625] In one embodiment, the linker portion is as shown in Formula 9A:

[0626]

[0627] in,

[0628] R 1 、R 2 、R 3 and R 4 , is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

[0629] R 1 and R 2 、R 3 and R 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;

[0630] A, W and B, at each occurrence, are independently selected from: none, or a divalent moiety selected from the following: R'-R", R'COR", R'CO2R", R'C(O)N(R 5 )R”、R'C(S)N(R5 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 5 )R”、R'N(R 5 )R”、R'N(R 5 )COR”、R'N(R 5 )CON(R 6 )R”、R'N(R 5 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0631] R' and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene) or a moiety comprising optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0632] R r Selected from: optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0633] R 5 and R 6 each independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0634] R' and R", R 5 and R 6 , R' and R 5 , R' and R 6 , R” and R 5 , R” and R 6 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

[0635] m is 0 to 15;

[0636] n, at each occurrence, is 0 to 15; and

[0637] o is 0 to 15.

[0638] In another embodiment, A, W and B, at each occurrence, are independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2)0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, -CO-NH, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 - and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0639] In another embodiment, W and m are as defined above; and A and B, at each occurrence, are each independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 1-2 -NH-CO, (CH2) 1-2 -CO-NH, NH-CO-(CH2) 1-2 、CO-NH-(CH2) 1-2 、(CH2) 1-2 -NH-(CH2) 1-2 -CO-NH, (CH2) 1-2 -NH-(CH2) 1-2-NH-CO, -CO-NH, CO-NH-(CH2) 1-2 -NH-(CH2) 1-2 、(CH2) 1-2 -NH-(CH2) 1-2 、-(CH2) 0-2 -R r -(CH2) 0-2 、-(CH2) 0-2 -(CO)-(CH2) 0-3 -R r -(CH2) 0-2 -、-(CH2) 0-2 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-2 -、-(CH2) 0-2 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-2 -、-(CH2) 0-2 -(NH)-(CH2) 0-3 -R r -(CH2) 0-2 -.

[0640] In another embodiment, R r Selected from: formulae C1a, C2a, C3a, C4a, C5a, C1, C2, C3, C4 and C5 as defined hereinafter.

[0641] In another embodiment, R r is selected from group R, and group R is defined as in Formula 9.

[0642] In one embodiment, the CBP / P300 ligand of the bivalent compound is attached to A in Formula 9A.

[0643] In other embodiments, A (when A is bound to a CBP / P300 ligand) is selected from the group consisting of: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2)1-3 -NH-(CH2) 1-3 -NH-CO, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -,in

[0644] R r is selected from Group R, and Group R is as defined in Formula 9; and

[0645] W and B are None.

[0646] In one embodiment, the linker portion is as shown in Formula 9A:

[0647] in,

[0648] R 1 、R 2 、R 3 and R 4 , at each occurrence, is independently selected from: hydrogen, optionally substituted C1-C8 alkyl (preferably, C1-C4 alkyl), or

[0649] R 1 and R 2 、R 3 and R 4 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl (preferably, a 3-5 membered cycloalkyl) ring or a 4-20 membered heterocyclyl ring.

[0650] A is as defined above; and W and B are none;

[0651] m is 0 to 15 (preferably, m is 0, 1 or 2);

[0652] n, at each occurrence, is from 1 to 15 (preferably, n is 1); and

[0653] o is 1 to 15 (preferably, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13).

[0654] In other embodiments, A is independently selected from: none, or a divalent moiety selected from: R'-R", R'COR", R'CO2R", R'C(O)N(R 5 )R”、R'C(S)N(R 5 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 5 )R”、R'N(R 5 )R”、R'N(R 5 )COR”、R'N(R 5 )CON(R 6 )R”、R'N(R 5 )C(S)R”; R′ and R” are as defined above.

[0655] In other embodiments, R' and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), or an optionally substituted C1-C8 alkyl group (preferably, an optionally substituted C1-C2 alkyl group).

[0656] In another embodiment, the linker portion is as shown in Formula 9B:

[0657]

[0658] in,

[0659] R 1 and R 2 , is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, C1-C8 alkylaminoC1-C8 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, or

[0660] R1 and R 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;

[0661] A and B, at each occurrence, are independently selected from: none, or a divalent moiety selected from the following: R'-R", R'COR", R'CO2R", R'C(O)N(R 3 )R”、R'C(S)N(R 3 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 3 )R”、R'N(R 3 )R”、R'N(R 3 )COR”、R'N(R 3 )CON(R 4 )R”、R'N(R 3 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0662] R' and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r-(C1-C8 alkylene) or a moiety comprising optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0663] R r Selected from: optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0664] R 3 and R 4 independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0665] R' and R", R 3 and R 4 , R' and R3 , R' and R 4 , R” and R 3 , R” and R 4 Together with the atoms to which they are attached, they form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

[0666] each m is 0 to 15; and

[0667] n is 0 to 15.

[0668] In another embodiment, A, W and B, at each occurrence, are independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-10 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0669] In another embodiment, Rr Selected from: formulae C1a, C2a, C3a, C4a, C5a, C1, C2, C3, C4 and C5 as defined hereinafter.

[0670] In another embodiment, R r is selected from group R, and group R is defined as in Formula 9.

[0671] In another embodiment, the linker portion is as shown in Formula 9C:

[0672]

[0673] in,

[0674] X is selected from O, NH and NR 7 ;

[0675] R 1 、R 2 、R 3 、R 4 、R 5 and R 6 , is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0676] A and B are independently selected from: none, or a divalent moiety selected from the following: R'-R", R'COR", R'CO2R", R'C(O)N(R 8 )R”、R'C(S)N(R 8 )R", R'OR", R'SR", R'SOR", R'SO2R", R'SO2N(R 8 )R”、R'N(R 8 )R”、R'N(R 8 )COR”、R'N(R 8 )CON(R 9 )R”、R'N(R 8)C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein

[0677] R' and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene) or a moiety comprising optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0678] R rSelected from: optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0679] R 7 、R 8 and R 9 each independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0680] R' and R", R 8 and R 9 , R' and R 8 , R' and R 9 , R” and R 8 , R” and R 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;

[0681] m, at each occurrence, is 0 to 15;

[0682] n, at each occurrence, is 0 to 15;

[0683] o is 0 to 15; and

[0684] p is 0 to 15.

[0685] In another embodiment, A and B are independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2)1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, -CO-NH, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 - and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0686] In another embodiment, Rr is selected from Group R, and Group R is as defined in Formula 9.

[0687] In another embodiment, A and B, at each occurrence, are independently selected from: none, CO, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2.

[0688] In another embodiment, o is 0-5.

[0689] 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.

[0690] In another embodiment, the linker moiety degradation tag comprises one or more rings selected from the group consisting of formula C1a, C2a, C3a, C4a, and C5a:

[0691]

[0692] in,

[0693] X' and Y' are independently selected from: N, CR b ;

[0694] A 1 、B 1 、C 1 and D 1 , at each occurrence, is independently selected from: none, O, CO, SO, SO2, NR b , CR b R c ;

[0695] A 2 、B 2 、C 2 and D 2 , at each occurrence, is independently selected from: N, CR b ;

[0696] A 3 、B 3 、C 3 、D 3 and E 3 , at each occurrence, is independently selected from: N, O, S, NR b , CR b ;

[0697] R b and R c , is independently selected at each occurrence from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0698] m 1 、n 1 、o 1 and p 1Independently selected from: 0, 1, 2, 3, 4 and 5.

[0699] In another embodiment, the linker moiety degradation tag comprises one or more rings selected from the group consisting of formula C1, C2, C3, C4, and C5:

[0700]

[0701] In another embodiment, the linker portion is as shown in Formula 9A.

[0702] In another embodiment, A, W and B, at each occurrence, are independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO, (CH2) 0-8 -CO-NH, NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH, (CH2) 1-3 -NH-(CH2) 1-3 -NH-CO, CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 - and -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -.

[0703] In another embodiment, R r Selected from: formulae C1a, C2a, C3a, C4a, C5a, C1, C2, C3, C4 and C5 as defined above.

[0704] In another embodiment, Rr is selected from Group R, and Group R is as defined in Formula 9.

[0705] In another embodiment, in Formula 9A, A and B are independently as defined above, and W is none.

[0706] In other embodiments, the linker is 0 to 40 chain atoms in length.

[0707] In other embodiments, the linker is 3 to 20 chain atoms in length.

[0708] In other embodiments, the linker is 5-15 chain atoms in length.

[0709] In another embodiment, when the CBP / P300 ligand of the divalent compound is bound to, A is selected from: -(CO)-, -(CH2) 1-2 (CO)-NH-, -(CH2) 0-8 -、-(CH2) 0-3 -CO-(CH2) 0-8 -、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 , where R r is selected from group R, and group R is defined as in formula 9.

[0710] In another embodiment, the linker is -(CO)-(CH2) 3-7 -.

[0711] In another embodiment, the linker is -(CH2) 1-2 (CO)-NH-(CH2) 3-7 -.

[0712] In another embodiment, the linker is -(CH2) 0-10 - and -(CH2) 0-3 -CO-(CH2) 0-10 -.

[0713] In another embodiment, the linker is -(CH2) 0-3 -Rr -(CH2) 0-3 -or-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 -, where R r is selected from group R, and group R is defined as in Formula 9.

[0714] 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.

[0715] The bivalent compounds disclosed herein can selectively affect CBP / P300-mediated disease cells compared to WT (wild-type) cells (i.e., the bivalent compounds can kill or inhibit the growth of CBP / P300-mediated disease cells while also having relatively low ability to lyse or inhibit the growth of WT cells), for example, having a GI of 1.5-fold or more, 2-fold or more, 2.5-fold or more, 3-fold or more, 4-fold or more, 5-fold or more, 6-fold or more, 7-fold or more, 8-fold or more, 9-fold or more, 10-fold or more, 15-fold or more, or 20-fold or more 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 .

[0716] In some aspects, provided herein is a method for identifying a bivalent compound that mediates degradation or reduction of CBP / P300, the method comprising: providing a heterobifunctional test compound comprising a CBP / P300 ligand conjugated to a degradation tag via a linker; contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and CBP / P300; determining whether the level of CBP / P300 in the cell is reduced; and identifying the heterobifunctional test compound that mediates 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.

[0717] Synthesis and testing of divalent compounds

[0718] 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 levels of the divalent compound to CBP / P300, CBP / P300 mutants or CBP / P300 fusion proteins, protein-protein interactions or the enzymatic activity of acetyltransferases can also be assessed. Mensuration suitable for any or all of these steps is known in the art, including, for example, Western blotting, 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 and include 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.

[0719] As non-limiting examples, detailed synthetic schemes are described in the Examples for specific exemplary divalent compounds.

[0720] 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). Specifically, 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.

[0721] Isotopic variants (e.g., containing 2Isotopic variants of H 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.

[0722] Pharmaceutically acceptable solvates of the compounds disclosed herein are contemplated. Solvates can be produced, for example, by replacing the solvent used to crystallize the compounds disclosed herein with an isotopic variant (e.g., D2O instead of H2O, d6-acetone instead of acetone, or d6-DMSO instead of DMSO).

[0723] 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 greater metabolic stability (e.g., increasing half-life in vivo or reducing dosage requirements).

[0724] 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. The prodrug may be inactive when administered to a subject, i.e., an ester, but is converted into an active compound in vivo, for example, by hydrolysis into a free carboxylic acid or a free hydroxyl group. 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 carrier that releases the active compound in vivo when such a prodrug is 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 cleaved into the parent active compound in conventional operations or in vivo. Prodrugs include compounds in which a hydroxyl, amino, or sulfhydryl group is bound 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 sulfhydryl 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.

[0725] Characterization of exemplary divalent compounds

[0726] 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-174) for the indicated hours. Cells were collected, lysed, and immunoblotted using antibodies specific for P300 or CBP protein. Tubulin or vinculin was included as a loading control. DMSO was used as a negative control. Following 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 11). 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 ).

[0727] 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 ).

[0728] Targeting the bromodomain or lysine acetyltransferase domain of CBP / P300 with 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 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 three replicates of untreated cells. Dose-dependent responses were analyzed using GraphPad Prism 5.0 software using the least squares nonlinear regression method. The bivalent compounds, 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.

[0729] Interaction with cereblon is crucial 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 binding, such as P-007, P-034, and P-100 ( Figure 8 ).

[0730] Together, these findings demonstrate that the bivalent compounds induce P300 / CBP protein degradation through a mechanism specifically mediated by cereblon, cullin E3 ligase, 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 administration, 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 ( Figure 9 ). In addition, ICR mice were treated orally with 40 mg / kg of the bivalent compound. Six hours after administration, the animals were sacrificed for immunoblotting of CBP in homogenized lung tissue. Figure 12 For example, the bivalent compound showed the ability to significantly reduce CBP protein levels after a single dose.

[0731] Definition of terms

[0732] As used herein, the terms "including" and "comprising" are used in their open, non-limiting sense.

[0733] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing 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., C1-C 15 In certain embodiments, the alkyl group contains from one to thirteen carbon atoms (e.g., C1-C 13 In certain embodiments, the alkyl group contains one to eight carbon atoms (e.g., C1-C8 alkyl). In certain embodiments, the alkyl group contains five to fifteen carbon atoms (e.g., C5-C 15Alkyl). In certain embodiments, the alkyl group contains five to eight carbon atoms (e.g., C5-C8 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, and the like.

[0734] "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., C2-C 12 In some embodiments, the alkenyl group comprises two to eight carbon atoms (e.g., C2-C8 alkenyl). In some embodiments, the alkenyl group comprises two to six carbon atoms (e.g., C2-C6 alkenyl). In some embodiments, the alkenyl group comprises two to four carbon atoms (e.g., C2-C4 alkenyl). The alkenyl group is connected 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.

[0735] As used herein, the term "allyl" refers to a -CH2CH=CH2 group.

[0736] 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. An 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, an alkynyl group contains two to twelve carbon atoms (e.g., C2-C 12 In some embodiments, the alkynyl group comprises two to eight carbon atoms (e.g., C2-C8 alkynyl). In some embodiments, the alkynyl group comprises two to six carbon atoms (e.g., C2-C6 alkynyl). In some embodiments, the alkynyl group comprises two to four carbon atoms (e.g., C2-C4 alkynyl). The alkynyl group is connected 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, etc.

[0737] As used herein, the term "alkoxy" refers to an alkyl group, as defined herein, 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, pentoxy, hexoxy, and the like.

[0738] 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., C6-C 14 In certain embodiments, the aryl group contains six to ten carbon atoms (e.g., C6-C 10 Examples of such groups include, but are not limited to, phenyl, fluorenyl, and naphthyl. As used herein, the terms "Ph" and "phenyl" refer to a -C6H5 group.

[0739] The term "heteroaryl" refers to a group derived from a 3- to 18-membered aromatic group comprising 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 fully unsaturated, that is, it comprises 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). Heteroaryl includes fused rings or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl group is connected to the rest of the molecule through 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 (cinnolinyl), indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, etc. In certain embodiments, heteroaryl is connected to the rest of the molecule through a ring carbon atom. In certain embodiments, heteroaryl is connected to the rest of the molecule through a nitrogen atom (N- connected) or a carbon atom (C- connected). For example, a group derived from pyrrole can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). For example, a group derived from imidazole can be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).

[0740] 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 atoms in its ring system and containing 3 to 12 carbon atoms and 1 to 4 heteroatoms independently selected from O, S and N, with the proviso 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 azetidinyl (derived from azetidine). An example of a 5-membered cycloheteroalkyl group is pyrrolidinyl. An example of a 6-membered cycloheteroalkyl group is piperidinyl. An example of a 9-membered cycloheteroalkyl group is indolinyl. An example of a 10-membered cycloheteroalkyl group is 4H-quinolinyl. Other examples of such heterocyclic groups include, 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, Heteroaryl can be connected to the rest of molecule by carbon atom (C-connection) or nitrogen atom (N-connection).For example, the group derived from piperazine can be piperazine-1-base (N-connection) or piperazine-2-base (C-connection).

[0741] 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. Cycloalkyl can be fused, bridged or spirocyclic. In certain embodiments, cycloalkyl includes 3 to 8 carbon ring atoms (3-8 membered carbocyclyl). In certain embodiments, cycloalkyl 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.

[0742] 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.

[0743] As used herein, the term "chain atom" refers to an atom located on the main chain of a linker moiety.

[0744] As used herein, the term "spirocyclic" has its conventional meaning, i.e., any ring system comprising two or more rings, wherein both rings have one common ring carbon. As defined herein, each ring of a spirocyclic system independently comprises from 3 to 20 ring atoms. Preferably, it has from 3 to 10 ring atoms. Non-limiting examples of spirocyclic systems include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.

[0745] The term "cyano" refers to a -C≡N group.

[0746] An "aldehyde" group refers to a -C(O)H group.

[0747] "Alkoxy" refers to an -O-alkyl group, as defined herein.

[0748] "Alkoxycarbonyl" refers to a -C(O)-alkoxy group, as defined herein.

[0749] "Alkylaminoalkyl" refers to an -alkyl-NR-alkyl group, as defined herein.

[0750] "Alkylsulfonyl" refers to a -SO2 alkyl group, as defined herein.

[0751] "Amino" refers to an optionally substituted -NH2.

[0752] "Aminoalkyl" means an -alkyl-amino group, as defined herein.

[0753] "Aminocarbonyl" refers to a -C(O)-amino group, as defined herein.

[0754] "Arylalkyl" means an -alkylaryl group in which alkyl and aryl are as defined herein.

[0755] An "aryloxy" group refers to both -O-aryl and -O-heteroaryl groups, as defined herein.

[0756] "Aryloxycarbonyl" means a -C(O)-aryloxy group, as defined herein.

[0757] "Arylsulfonyl" means a -SO2 aryl group, as defined herein.

[0758] "Carbonyl" means a -C(O)- group, as defined herein.

[0759] A "carboxylic acid" group refers to a -C(O)OH group.

[0760] "Cycloalkoxy" refers to an -O-cycloalkyl group, as defined herein.

[0761] A "halo" or "halogen" group refers to fluoro, chloro, bromo, or iodo.

[0762] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0763] "Hydroxy" refers to an -OH group.

[0764] A "nitro" group refers to a -NO2 group.

[0765] An "oxo" group refers to a =0 substituent.

[0766] "Trihalomethyl" refers to a methyl group substituted with three halogen atoms.

[0767] The term "substituted" means that the designated group or moiety bears one or more substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogen, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo, -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl) C4-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C4 haloalkyl).

[0768] The term "absent" refers to the absence of an atom or moiety and the presence of bonds between adjacent atoms in the structure.

[0769] The term "optionally substituted" means that the specified group may be unsubstituted or substituted with one or more substituents as defined herein. It should be understood that in the compounds of the present invention, when a group is referred to as "unsubstituted," or "substituted" with a group that is less than the valence of all atoms in the compound, the remaining valences of the group are filled with hydrogen. For example, if a C6 aryl group, also referred to herein as "phenyl," is substituted with an additional substituent, one of ordinary skill in the art will understand that such a group has 4 open positions on the carbon atoms of the C6 aromatic ring (6 initial positions, minus one position and one additional substituent to which the rest of the compounds of the present invention are attached, leaving 4 positions open). In this case, each of the remaining 4 carbon atoms is combined with a hydrogen atom to fill their valences. Similarly, if a C6 aryl group in a compound of the present invention is referred to as "disubstituted," one of ordinary skill in the art will understand that it means that the C6 aryl group has 3 unsubstituted remaining carbon atoms. Each of these three unsubstituted carbon atoms is combined with a hydrogen atom to fill their valences. Unless otherwise indicated, an optionally substituted group may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, OR m SR m NR n R o 、COR m 、CO2R m 、CONR n R o 、SOR m 、SO2R m 、SO2NR n R o NR n COR o NR m C(O)NR n R o NR n SOR o NR n SO2R o , C1-C8 alkyl, C1-C8 alkoxy C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino C1-C8 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl and heteroaryl, wherein R m 、R n and R o are independently selected from: none, hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, aryl and heteroaryl, or R n and R oTogether with the atoms to which they are attached, they form a 4-8 membered cycloalkyl ring or heterocyclyl ring.

[0770] As used herein, the same symbols in different formulas represent different definitions. For example, in Formula 1, R 1 The definition of is the definition of formula 1, and R in formula 6 1 The definition of is the same as that of Equation 6.

[0771] 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 any integer within the defined range.

[0772] As used herein, (CH2) a-b (a and b are integers) means (CH2) c 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, (CH2) 0-3 represents the following groups: none, (CH2), (CH2)2 or (CH2)3.

[0773] "Pharmaceutically acceptable salts" include both 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.

[0774] "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, and the like. 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, as well as salts 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 sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, toluate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, 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.

[0775] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acids and 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 and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, 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.

[0776] Pharmaceutical composition

[0777] 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.

[0778] 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.

[0779] 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.

[0780] 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 generally do not produce allergic or similar adverse reactions, such as stomach upset, 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 non-toxic 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 delaying agents that are compatible with drug administration.

[0781] 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 carboxymethyl cellulose, 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.

[0782] 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 also typically added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension or emulsion is administered orally, the active ingredient can be suspended or dissolved in an oil phase and mixed with an emulsifier or suspending agent. If desired, certain sweeteners, flavorings, or coloring agents can be added.

[0783] 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 disclosed herein or medicaments, such as carbamates, esters, phosphates, salts of esters or other derivatives, which can provide (directly or indirectly) compounds as described herein or their active metabolites or residues after being applied to a recipient. Particularly preferred derivatives and prodrugs are when compounds disclosed herein are applied to a subject to increase the bioavailability of compounds disclosed herein (e.g., by making orally administered compounds more easily absorbed into the blood) or to enhance the delivery of parent compounds to biological compartments (e.g., brain or lymphatic system) relative to parent species. Preferred prodrugs include derivatives that are groups that enhance water solubility or active transport by intestinal membranes attached to the formula structure described herein. Those skilled in the art can identify such derivatives without excessive 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.

[0784] The divalent compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereomers, mixtures of diastereomers, 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.

[0785] 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 "novel 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.

[0786] A "solvate" is formed by the interaction of a solvent and a compound. The term "compound" is intended to include solvates of the compound. Similarly, "pharmaceutically acceptable salt" includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrates.

[0787] In some aspects, the pharmaceutical compositions disclosed herein can comprise an effective amount of one or more bivalent compounds.

[0788] As used herein, the terms "effective amount" and "effective treatment" refer to an amount or concentration of one or more compounds or pharmaceutical compositions described herein that is effective to cause a desired effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer) over a period of time (including acute or chronic administration and periodic or continuous administration) within its dosing range. In some aspects, the pharmaceutical composition may further comprise one or more additional compounds, drugs, or agents (e.g., conventional chemotherapeutic agents) for the treatment of cancer in an amount effective to cause a desired effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer).

[0789] In some aspects, the pharmaceutical compositions disclosed herein can be formulated for sale in, imported into, or exported from the United States.

[0790] Administration of pharmaceutical compositions

[0791] Pharmaceutical compositions disclosed herein can be formulated or adjusted for administration to a subject by any approach such as that approved by the Food and Drug Administration (FDA). Exemplary methods are described in the FDA Data Standards Manual (DSM) (available at http: / / www.fda.gov / Drugs / DevelopmentApprovalProcess / FormsSubmissionRequirements / ElectronicSubmissions / 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.

[0792] For example, the pharmaceutical compositions 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.

[0793] For example, the pharmaceutical compositions of the present invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.

[0794] For example, the pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is 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.

[0795] 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.

[0796] For example, the pharmaceutical compositions of the present invention can be administered by injection (e.g., as a solution or powder). Such compositions can be formulated according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent, such as a solution 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 commonly used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, can be used to prepare injectable preparations, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethylcellulose or similar dispersants, which are commonly used to formulate 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 that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0797] In some aspects, effective doses of the pharmaceutical compositions of the present 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, 0.8 , 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2500, 5000, or 10000 mg / kg / day, or as required for a particular pharmaceutical composition.

[0798] 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 can be between about 1% and 100%, more preferably between about 5% and 95% of the dose typically administered as a single-drug treatment regimen. The additional agents can be administered separately from the compounds of the invention as part of a multiple-dose regimen. Alternatively, these agents can be part of a single dosage form, mixed with the compounds of the invention in a single composition.

[0799] In some aspects, a pharmaceutical composition disclosed herein may be included in a container, pack, or dispenser together with instructions for administration.

[0800] Treatment

[0801] Method disclosed herein contemplates administering an effective amount of a compound or composition to achieve the desired or prescribed effect. Typically, the compound or composition of the present invention is administered daily for approximately 1 to approximately 6 times, or, or, or in addition, as a continuous infusion. This administration can be used as a chronic or acute treatment. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form will vary according to the host being treated and a specific mode of administration. Typical preparations will contain approximately 5% to approximately 95% active compound (w / w). Alternatively, such preparations can include approximately 20% to approximately 80% active compound.

[0802] In some aspects, provided herein are bivalent compounds described herein for use in preventing or treating a disease or disorder.

[0803] 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 cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, 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 cancer, 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 inflammatory disease or 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 mellitus, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis. In certain embodiments, the disease or condition is refractory to one or more prior therapies.

[0804] 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.

[0805] 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) who is in need or determined to be in need of such treatment. In some aspects, the disclosed methods include selecting a subject and administering to the subject an effective amount of one or more compounds or compositions described herein, and optionally repeating the administration as needed to prevent or treat cancer.

[0806] In some aspects, selection of a subject can include obtaining a sample from the subject (e.g., a candidate subject) and testing the sample to indicate that the subject is suitable for the selection. In some aspects, a subject can be confirmed or identified as having, having an elevated risk of having, or having a certain condition or disease, such as by a healthcare professional. In some aspects, suitable subjects include, for example, subjects who have or have had a condition or disease but have resolved the disease or an aspect thereof, subjects who exhibit a reduction in disease symptoms (e.g., relative to other subjects (e.g., most subjects) with the same condition or disease, or who survive the condition or disease for a longer period of time (e.g., relative to other subjects (e.g., most subjects) with the same condition or disease), for example, who are asymptomatic (e.g., relative to other subjects (e.g., most subjects) with the same condition or disease). In some aspects, demonstration of a positive immune response to the condition or disease can be made through patient records, family history, or an indication of testing for a positive immune response. In some aspects, subject selection can be multi-party. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample. In some aspects, the subject can be selected or referred by a medical practitioner (e.g., a general practitioner). In some aspects, selection of the subject can include obtaining a sample from the selected subject and storing the sample or using the sample in the methods disclosed herein. The sample can include, for example, a cell or a population of cells.

[0807] In some aspects, methods of treatment may include the needs of preventing or treating a disease disclosed herein or illness (e.g., a CBP / P300-mediated disease), single administration, multiple administration, and repeated administration of one or more compounds disclosed herein. In some aspects, methods 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.

[0808] As used herein, the term "subject" refers to any animal. In some cases, the subject is a mammal. In some cases, the term "subject" as used herein refers to a human (e.g., a man, woman, or child).

[0809] As used herein, the terms "administer," "apply," or "administering" 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.

[0810] 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 the symptoms of a particular condition (e.g., cancer) refers to any alleviation, whether permanent or temporary, long-lasting or transient, attributable to or associated with treatment with the bivalent compounds, compositions, and methods of the invention. In some embodiments, treatment can 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 before 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 before treatment; a decrease in the growth rate of tumor cells; 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 subject's symptoms before treatment.

[0811] As used herein, the terms "prevent," "preventing," and "prophylaxis" shall refer to a reduction in the occurrence of a disease or a decrease in the risk of developing a disease or its associated symptoms in a subject. Prevention can be complete, e.g., the complete absence of disease or pathological cells in the subject. Prevention can also be partial, such that the disease or pathological cells in the subject are less likely to occur, appear later, or progress more slowly than in the absence of the present invention. In certain embodiments, the subject is at increased risk for developing one or more CBP / P300-mediated diseases.Exemplary CBP / P300 mediated diseases that can be treated with 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, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative change), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, 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, mucinous 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 tumor, uterine cancer, Wilms' tumor, Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behçet's disease 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 1 diabetes mellitus, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

[0812] 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.

[0813] 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 can include a single treatment or a series of treatments. For example, an effective amount can be administered at least once. The composition can be administered once or more per day to once or more per week; including once every other day. It will be understood by those skilled in the art that certain factors may affect the dosage 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.

[0814] After administration, the subject can be assessed to detect, evaluate or determine their disease level. In some cases, treatment can continue until a change (such as a 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.

[0815] 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. Indeed, many modifications and variations will be apparent to those skilled in the art upon reading this specification, and such changes may 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

[0816] Synthesis of linker-attached degradation tags for bivalent compounds

[0817] Example 1: 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 1)

[0818]

[0819] 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 resulting 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, 16% yield) 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 and washed with MTBE and dried to afford 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione as a yellow solid (Linker 1) (1.3 g, 98% yield). 1 H NMR (400MHz, DMSO-d6) 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),2.94-2.8 5(m,1H),2.62-2.50(m,2H),2.05-2.00(m,1H).MS(ESI)m / z=317.1[M+H] + .

[0820] Example 2: 4-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 2)

[0821]

[0822] 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] +

[0823] Example 3: 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 3)

[0824]

[0825] Linker 3 was synthesized according to the same procedure as Linker 1 described in Example 1 (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]+

[0826] Example 4: 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 4)

[0827]

[0828] Linker 4 was synthesized following the same procedure as Linker 1 described in Example 1 (2.3 g, yield: 26%, two steps). 1H NMR (400MHz, DMSO-d6) 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),3.32-3.28(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] +

[0829] Example 5: 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 5)

[0830]

[0831] 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] +

[0832] Example 6: 4-((7-aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 6)

[0833]

[0834] 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] +

[0835] Example 7: 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 7)

[0836]

[0837] 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 (400MHz, DMSO-d6) 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),3.3 4-3.26(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[M+H] +

[0838] Example 8: 4-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 8)

[0839]

[0840] Linker 8 was synthesized following the same procedure as Linker 1 described in Example 1 (2.0 g, yield: 23%, two steps). 1H NMR (400MHz, DMSO-d6) 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= 5.2,12.8Hz,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] +

[0841] Example 9: 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 9)

[0842]

[0843] 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] +

[0844] Example 10: 4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 10)

[0845]

[0846] 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] +

[0847] Example 11: 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 11)

[0848]

[0849] 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] +

[0850] Example 12: 4-((17-amino-3,6,9,12,15-pentaoxaheptadecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 12)

[0851]

[0852] Linker 12 was synthesized following the same procedure as that of 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] +

[0853] Example 13: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine (Linker 13)

[0854]

[0855] Linker 13 was synthesized following the same procedure as that of 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] -

[0856] Example 14: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoic acid (Linker 14)

[0857]

[0858] Linker 14 was synthesized following the same procedure as Linker 1 described in Example 1 (1.42 g, yield: 24%, two steps). 1H NMR (400MHz, DMSO-d6) 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,1 H),5.05(dd,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] +

[0859] Example 15: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoic acid (Linker 15)

[0860]

[0861] Linker 15 was synthesized following the same procedure as that of Linker 1 described in Example 1 (1.27 g, yield: 13%, two steps). 1 H NMR(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] +

[0862] Example 16: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoic acid (Linker 16)

[0863]

[0864] Linker 16 was synthesized following the same procedure as that of linker 1 described in Example 1 (1.4 g, yield: 15%, two steps). 1H NMR(400MHz,DMSO-d6)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),5.0 7-5.03(m,1H),3.32-3.02(m,2H),2.93-2.84(m,1H),2.61-2.54(m,2H),2.28 -2.25(m,2H),2.05-2.01(m,1H),1.60-1.51(m,4H).MS(ESI)m / z=374.1[M+H] +

[0865] Example 17: 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoic acid (Linker 17)

[0866]

[0867] Linker 17 was synthesized following the same procedure as Linker 1 described in Example 1 (1.43 g, yield: 18%, two steps). 1 H NMR (400MHz, DMSO-d6) 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=5.6,12.8H z,1H),3.30(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] +

[0868] Example 18: 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoic acid (Linker 18)

[0869]

[0870] 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] +

[0871] Example 19: 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoic acid (Linker 19)

[0872]

[0873] Linker 19 was synthesized following the same procedure as that of Linker 1 described in Example 1 (1.14 g, yield: 35%, two steps). 1 H NMR (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] +

[0874] Example 20: 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid (Linker 20)

[0875]

[0876] 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] +

[0877] Example 21: 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid (Linker 21)

[0878]

[0879] 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] +

[0880] 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)

[0881]

[0882] 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] +

[0883] Example 23: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)3,6,9,12-tetraoxapentadecan-15-oic acid (Linker 23)

[0884]

[0885] 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] +

[0886] 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)

[0887]

[0888] 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] +

[0889] Example 25: (2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 25)

[0890]

[0891] Step 1:

[0892] 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 0°C. 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 silica gel column chromatography (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] +

[0893] Step 2:

[0894] 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 give the desired product, which was dissolved in water (100 mL) and lyophilized to give (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(400MHz, DMSO-d6)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),4.36-4.4 7(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] +

[0895] Example 26: (2S,4R)-1-((S)-2-(3-aminopropionylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 26)

[0896]

[0897] Linker 26 was synthesized following the same procedure as linker 25 described in Example 25 (1.38 g, yield: 37%, two steps). 1HNMR(400MHz, DMSO-d6)9.36(s,1H),8.68(s,1H),8.26(d,J=9.2Hz,1H),8.16( s,3H),7.49-7.39(m,4H),4.53(d,J=9.2Hz,1H),4.47-4.35(m,3H),4.24-4.19 (m,1H),3.69-3.60(m,2H),2.94-2.93(m,2H),2.64(t,J=7.2Hz,2H),2.48(s,3 H),2.06-2.01(m,1H),1.92-1.85(m,1H),0.95(s,9H).MS(ESI)m / z=502.3[M+H] +

[0898] 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)

[0899]

[0900] Linker 27 was synthesized following the same procedure as linker 25 described in Example 25 (1.38 g, yield: 46%, two steps). 1 HNMR(400MHz, DMSO-d6)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] + .

[0901] 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)

[0902]

[0903] Linker 28 was synthesized following the same procedure as linker 25 described in Example 25 (1.50 g, yield: 57%, two steps). 1 HNMR(400MHz, DMSO-d6)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] +

[0904] 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)

[0905]

[0906] Linker 29 was synthesized following the same procedure as linker 25 described in Example 25 (2.70 g, yield: 87%, two steps). 1 H

[0907] 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] + .

[0908] 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)

[0909]

[0910] Linker 30 was synthesized following the same procedure as linker 25 described in Example 25 (2.13 g, yield: 76%, two steps). 1 HNMR(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. 44(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] + .

[0911] 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)

[0912]

[0913] Linker 31 was synthesized following the same procedure as linker 25 described in Example 25 (1.81 g, yield: 65%, two steps). 1 HNMR(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. 44(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] + .

[0914] 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)

[0915]

[0916] Linker 32 was synthesized following the same procedure as linker 25 described in Example 25 (2.32 g, yield: 80%, two steps). 1HNMR(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] + .

[0917] 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)

[0918]

[0919] Linker 33 was synthesized following the same procedure as 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] + .

[0920] 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)

[0921]

[0922] Linker 34 was synthesized following the same procedure as linker 25 described in Example 25 (1.10 g, yield: 37%, two steps). 1 HNMR(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] + .

[0923] Example 35: (2S,4R)-1-((S)-2-(2-aminoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 35)

[0924]

[0925] Linker 35 was synthesized following the same procedure as linker 25 described in Example 25 (1.35 g, yield: 55%, two steps). 1HNMR(400MHz, DMSO-d6)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] +

[0926] 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)

[0927]

[0928] Linker 36 was synthesized following the same procedure as linker 25 described in Example 25 (1.32 g, yield: 49%, two steps). 1 HNMR(400MHz, DMSO-d6)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] + .

[0929] 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)

[0930]

[0931] Linker 37 was synthesized following the same procedure as linker 25 described in Example 25 (1.2 g, yield: 49%, two steps). 1 H NMR (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] +

[0932] Example 38: (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 38)

[0933]

[0934] Linker 38 was synthesized following the same procedure as described for linker 25 in Example 25 (1.34 g, yield: 49%, two steps). 1 HNMR(400MHz, DMSO-d6)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,1 H),3.70-3.50(m,10H),3.00-2.96(m,2H),2.57-2.55(m,1H),2.45(s,3H),2.41-2.3 8(m,1H),2.06-2.04(m,1H),1.95-1.93(m,1H),0.95(s,9H).MS(ESI)m / z=590.1[M+H] +

[0935] 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)

[0936]

[0937] Linker 39 was synthesized following the same procedure as linker 25 described in Example 25 (1.53 g, yield: 56%, two steps). 1 HNMR (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),3.99(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] +

[0938] Example 40: (2S,4R)-1-((S)-1-amino-14-(tert-butyl)-12-oxo-3,6,9-trioxa-13-azapentadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 40)

[0939]

[0940] Linker 40 was synthesized following the same procedure as linker 25 described in Example 25 (1.52 g, yield: 51%, two steps). 1HNMR(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,1 H),3.70-3.48(m,14H),3.00-2.97(m,2H),2.59-2.52(m,1H),2.46(s,3H),2.39-2.3 4(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] +

[0941] 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)

[0942]

[0943] Linker 41 was synthesized following the same procedure as linker 25 described in Example 25 (1.12 g, yield: 37%, two steps). 1 HNMR(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, 4H),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, 5H),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] +

[0944] Example 42: (2S,4R)-1-((S)-1-amino-20-(tert-butyl)-18-oxo-3,6,9,12,15-pentaoxa-19-azaheneicos-21-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 42)

[0945]

[0946] Linker 42 was synthesized following the same procedure as linker 25 described in Example 25 (1.1 g, 1.52 mmol, yield: 32% over two steps). 1 H NMR(400MHz, DMSO-d6)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] +

[0947] 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)

[0948]

[0949] 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 / HO) to give the title compound, connector 43 (1.05 g, 86% yield). 1H NMR (400MHz, DMSO-d6): 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). 13 C 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] +

[0950] 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)

[0951]

[0952] Linker 44 was synthesized according to the same procedure as linker 43 described in Example 43 (1.5 g, yield: 79%). 1H NMR (400MHz, DMSO-d6): δ8.99(s,1H),8.59(t,J=6.0Hz,1H),7.91(d,J=9.2Hz,1 H),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 (100MHz, DMSO-d6): δ174.18,171.94,171.63,169.66,151.41,147.70,139.46,131.15,129.61,128.62,1 27.41,68.86,58.69,56.38,41.65,37.91,35.16,34.03,33.10,26.35,20.89,15.92.MS(ESI)m / z=543.2[MH] -

[0953] 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)

[0954]

[0955] 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, CDCl3)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] +

[0956] 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)

[0957]

[0958] 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, CDCl3)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),1.5 5-1.51(m,4H),1.29-1.24(m,2H),0.94(s,9H).MS(ESI)m / z=573.1[M+H] +

[0959] 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)

[0960]

[0961] Linker 47 was synthesized following the same procedure as linker 45 described in Example 45 (1.08 g, yield: 52%, two steps). 1 HNMR(400MHz, DMSO-d6)8.99(s,1H),8.55(t,J=2.4Hz,1H),7.83(d,J=9.2H z,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] +

[0962] 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)

[0963]

[0964] Linker 48 was synthesized following the same procedure as linker 45 described in Example 45 (1.16 g, yield: 44%, two steps). 1 HNMR(400MHz, CDCl3)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),4.08-4.0 5(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] +

[0965] 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)

[0966]

[0967] Linker 49 was synthesized following the same procedure as linker 45 described in Example 45 (1.1 g, yield: 35%). 1H NMR (400MHz, DMSO-d6): 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 ),2.03-2.01(m,1H),1.94-1.88(m,1H),1.47(m,4H),1.24(b,8H),0.94(s,9H). 13 C NMR (100MHz, DMSO-d6): δ172.07,171.92,169.69,151.41,147.70,139.48,131.14,129.62,128.61,127.40,6 8.84,58.67,56.32,56.26,41.64,37.93,35.18,34.85,28.62,26.36,25.39,15.93.MS(ESI)m / z=615.3[M+H] +

[0968] 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)

[0969]

[0970] Linker 50 was synthesized following the same procedure as linker 45 described in Example 45 (1.1 g, yield: 50%). 1 H NMR (400MHz, DMSO-d6): 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). 13C NMR (100MHz, DMSO-d6): 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] +

[0971] 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)

[0972]

[0973] Linker 51 was synthesized following the same procedure as linker 45 described in Example 45 (1.1 g, yield: 42%). 1 H 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] +

[0974] 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)

[0975]

[0976] 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] +

[0977] 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)

[0978]

[0979] Linker 53 was synthesized following the same procedure as linker 45 described in Example 45 (1.4 g, 23% yield, two steps). 1 H NMR(400MHz, DMSO-d6):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,7H),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] +

[0980] 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)

[0981]

[0982] Linker 54 was synthesized following the same procedure as linker 53 described in Example 53 (1.13 g, 20% yield, two steps). 1 HNMR (400MHz, DMSO-d6): 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), 4.2 8-4.23(m,1H),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] +

[0983] 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)

[0984]

[0985] Linker 55 was synthesized following the same procedure as described for linker 45 in Example 45 (1.7 g, 37% yield). 1HNMR(400MHz, DMSO-d6):8.99(s,1H),8.56(t,J=6.0Hz,1H),7.91(d,J=9.6Hz,1H),7.4 4-7.38(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 ),3.70-3.55(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] -

[0986] 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)

[0987]

[0988] 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, CDCl3): 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] +

[0989] 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)

[0990]

[0991] Linker 57 was synthesized following the same procedure as described for linker 45 in Example 45 (1.6 g, 43% yield). 1 HNMR (400MHz, CDCl3): 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] +

[0992] 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)

[0993]

[0994] Linker 58 was synthesized following the same procedure as 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] +

[0995] 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)

[0996]

[0997] 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] +

[0998] Example 60: 5-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 60)

[0999]

[1000] A mixture of 5-fluoroisobenzofuran-1,3-dione (87 g, 524 mmol), 3-aminopiperidine-2,6-dione (85.7 g, 524 mmol) and CH3COONa (85.9 g, 1050 mmol) in CH3COOH (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 obtain 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] +

[1001] 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) and washed with water (200 mL x 2) and brine (200 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give 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] +

[1002] 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 (400MHz, DMSO-d6) 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).

[1003] Example 61: 5-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 61)

[1004]

[1005] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 61 (1.4 g, yield: 71%). MS (ESI) m / z = 405.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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),2.972.92(m,2H),2.91-2.83(m,1H),2.60-2.50(m,2H),2.01-1.99(m,1H).

[1006] Example 62: 5-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 62)

[1007]

[1008] 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 (400MHz, DMSO-d6) 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).

[1009] Example 63: 5-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 63)

[1010]

[1011] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 63 (1.2 g, yield: 73%). MS (ESI) m / z = 493.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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) ,2.99-2.95(m,2H),2.89-2.83(m,1H),2.60-2.53(m,2H)2.01-1.97(m,1H).

[1012] Example 64: 5-((17-amino-3,6,9,12,15-pentaoxaheptadecanyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 64)

[1013]

[1014] 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 (400MHz, DMSO-d6) 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=5.2Hz,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).

[1015] Example 65: (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine (Linker 65)

[1016]

[1017] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 65 (1.0 g, yield: 84%). MS (ESI) m / z = 332.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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).

[1018] Example 66: 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propanoic acid (Linker 66)

[1019]

[1020] 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 (400MHz, DMSO-d6) 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).

[1021] Example 67: 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butanoic acid (Linker 67)

[1022]

[1023] 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 (400MHz, DMSO-d6) 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),2.6 0-2.51(m,2H),2.34(t,J=7.2Hz,2H),2.01-1.97(m,1H),1.82-1.75(m,2H).

[1024] Example 68: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoic acid (Linker 68)

[1025]

[1026] 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 (400MHz, DMSO-d6) 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),2.6 0-2.53(m,2H),2.26-2.25(m,2H),2.01-1.98(m,1H),1.60-1.59(m,4H).

[1027] Example 69: 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoic acid (Linker 69)

[1028]

[1029] 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 (400MHz, DMSO-d6) 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,12.8Hz,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),1.411.33(m,2H).

[1030] Example 70: 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoic acid (Linker 70)

[1031]

[1032] 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 (400MHz, DMSO-d6) 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).

[1033] Example 71: 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoic acid (Linker 71)

[1034]

[1035] 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 (400MHz, DMSO-d6) 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).

[1036] Example 72: 5-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 72)

[1037]

[1038] 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 (400MHz, DMSO-d6) 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).

[1039] Example 73: 5-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 73)

[1040]

[1041] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 73 (1.3 g, yield: 557%). MS (ESI) m / z = 331.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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).

[1042] Example 74: 5-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 74)

[1043]

[1044] 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 (400MHz, DMSO-d6) 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).

[1045] Example 75: 5-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 75)

[1046]

[1047] 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 (400MHz, DMSO-d6) 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=7.2Hz,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).

[1048] Example 76: 5-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 76)

[1049]

[1050] 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 (400MHz, DMSO-d6) 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,J=5.2Hz,12.8Hz,1H),3.17-3.16(m,2H),2.88-2.77(m,3H),2 .60-2.53(m,2H),2.01-1.98(m,1H),1.59-1.51(m,4H),1.37-1.36(m,4H).

[1051] Example 77: 5-((7-aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 77)

[1052]

[1053] The same procedure as described for connector 60 in Example 60 was followed to synthesize connector 77 (1.3 g, yield: 70%). MS (ESI) m / z = 387.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) 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,J=5.6Hz,12.8Hz,1H),3.18-3.14(m,2H),2.92-2.76(m,3H),2 .60-2.51(m,2H),2.01-1.98(m,1H),1.59-1.51(m,4H),1.36-1.32(m,6H).

[1054] Example 78: 5-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Linker 78)

[1055]

[1056] 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 (400MHz, DMSO-d6) 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,12.8Hz,1H),3.15(t,J=7.2Hz,2H),2.89-2.83(m,1H),2.80-2.75(m,2H ),2.60-2.54(m,2H),2.02-1.98(m,1H),1.59-1.51(m,4H),1.37-1.30(m,8H).

[1057] Example 79: 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propanoic acid (Linker 79)

[1058]

[1059] The s...

Claims

1. A bivalent compound, or a pharmaceutically acceptable salt or analog thereof, comprising a cyclic AMP response element binding protein (CBP) and / or a 300 kDa adenovirus E1A binding protein (P300) ligand (CBP / P300 ligand) bound to a degradation tag via a linker moiety; in, (I) (I-1) The CBP / P300 ligand comprises a moiety of formula 1: in, The linker portion of the divalent compound is bound to R 2 ; 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; X 2 Selected from: CR', O and NR', where R' is selected from: H, optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclic ring; A is selected from: None, CR 4 R 5 , CO, O, S, SO, SO2 and NR 4 ,in R 4 and R 5 independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; 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; 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, NO2, OR 6 , SR 6 NR 6 R 7 ,OCOR 6 、OCO2R 6 、OCONR 6 R 7 , COR 6 、CO2R 6 ,CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 NR 8 CO2R 6 NR 8 COR 6 NR 8 C(O)NR 6 R 7 NR 8 SOR 6 NR 8 S02R 6 NR 8 SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 6 , R 7 and R 8 is independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 6 and R 7 , R 6 and R 8 together with the atoms to which they are attached form a 4-20 membered heterocyclyl ring; R 1 Selected from: hydrogen, halogen, CN, NO2, OR 9 , SR 9 NR 9 R 10 ,OCOR 9 、OCO2R 9 、OCONR 9 R 10 , COR 9 、CO2R 9 ,CONR 9 R 10 、SOR 9 、SO2R 9 、SO2NR 9 R 10 NR 11 CO2R 9 NR 11 COR 9 NR 11 C(O)NR 9 R 10 NR 11 SOR 9 NR 11 S02R 9 NR 11 SO2NR 9 R 10 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 9 , R 10 and R 11 is independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 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; R 2 The "connector" part connected to the divalent compound and is selected from: none, R ” O.R ” S, R ” NR 12 , R ” OC(O),R ” OC(O)O、R ” OCONR 12 , R ” C(O), R ” C(O)O、R ” CONR 12 , R ” S(O),R ” S(O)2、R ” SO2NR 12 , R ” NR 13 C(O)O、R ” NR 13 C(O), R ” NR 13 C(O)NR 12 , R ” NR 13 S(O),R ” NR 13 S(O)2、R ” NR 13 S(O)2NR 12 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein, R ” is none, or a divalent moiety selected from the group consisting of an optionally substituted C1-C8 alkylene group, an optionally substituted C2-C8 alkenylene group, an optionally substituted C2-C8 alkynylene group, an optionally substituted C1-C8 alkoxy C1-C8 alkylene group, an optionally substituted C1-C8 haloalkylene group, an optionally substituted C1-C8 hydroxyalkylene group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-10 membered heterocyclyl group, an optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 12 and R 13 is independently selected from: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or 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 R 3 Selected from: Hydrogen, COR 14 、CO2R 14 ,CONR 14 R 15 、SOR 14 、SO2R 14 、SO2NR 14 R 15 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R 14 and R 15 is independently selected from: hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or R 14 and R 15 Together with the atoms to which they are attached, they form a 4-20 membered heterocyclyl ring; Or (I-2) the CBP / P300 ligand comprises a part of formula 2: in, The linker portion of the divalent compound is bound to R 1 ;as well as 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; X 2 Selected from: CR', O and NR', where R' is selected from: H, optionally substituted C1-C8 alkyl and optionally substituted 3-10 membered carbocyclic ring; A is selected from: None, CR 4 R 5 , CO, O, S, SO, SO2 and NR 4 ,in R 4 and R 5 independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; 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 ring or a 4-20 membered heterocyclyl ring; 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, NO2, OR 6 , SR 6 NR 6 R 7 ,OCOR 6 、OCO2R 6 、OCONR 6 R 7 , COR 6 、CO2R 6 ,CONR 6 R 7 、SOR 6 、SO2R 6 、SO2NR 6 R 7 NR 8 CO2R 6 NR 8 COR 6 NR 8 C(O)NR 6 R 7 NR 8 SOR 6 NR 8 S02R 6 NR 8 SO2NR 6 R 7 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 6 , R 7 and R 8 is independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 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 R 1 The "connector" part connected to the divalent compound and is selected from: none, R ” O.R ” S, R ” NR 9 , R ” OC(O),R ” OC(O)O、R ” OCONR 9 , R ” C(O), R ” C(O)O、R ” CONR 9 , R ” S(O),R ” S(O)2、R ” SO2NR 9 , R ” NR 10 C(O)O、R ” NR 10 C(O), R ” NR 10 C(O)NR 9 , R ” NR 10 S(O),R ” NR 10 S(O)2、R ” NR 10 S(O)2NR 9 , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein, R ” is none, or a divalent moiety selected from the group consisting of an optionally substituted C1-C8 alkylene group, an optionally substituted C2-C8 alkenylene group, an optionally substituted C2-C8 alkynylene group, an optionally substituted C1-C8 alkoxy C1-C8 alkylene group, an optionally substituted C1-C8 haloalkylene group, an optionally substituted C1-C8 hydroxyalkylene group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-10 membered heterocyclyl group, an optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 and R 10 is independently selected from: optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, or R 9 and R 10 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 R 2 Selected from: hydrogen, halogen, CN, NO2, OR 11 , SR 11 NR 11 R 12 ,OCOR 11 、OCO2R 11 、OCONR 11 R 12 , COR 11 、CO2R 11 ,CONR 11 R 12 、SOR 11 、SO2R 11 、SO2NR 11 R 12 NR 13 CO2R 11 NR 13 COR 11 NR 13 C(O)NR 11 R 12 NR 13 SOR 11 NR 13 S02R 11 NR 13 SO2NR 11 R 12 , optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R 11 , R 12 and R 13 is independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 11 and R 12 , R 11 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 R 3 Selected from: Hydrogen, COR 14 、CO2R 14 ,CONR 14 R 15 、SOR 14 、SO2R 14 、SO2NR 14 R 15 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, wherein R 14 and R 15 is independently selected from: hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl and optionally substituted 4-6 membered heterocyclyl, or R 14 and R 15 Together with the atoms to which they are attached, they form a 4-6 membered heterocyclyl ring; and (II) (II-1) The degradation tag is a moiety selected from the group consisting of formula 5A, 5B, 5C, and 5D: in, V, W and X are independently selected from: CR 2 and N; Y is selected from: CO, CR 3 R 4 、N=CR 3 and N = N; Z is selected from: None, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 alkylene, an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; preferably, Z is selected from: none, CH2, CH=CH, C≡C, NH and O; R 1 and R 2 independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6-membered carbocyclyl, and optionally substituted 4 to 6-membered heterocyclyl; R 3 and R 4 R is independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6-membered carbocyclyl, and optionally substituted 4 to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl; and R 5 and R 6 R is independently selected from: anhydrous, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or 5 and R 6 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclic group or a 4-6 membered heterocyclic group; Alternatively, (II-2) the degradation tag is a moiety selected from the group consisting of formula 5E, 5F, 5G, 5H and 5I: in, U, V, W and X are independently selected from: CR 2 and N; Y is selected from: CR 3 R 4 NR 3 and O; preferably, Y is selected from: CH2, NH, NCH3 and O; Z is selected from: None, CO, CR 5 R 6 NR 5 , O, optionally substituted C1-C 10 Alkylene, optionally substituted C1-C 10 Alkenylene, optionally substituted C1-C 10 alkylene, an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; preferably, Z is selected from: none, CH2, CH=CH, C≡C, NH and O; R 1 and R 2 independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6-membered carbocyclyl, and optionally substituted 4 to 6-membered heterocyclyl; R 3 and R 4 R is independently selected from: hydrogen, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6-membered carbocyclyl, and optionally substituted 4 to 6-membered heterocyclyl; or 3 and R 4 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclyl or a 4-6 membered heterocyclyl; and R 5 and R 6 R is independently selected from: anhydrous, hydrogen, halogen, oxo, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or 5 and R 6 Together with the atoms to which they are attached, they form a 3-6 membered carbocyclic group or a 4-6 membered heterocyclic group; Alternatively, (II-3) the degradation tag is a moiety selected from the group consisting of formula 5J, 5K, 5L, 5M, 5N, 5O, 5P and 5Q: in, X' is independently selected from: CR 2 and N; Y', Y" and Y"' are independently selected from: CR 3 R 4 ; R' is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered carbocyclyl, and optionally substituted 4- to 6-membered heterocyclyl; U, V, W, X, Z, R 1 and R 2 As defined in Formula 5E, 5F, 5G, 5H or 5I; Or (III-4) the degradation tag is a part of formula 6B, 6C and 6D: in, R 1 and R 2 independently selected from: hydrogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl; R 3 is selected from the group consisting of hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4 -10 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)OC1-C8 C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted optionally substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2 and optionally substituted P(O)(OC1-C8 aryl)2, and R 4 Selected from: NR 7 R 8 , optionally substituted C1-C8 alkoxyalkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R 5 is H or F; R 7 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkyl-CO, optionally substituted C1-C8 cycloalkyl-CO, optionally substituted C1-C8 cycloalkyl-C1-C8 alkyl-CO, optionally substituted 4-10 membered heterocyclyl-CO, optionally substituted 4-10 membered heterocyclyl-C1-C8 alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-C1-C8 alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-C1-C8 alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl; R 8 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, and optionally substituted C1-C8 cycloalkyl; R 9 , at each occurrence, is independently selected from: hydrogen, halogen, cyano, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 heterocycloalkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 cycloalkyloxy, halogenated C1-C8 alkyl, halogenated C1-C8 cycloalkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 cycloalkyloxy, and halogenated C1-C8 heterocycloalkyl; X is selected from: CH and N; and n is 0, 1, 2, 3 or 4; R 6 Selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted C1-C8 alkoxy, and optionally substituted C1-C8 cycloalkyloxy, optionally substituted C1-C8 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.

2. The divalent compound according to claim 1, characterized in that The connector part is shown in Formula 9: in, A, W and B, at each occurrence, are independently selected from: none, or a divalent moiety selected from: R ’ -R”、R ’ COR”, R ’ CO2R”、R ’ C(O)N(R 1 )R”、R ’ C(S)N(R 1 )R”、R ’ OR”, R ’ SR”、R ’ SOR”, R ’ SO2R”、R ’ SO2N(R 1 )R”、R ’ N(R 1 )R”、R”N(R 1 )COR”、R”N(R 1 )CON(R 2 )R”、R ’ N(R 1 )C(S)R", optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl, wherein R ’ and R" are independently selected from: none, optionally substituted (C1-C8 alkylene)-R r (Preferably, CH2-R r ), optionally substituted R r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R r -(C1-C8 alkylene) or a moiety comprising optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R r is selected from: an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted C3-C 13 Fused cycloalkyl, optionally substituted C3-C 13 Fused heterocyclic group, optionally substituted C3-C 13 Bridged cycloalkyl, optionally substituted C3-C 13 Bridged heterocyclic group, optionally substituted C3-C 13 Spirocycloalkyl, optionally substituted C3-C 13 spiroheterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 1 and R 2 independently selected from: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R ’ and R”, R 1 and R 2 , R ’ and R 1 , R ’ and R 2 , R” and R 1 , R” and R 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 m is 0 to 15.

3. The divalent compound according to claim 1 or 2, characterized in that (I-1) In formula 1, X 1 is C; and X 2 and X 3 is N; Formula I is Formula 1A: in, A, Ar, R 1 , R 2 and R 3 Same as in formula 1; or (I-2) In formula 2, X 1 is C; and X 2 and X 3 is N, and Formula 2 is Formula 2A: in, A, Ar, R 1 , R 2 and R 3 Same as in formula 2.

4. The divalent compound according to claim 1 or 2, characterized in that (I-1) In formula 1, A-Ar-R 1 For the formula A1 part: in, A and R 1 Same as in formula 1; X is selected from: CR ”’ and N, where R ”’ is selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, 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 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 OCO2R 16 , R b OCONR 16 R 17 , R b COR 16 , R b CO2R 16 , R b CONR 16 R 17 , R b SOR 16 , R b S02R 16 , R b SO2NR 16 R 17 , R b NR 18 CO2R 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 S02R 16 , R b NR 18 SO2NR 16 R 17 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynyl, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R b is none, or a divalent or trivalent moiety selected from the group consisting of optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 16 , R 17 and R 18 is independently selected from: none, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 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; or, (I-2) In formula 2, A-Ar-R 1 For the formula B1 part: in, * indicates the connection with the linker part of the divalent compound; A and R 1 Same as in formula 2; X is selected from: CR ”’ and N, where R ”’ is selected from the group consisting of: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylamino, 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 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 OCO2R 16 , R b OCONR 16 R 17 , R b COR 16 , R b CO2R 16 , R b CONR 16 R 17 , R b SOR 16 , R b S02R 16 , R b SO2NR 16 R 17 , R b NR 18 CO2R 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 S02R 16 , R b NR 18 SO2NR 16 R 17 , optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynyl, optionally substituted C2-C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein R b is none, or a divalent or trivalent moiety selected from the group consisting of optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 16 , R 17 and R 18 is independently selected from: none, a bond, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 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.

5. The divalent compound according to claim 1 or 2, characterized in that (I-1) In formula 1, A is None; or, A is NR 4 ,in, R 4 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or, (I-2) In formula 2, A is None; or A is NR 4 ,in, R 4 is selected from the group consisting of: hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

6. The divalent compound according to claim 1 or 2, characterized in that (I-1) In formula 1, Ar-R 1 For the formula A2 or A3 part: in, R 1 Same as in formula 1; or, A-Ar-R 1 For the formula A4, A5 or A6 part: in, R 1 Same as in formula 1; or, (I-2) In formula 2, Ar-R 1 For the formula B2 or B3 part: in, * indicates connection to the linker portion of the divalent compound; and R 1 Same as in Formula 2; or, A-Ar-R 1 For the formula B4, B5 or B6 part: in, * indicates connection to the linker portion of the divalent compound; and R 1 Same as in formula 2.

7. The divalent compound according to claim 1 or 2, characterized in that (I-1) In formula 1, R 1 is selected from: an optionally substituted 3-10 membered carbocyclyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted aryl and an optionally substituted heteroaryl; preferably, R 1 is selected from: optionally substituted aryl and optionally substituted heteroaryl; more preferably, R 1 is selected from: optionally substituted pyrazole and optionally substituted pyridinyl; and / or R 2 is selected from: optionally substituted C1-C8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; and / or R 3 Selected from: COR 14 and CONR 14 R 15 Preferably, R 3 Selected from: COMe and CONHMe; or, (I-2) In formula 2, R 1 is selected from: an optionally substituted 3-10 membered carbocyclylene, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted aryl and an optionally substituted heteroaryl; preferably, R 1 is selected from: optionally substituted aryl and optionally substituted heteroaryl; more preferably, R 1 is selected from: optionally substituted pyrazole and optionally substituted pyridinyl; and / or R 2 is selected from: optionally substituted C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; and / or R 3 Selected from: COR 14 and CONR 14 R 15 Preferably, R 3 Selected from: COMe and CONHMe.

8. The divalent compound according to claim 1 or 2, characterized in that The degradation tag is a portion of Formula 6A: in, R 1 and R 2 independently selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl; and R 3 is selected from the group consisting of hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4 -10 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8 alkylamino C1-C8 alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8 alkoxy C1-C8 alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted Substituted C(O)NC1-C8 alkylaminoC1-C8 alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2 and optionally substituted P(O)(OC1-C8 aryl)2.

9. The divalent compound according to claim 1 or 2, characterized in that The CBP / P300 ligand is selected from the group consisting of: and / or, The degradation tag is selected from the group consisting of:

10. The divalent compound according to claim 1 or 2, characterized in that (I) the CBP / P300 comprises a moiety of formula 1; and (II) The degradation tag is a portion selected from the group consisting of Formula 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5P and 5Q.

11. The divalent compound according to claim 1 or 2, characterized in that (I) The CBP / P300 ligand comprises a moiety of formula 1A: in, The linker portion of the divalent compound is bound to R 2 ; A-Ar-R 1 For the formula A5 part: R 1 is an optionally substituted pyrazole; R 2 is selected from: an optionally substituted C1-C8 alkylene group, an optionally substituted 3-10-membered carbocyclyl group, an optionally substituted 4-8-membered heterocyclyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group; preferably, R 2 An optionally substituted 4-8 membered heterocyclic group; preferably, R 2 optionally substituted piperidine; R 3 Selected from: COR 14 and CONR 14 R 15 ; Furthermore, R 3 Selected from: COMe and CONHMe; R 14 and R 15 Each is independently selected from: hydrogen and C1-C6 alkyl; (II) The degradation tag is a moiety selected from the group consisting of Formula 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5P and 5Q.

12. The divalent compound according to claim 10 or 11, characterized in that The degradation tag is a moiety of formula 5A, 5B, 5C and 5D selected from the group consisting of: in, V, W and X are independently selected from CR 2 and N; Y is selected from: CO and N=N; Z is selected from the group consisting of: CH2, NH and O; and R 1 and R 2 Independently selected from: hydrogen, halogen, cyano, nitro and C1-C5 alkyl.

13. The divalent compound according to claim 2, characterized in that In formula 9, A, B and W, at each occurrence, are independently selected from: none, CO, NH, NH-CO, CO-NH, -(CH2) 0-8 -、 -(CH2) 0-3 -CO-(CH2) 0-8 -、(CH2) 0-8 -NH-CO、(CH2) 0-8 -CO-NH、NH-CO-(CH2) 0-8 、CO-NH-(CH2) 0-8 、(CH2) 1-3 -NH-(CH2) 1-3 -CO-NH、(CH2) 1-3 -NH-(CH2) 1-3 -NH-CO、-CO-NH、CO-NH-(CH2) 1-3 -NH-(CH2) 1-3 、(CH2) 1-3 -NH-(CH2) 1-3 、-(CH2) 0-3 -R r -(CH2) 0-3 、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 - -(CH2) 0-3 -(CO-NH)-(CH2) 0-3 -R r -(CH2) 0-3 -、-(CH2) 0-3 -(NH-CO)-(CH2) 0-3 -R r -(CH2) 0-3 -,as well as -(CH2) 0-3 -(NH)-(CH2) 0-3 -R r -(CH2) 0-3 -。 14. The divalent compound according to claim 2, characterized in that In formula 9, A and B, at each occurrence, are each independently selected from the group consisting of none, CO, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2.

15. The divalent compound according to claim 1 or 2, characterized in that The linker portion degradation tag comprises one or more rings of formula C1a, C2a, C3a, C4a and C5a selected from the group consisting of: in, X' and Y' are independently selected from: N, CR b ; A 1 , B 1 , C 1 and D 1 , at each occurrence, is independently selected from: None, O, CO, SO, SO2, NR b , CR b R c ; A 2 , B 2 , C 2 and D 2 , at each occurrence, independently selected from: N, CR b ; A 3 , B 3 , C 3 , D 3 and E 3 , at each occurrence, is independently selected from: N, O, S, NR b , CR b ; R b and R c , at each occurrence, is independently selected from: hydrogen, halogen, hydroxy, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkyloxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and m 1 、n 1 , o 1 and p 1 Independently selected from 0, 1, 2, 3, 4 and 5.

16. The divalent compound according to claim 1 or 2, characterized in that The length of the linker is 0 to 40 chain atoms; preferably, the length of the linker is 3 to 20 chain atoms; more preferably, the length of the linker is 5 to 15 chain atoms.

17. The divalent compound according to claim 1 or 2, characterized in that The linker is selected from: -(CH2) 0-11 -、-(CH2) 0-3 -CO-(CH2) 0-10 -、-(CO)-(CH2) 3-10 -、-(CH2) 0-3 (CONH)-(CH2) 0-10 -、-(CH2) 0-3 -(CO)-(CH2) 0-5 -R r -(CH2) 0-5 -、-(CH2) 0-3 -(CONH)-(CH2) 0-5 -R r -(CH2) 0-5 - and -(CH2) 0-5 -R r -(CH2) 0-5 Preferably, -(CH2) 0-11 -、-(CH2) 0-3 -CO-(CH2) 0-10 -、-(CO)-(CH2) 3-7 -、-(CH2) 0-3 -(CONH)-(CH2) 3-9 、-(CH2) 1-2 (CO)-NH-(CH2) 3-7 -、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 and -(CH2) 0-3 -R r -(CH2) 1-2 .

18. The divalent compound according to claim 2, characterized in that R r is selected from the formula C1, C2, C3, C4 and C5 as defined in claim 15; preferably, R r Selected from:

19. The divalent compound according to claim 1 or 2, characterized in that "Optionally substituted" means that the specified group may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, OR m , SR m NR n R o , COR m 、CO2R m ,CONR n R o 、SOR m 、SO2R m 、SO2NR n R o NR n COR o NR m C(O)NR n R o NR n SOR o NR n S02R o , C1-C8 alkyl, C1-C8 alkoxy C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkylamino C1-C8 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl and heteroaryl, wherein R m , R n and R o are independently selected from: none, hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, 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; Preferably, "optionally substituted" means that the specified group may be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl.

20. The divalent compound according to claim 1, wherein (I) The CBP / P300 ligand comprises a moiety of formula 1A: in, The linker portion of the divalent compound is bound to R 2 ; A-Ar-R 1 For the formula A5 part: R 1 is an optionally substituted pyrazole; R 2 optionally substituted piperidine; R 3 Selected from: COR 14 and CONR 14 R 15 ; Furthermore, R 3 Selected from: COMe and CONHMe; R 14 and R 15 Each is independently selected from: hydrogen and C1-C6 alkyl; (II) the degradation tag is a moiety selected from the group consisting of Formulas 5A, 5B, 5C and 5D; wherein V, W and X are independently selected from: CR 2 and N; Y is selected from: CO and N=N; Z is selected from the group consisting of: CH2, NH and O; and R 1 and R 2 Independently selected from: hydrogen, halogen, cyano, nitro and C1-C5 alkyl; (III) The connector is selected from: -(CH2) 0-11 -、-(CH2) 0-3 -CO-(CH2) 0-10 -、-(CO)-(CH2) 3-7 -、-(CH2) 0-3 -(CONH)-(CH2) 3-9 、 -(CH2) 1-2 (CO)-NH-(CH2) 3-7 -,、-(CH2) 0-3 -(CO)-(CH2) 0-3 -R r -(CH2) 0-3 、 and -(CH2) 0-3 -R r -(CH2) 1-2 ;in, R r Selected from: "Optionally substituted" means that the specified group may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, CN, C1-C8 alkyl, C1-C8 haloalkyl.

21. The divalent compound according to claim 1, characterized in that The divalent compound is selected from the following group:

22. The divalent compound according to claim 1, characterized in that The divalent compound is 3-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-004) 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-005); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-006); 3-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-007); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-015); 3-(7-(difluoromethyl)-6-(1-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-020); 3-(7-(difluoromethyl)-6-(1-(2-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-026); 3-(7-(difluoromethyl)-6-(1-(2-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-027); 3-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-033); 3-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-034); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-035); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-036); or 3-(7-(difluoromethyl)-6-(1-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-041); 3-(7-(difluoromethyl)-6-(1-(2-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-043); 3-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-085); 3-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-088); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-090); 3-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-091); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-ynyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-093); 3-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-096); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-097); 4-((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)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-100); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)ethyl)piperidin-1-yl)acetyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-104); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)heptanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-106); 3-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-109); 3-(4-((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)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-110); 3-(4-((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)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-111); 4-((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)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-112); 4-((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)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-113); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(6-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)hexanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-115); 3-(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)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-116); 5-((8-(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)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-119); 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)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-120); 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1-(7-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)heptanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-129); 3-(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)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-130); 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)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-131); 2-(4-(1-(5-acetyl-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)-N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)acetamide (P-133); 3-(3-(8-(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)-8-oxooctyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-135); 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)-2-oxoethyl)morpholin-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-142); 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)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-143); 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)-4-oxobutyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-146); 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)-2-oxoethyl)piperidin-4-yl)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-147); 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)-3-oxopropyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-148); 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)methyl)piperidin-1-yl)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-149); 3-(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)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2,6-dione (P-151); 3-(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)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2,6-dione (P-153); 3-(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)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2,6-dione (P-155); 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)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (P-157); 3-(4-((8-(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)-8-oxooctyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-159); 3-(4-((9-(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)-9-oxononyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-160); 3-(5-((8-(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)-8-oxooctyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-161); 3-(5-((9-(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)-9-oxononyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-162); 3-(3-(9-(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)-9-oxononyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-163); 3-(3-(10-(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)-10-oxodecanyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (P-164); 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)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-166); 3-(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)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-173); or 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)phenethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (P-174).

23. A pharmaceutical composition comprising the divalent compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. Use of a divalent compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 22, or a composition as claimed in claim 23, in the preparation of a medicament for treating a disease mediated by CBP / P300; preferably, the disease mediated by CBP / P300 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, dysplasia, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, 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, nipple carcinoma, pinealoma, polycythemia vera, prostate cancer, colorectal 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, Wilm's tumor, breast cancer, 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, Wegener's granulomatosis, acute monocytic leukemia, chronic myeloid leukemia, prostate cancer, and breast cancer.

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