WO2020173440A1 - Cyclic-amp response element binding protein (cbp) and/or adenoviral e1a binding protein of 300 kda (p300) degradation compounds and methods of use - Google Patents

Cyclic-amp response element binding protein (cbp) and/or adenoviral e1a binding protein of 300 kda (p300) degradation compounds and methods of use Download PDF

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WO2020173440A1
WO2020173440A1 PCT/CN2020/076648 CN2020076648W WO2020173440A1 WO 2020173440 A1 WO2020173440 A1 WO 2020173440A1 CN 2020076648 W CN2020076648 W CN 2020076648W WO 2020173440 A1 WO2020173440 A1 WO 2020173440A1
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optionally substituted
alkyl
membered
heterocyclyl
cycloalkyl
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PCT/CN2020/076648
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French (fr)
Inventor
Jing Liu
Michael Bruno Plewe
Jialiang Wang
Xiaoran HAN
Liqun Chen
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Cullgen (Shanghai), Inc.
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Priority to EP20762098.0A priority Critical patent/EP3930759A4/en
Priority to US17/434,587 priority patent/US20230073777A1/en
Priority to CN202080017498.6A priority patent/CN113646002A/en
Publication of WO2020173440A1 publication Critical patent/WO2020173440A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • bivalent compounds e.g., bi-functional small molecule compounds
  • compositions comprising one or more of the bivalent compounds
  • methods of use of the bivalent compounds for the treatment of certain disease in a subject in need thereof The disclosure also relates to methods for identifying such bivalent compounds.
  • a bivalent compound disclosed herein comprises a cyclic -AMP response element binding protein (CBP) and/or adenoviral E1A binding protein of 300 kDa (P300) ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof.
  • CBP cyclic -AMP response element binding protein
  • P300 adenoviral E1A binding protein of 300 kDa (P300) ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof.
  • the CBP/P300 ligand is capable of binding to a CBP/P300 protein comprising a CBP/P300, a CBP/P300 mutant, a CBP/P300 deletion, or a CBP/P300 fusion protein.
  • the CBP/P300 ligand is a CBP/P300 inhibitor or a portion of CBP/P300 inhibitor.
  • 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.
  • the degradation tag binds to an ubiquitin ligase or is a hydrophobic group or a tag that leads to misfolding of the CBP/P300 protein.
  • the ubiquitin ligase is an E3 ligase.
  • the E3 ligase is selected from the group consisting of a cereblon E3 ligase, a VHL E3 ligase, an IAP ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, DCAF16 ligase, RNF4 ligase, RNF114 ligase, and AhR ligase.
  • the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, l-((4,4,5,5,5-pentafluoropentyl)sulfmyl)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.
  • the CBP/P300 ligand is conjugated to the degradation tag via a linker moiety.
  • the CBP/P300 ligand comprises a moiety of FORMULA 1:
  • linker moiety of the bivalent compound is attached to R 2 ;
  • X 1 and X 3 are independently selected from C and N, with the proviso that at least one of X 1 and X 3 is C and at most only one of X 1 and X 3 is N;
  • X 2 is selected from CR’, O, and NR’, wherein R’ is selected from H, optionally substituted Ci-Cg alkyl, and optionally substituted 3-10 membered carbocyclyl;
  • A is selected from null, CR 4 R 5 , CO, O, S, SO, SO2, and NR 4 , wherein
  • R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, optionally substituted C r C x alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C Cs alkoxy, optionally substituted C 1 -C x alkoxyC 1 -C x alkyl.
  • Ci-C 8 alkylamino optionally substituted Ci-CsalkylaminoCi-Csalkyl, 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;
  • Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R 1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, N0 , OR 6 , SR 6 , NR 6 R 7 , OCOR 6 ,
  • OCO2R 6 OCONR 6 R 7 , COR 6 , CO 2 R 6 , CONR 6 R 7 , SOR 6 , SO 2 R 6 , SO 2 NR 6 R 7 , NR 8 CO 2 R 6 , NR 8 COR 6 ,
  • R 6 , R 7 , and R 8 are independently selected from hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr CsalkoxyCi-Csalkyl, optionally substituted C 1 - C x al k y 1 am i n o C 1 - C x al k y 1. 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 atom to which they are connected form a 4-20 membered heterocyclyl ring;
  • R 1 is selected from hydrogen, halogen, CN, N0 2 , OR 9 , SR 9 , NR 9 R 10 , OCOR 9 , 0C0 2 R 9 , OCONR 9 R 10 , COR 9 , C0 2 R 9 , C0NR 9 R 10 , SOR 9 , S0 2 R 9 , S0 2 NR 9 R 10 , NR U C0 2 R 9 , NR U COR 9 , NR U C(0)NR 9 R 10 , NR U C(0)NR 9 R 10 , NR U u SOR 9 , NR U S0 2 R 9 , NR U S0 2 NR 9 R 10 , optionally substituted C' 1 -CN alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-Cs alkoxy, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8
  • R 9 , R 10 , and R 11 are independently selected from hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr CsalkoxyCi-Csalkyl, optionally substituted C 1 - C x al k y 1 am i n o C 1 - C x al k y 1. 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • R 2 is connected to the“linker” moiety of the bivalent compound, and is selected from null, R O, R S, R NR 12 , R OC(O), R 0C(0)0, R OCONR 12 , R C(O), R C(0)0, R CONR 12 , R S(O), R S(0) 2 , R S0 2 NR 12 , R NR 13 C(0)0, R NR 13 C(0), R NR 13 C(0)NR 12 , R NR 13 S(0), R NR 13 S(0) 2 , R NR 13 S(0) 2 NR 12 , optionally substituted C C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted 3-10 membered carbocyclyl,
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl, wherein
  • R is null, or a bivalent moiety selected from optionally substituted Ci-C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted Cr
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R 12 and R 13 are independently selected from optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyCr C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • R 3 is selected from hydrogen, COR 14 , C0 2 R 14 , CONR 14 R 15 , SOR 14 , S0 2 R 14 , S0 2 NR 14 R 15 , optionally substituted C 1 -C ( alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, 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 are independently selected from hydrogen, optionally substituted C 1 -C ( , alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, 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 atom to which they are connected form a 4-20 membered heterocyclyl ring.
  • X 1 is C; and X 2 and X 3 are N.
  • the FORMULA I is FORMULA 1A:
  • A-Ar-R 1 is a moiety of formulae Al:
  • a and R 1 are the same as in FORMULA 1.
  • X is selected from CR”’ and N, wherein
  • R is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
  • R a is optionally formed a ring with A, and is selected from null, hydrogen, halogen, R b NR .
  • R b OR 16 is selected from null, hydrogen, halogen, R b NR .
  • R b NR 18 S0 2 R 16 , R b NR 18 S0 2 NR 16 R 17 optionally substituted C
  • R b is is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-C x alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C x alkoxyCi-C x alkylene, optionally substituted C 1 - C x al k y 1 am i n o C 1 - C x al k y 1 e n e .
  • Ci-Cs haloalkylene optionally substituted C 1 -C x 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 are independently selected from null, hydrogen, optionally substituted C 1 -C x alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr C x alkoxyCi-C x alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 3-20 membered cycloalkyl or heterocyclyl ring.
  • A is null.
  • A is null; Ar is a bicyclic aryl or a bicyclic heteroaryl; and A-Ar-R 1 is a moiety of FORMULAE A2 or A3:
  • R 1 is the same as in FORMULA 1.
  • A is NR 4 , wherein R 4 is selected from hydrogen, optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C i -C 8 alkoxyC i -C 8 alkyl. optionally substituted C I -C 8 alkylaminoC i -C 8 alkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 1 is the same as in FORMULA 1.
  • R 1 is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.
  • R 1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • R 1 is is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
  • R 2 is selected from optionally substituted C i -C 8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocycly, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 3 is selected from COR 14 and CONR 14 R 15 .
  • R 3 is selected from COMe and CONHMe.
  • the CBP/P300 ligand comprises a moiety of FORMULA 2:
  • X 1 and X 3 are independently selected from C and N, with the proviso that at least one of X 1 and X 3 is C and at most only one of X 1 and X 3 is N;
  • X 2 is selected from CR’, O, and NR’, wherein
  • R’ is selected from H, optionally substituted C r C 8 alkyl, and optionally substituted 3-10 membered carbocyclyl;
  • A is selected from null, CR 4 R 5 , CO, O, S, SO, S0 2 , and NR 4 , wherein
  • R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylamino, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3- 10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R 1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, N0 , OR 6 , SR 6 , NR 6 R 7 , OCOR 6 ,
  • OCO 2 R 6 OCONR 6 R 7 , COR 6 , CO 2 R 6 , CONR 6 R 7 , SOR 6 , SO 2 R 6 , SO 2 NR 6 R 7 , NR 8 CO 2 R 6 , NR 8 COR 6 ,
  • R 6 , R 7 , and R 8 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Cr C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 4-20 membered heterocyclyl ring;
  • R 1 is connected to the“linker” moiety of the bivalent compound, and R 1 is selected from null, R O,
  • R S R NR 9 , R OC(O), R 0C(0)0, R OCONR 9 , R C(O), R C(0)0, R CONR 9 , R S(O), R S(0) 2 ,
  • R is null, or a bivalent moiety selected from optionally substituted Ci-C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted Cr
  • R 9 and R 10 are independently selected from optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyCi- C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • R 2 is selected from hydrogen, halogen, CN, N0 2 , OR 11 , SR 11 , NR U R 12 , OCOR 11 , OC0 2 R u , OCONR u R 12 , COR 11 , C0 2 R u , CONR U R 12 , SOR 11 , S0 2 R u , S0 2 NR u R 12 , NR 13 C0 2 R u , NR 13 COR u , NR 13 C(0)NR u R 12 ,NR 13 S0R u , NR 13 S0 2 R u , NR 13 S0 2 NR U R 12 , optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylamin
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Cr C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
  • R and R , R and R together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • R 3 is selected from hydrogen, COR 14 , C0 2 R 14 , CONR 14 R 15 , SOR 14 , S0 2 R 14 , S0 2 NR 14 R 15 , optionally substituted C i -C ( alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, wherein
  • R 14 and R 15 are independently selected from hydrogen, optionally substituted C i -C ( , alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, and optionally substituted 4-6 membered heterocyclyl, or
  • R 14 and R 15 together with the atom to which they are connected form a 4-6 membered heterocyclyl ring.
  • X 1 is C; and X 2 and X 3 are N.
  • the FORMULA 2 is FORMULA 2A:
  • A-Ar-R 1 is a moiety of formulae B 1 :
  • a and R 1 are the same as in FORMULA 2;
  • X is selected from CR”’ and N, wherein R and is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C 6 alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted C i -C ( alkoxy, optionally substituted C i -C ( alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl; and
  • R a optionally forms a ring with A, and is selected from null, hydrogen, halogen, R b NR 16 , R b OR 16 ,
  • R b NR 18 S0 2 R 16 , R b NR 18 S0 2 NR 16 R 17 optionally substituted C
  • R b is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted Ci-C 8 alkoxyCi-C 8 alkylene, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkylene, optionally substituted Ci-C 8 haloalkylene, optionally substituted C r C 8 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 are independently selected from null, a bond, hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring.
  • A is null.
  • A is null;
  • Ar is a bicyclic aryl or a bicyclic heteroaryl; and
  • A-Ar-R 1 is a moiety of FORMULAE B2 or B3:
  • R 1 is the same as in FORMULA 2.
  • A is NR 4 , wherein
  • R 4 is selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • A is NR 4 ; and A-Ar-R 1 is a moiety of FORMULAE B4, B5 or B6:
  • R 1 is the same as in FORMULA 2.
  • R 1 is selected from optionally substituted 3-10 membered carbocyclylene, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • R 1 is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
  • R 2 is selected from optionally substituted C i -C x alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 3 is selected from COR 14 and CONR 14 R 15 .
  • R 3 is selected from COMe and CONHMe.
  • the CBP/P300 ligand is derived from any of the following:
  • the CBP/P300 ligand is derived from the following CBP/P300 inhibitors: C646, naphthol-AS-E, compound 1-10, MYBMIM, CCS 1477, ICG-001, YH249, YH250, HBS1, OHM1, and KCN1.
  • the CBP/P300 ligand is selected from the group consisting of:
  • the degradation tag is a moiety selected from the group consisting of
  • V, W, and X are independently selected from CR 2 and N;
  • R 1 , and R 2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
  • R 3 , and R 4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 3 and R 4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
  • R 5 and R 6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C ( alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 5 and R 6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl.
  • the degradation tag is a moiety selected from the group consisting of
  • V, W, and X are independently selected from CR 2 and N;
  • Z is selected from CH 2 , NH and O;
  • R 1 and R 2 are independently selected from hydrogen, halogen, cyano, nitro, and C 1 -C 5 alkyl.
  • the degradation tag is a moiety selected from the group consisting of FORMULAE 5E, 5F, 5G, 5H, and 51:
  • 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 CH 2 , NH, NG3 ⁇ 4 and O;
  • R 1 , and R 2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
  • R 3 , and R 4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 3 and R 4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
  • R 5 and R 6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 5 and R 6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl.
  • the degradation tag is a moiety selected from the group consisting of FORMULAE 5J, 5K, 5L, 5M, 5N, 50, 5P, and 5Q:
  • U, V, W, Y, X, Z, R 1 , and R 2 are defined as in FORMULAE 5E, 5F, 5G, 5H, or 51;
  • Y’, Y”, and Y”’ are independently selected from CR 3 R 4 ;
  • X’ are independently selected from CR 2 and N;
  • R’ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl.
  • the degradation tag is a moiety of FORMULA 6A:
  • R 1 and R 2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C r C x alkyl, optionally substituted C -C alkenyl, and optionally substituted C -C alkynyl, optionally substituted C -C x alkoxyC -C x alkyl.
  • optionally substituted C -C x haloalkyl optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 aminoalkyl, optionally substituted Ci- CsalkylaminoCi-Csalkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4- 10 membered heterocyclyl.
  • R 3 is selected from hydrogen, optionally substituted C(0)Ci-C 8 alkyl, optionally substituted C(0)Cr CsalkoxyCi-Csalkyl, optionally substituted C(0)Ci-C 8 haloalkyl, optionally substituted C(0)Ci-C 8 hydroxyalkyl, optionally substituted C(0)Ci-C 8 aminoalkyl, optionally substituted C(0)Cr
  • CsalkylaminoCi-Csalkyl optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C 2 -C 8 alkenyl, optionally substituted C(0)C 2 -C 8 alkynyl, optionally substituted C(0)OCi-C 8 alkoxyCi-C 8 alkyl, optionally substituted C(0)0Ci-C 8 haloalkyl, optionally substituted C(0)0Ci-C 8 hydroxyalkyl, optionally substituted C(0)0Cr C 8 aminoalkyl, optionally substituted C(0)OCi-C 8 alkylaminoCi-C 8 alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C -C 8 alkenyl, optionally substituted C(0)0
  • the degradation tag is a moiety of FORMULAE 6B, 6C, and 6D:
  • R 1 and R 2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl;
  • Ci-C 8 alkoxyCi-C 8 alkyl optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 aminoalkyl, optionally substituted Cr
  • R 3 is selected from hydrogen, optionally substituted C(0)Ci-C 8 alkyl, optionally substituted C(0)Cr C 8 alkoxyCi-C 8 alkyl, optionally substituted C(0)Ci-C 8 haloalkyl, optionally substituted C(0)Ci-C 8 hydroxyalkyl, optionally substituted C(0)Ci-C 8 aminoalkyl, optionally substituted C(0)Cr
  • C 8 alkylaminoCi-C 8 alkyl optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C 2 -C 8 alkenyl, optionally substituted C(0)C 2 -C 8 alkynyl, optionally substituted C(0)OCi-C 8 alkoxyCi-C 8 alkyl, optionally substituted
  • C(0)OCi-C 8 haloalkyl optionally substituted C(0)OCi-C 8 hydroxyalkyl, optionally substituted C(0)OCr C 8 aminoalkyl, optionally substituted C(0)OCi-C 8 alkylaminoCi-C 8 alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C 2 -C 8 alkenyl, optionally substituted C(0)0C 2 -C 8 alkynyl, optionally substituted C(0)NCi-C 8 alkoxyCi-C 8 alkyl, optionally substituted C(0)NCi-C 8 haloalkyl, optionally substituted C(0)NC I -C 8 hydroxyalkyl, optionally substituted C(0)NCi-C 8 aminoalkyl, optionally substituted C(0)NCi-C 8 alkylaminoCi-C 8 alkyl, optionally substituted C(O
  • R 4 is selected from NR 7 R 8 , optionally substituted Ci-C 8 alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteraryl, in which
  • R is selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C r
  • C 8 cycloalkyl optionally substituted Ci-C 8 alkyl-CO, optionally substituted Ci-C 8 cycloalkyl-CO optionally substituted Ci-C 8 cycloalkyl-Ci-C 8 alkyl-CO, optionally substituted 4-10 membered heterocyclyl-CO, optionally substituted 4-10 membered heterocyclyl-Ci-C 8 alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-Ci-C 8 alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-Ci-C 8 alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 8 is selected from hydrogen, optionally substituted Ci-C 8 alkyl, and optionally substituted Cr C 8 cycloalkyl;
  • R 9 is independently selected from hydrogen, halogen, cyano, optionally substituted Ci-C 8 alkyl, optionally substituted Ci-C 8 cycloalkyl, optionally substituted Ci- C 8 heterocycloalkyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Ci-C 8 cycloalkoxy, halo substituted Ci-C 8 alkyl, halo substituted Ci-C 8 cycloalkyl, halo substituted Ci-C 8 alkoxl, halo substituted Ci- C 8 cycloalkoxy, and halo substituted Ci-C 8 heterocycloalkyl;
  • X is selected from CH and N;
  • n 0, 1, 2, 3, or 4;
  • R 6 is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci- C 8 alkyl, optionally substituted Ci-C 8 cycloalkyl, optionally substituted Ci-C 8 alkoxy, and optionally substituted Ci-C 8 cycloalkoxy, optionally substituted Ci-C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, preferably, halogen , cyano, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted oxadiazole, optionally substituted triazole, 4- methylthiazol-5-yl, or oxazol-5-yl group.
  • the degradation tag is a moiety of FORMULA 7A:
  • V, W, X, and Z are independently selected from CR 4 and N;
  • R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl; optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Cr C 8 alkylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.
  • the degradation tag is a moiety of FORMULA 7B:
  • Ci-Cg hydroxyalkyl optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl;
  • R 4 and R 5 are independently selected from hydrogen, COR 6 , CO2R 6 , CONR 6 R 7 , SOR 6 , SO2R 6 , S0 NR 6 R 7 , optionally substituted Ci-C 8 alkyl, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted C 1 -C ⁇ alkylaminoC 1 -C x alkyl. optionally substituted aryl-Ci-Csalkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
  • R 6 and R 7 are independently selected from hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C 1 -C x alkoxyC 1 -C x alkyl. optionally substituted C 1 -C ⁇ alkylaminoC 1 -C x alkyl. optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
  • R 6 and R 7 together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.
  • the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, and 51.
  • the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, and 5F.
  • the degradation tag is derived from any of the following:
  • the degradation tag is derived from any 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.
  • the degradation tag is selected from the group consisting of:
  • the degradation tag is selected from the group consisting of: FORMULA 8 A 8B, 8C, 8D, 8E, 8F, 8G, 8H, 81, 8J, 8K, 8L, 8M, 80, 8P, 8Q, 8R, 8AQ, 8AR, 8AS, 8AT, 8AU, 8AV, 8AW, 8 AX, 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, 8 CM, 8CN, 8CO, 8CP, 8CQ, 8CR, 8CS, 8CT, 8CU, 8CV, 8CW, 8CX, 8CY, 8CZ, 8DA, 8DB, 8DC, 8DD, 8
  • the linker moiety is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl linker moiety
  • A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR ” , R C0 2 R , R C(0)N(R 1 )R , R C(S)N(R 1 )R , R OR , R SR , R SOR , R S0 2 R ,
  • R and R are independently selected from null, optionally substituted (C C 8 alkylene)-R r (preferably, CH 2 -R r ), optionally substituted R r -(Ci-C 8 alkylene), optionally substituted (Ci-C 8 alkylene)- R r -(Ci-C 8 alkyl), or a moiety comprising of optionally substituted Ci-C 8 alkyl, optionally substituted C 2 - C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R r is 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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C -C alkenyl, optionally substituted C -C alkynyl, optionally substituted C -C x alkoxyalkyl, optionally substituted C Cs haloalkyl, optionally substituted Ci-Cs hydroxyalkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • m 0 to 15.
  • W and m are defined as above; and A and B, at each occurrence, are
  • R r is selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined hereinafter.
  • R r is selected from FORMULA Cl, C2, C3, C4, and C5 as defined hereinafter.
  • R r is selected from Group R, and Group R consists of
  • the linker moiety is of FORMULA 9A:
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl amino, cyano, nitro, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Ci-C 8 alkoxyalkyl, optionally substituted C r C 8 haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkylamino, and optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered membered heterocyclyl, optionally substituted aryl, and optionally
  • R 1 and R 2 , R 3 and R 4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR , R C0 2 R , R C(0)N(R 5 )R , R C(S)N(R 5 )R , R OR , R SR , R SOR , R S0 2 R
  • R and R are independently selected from null, optionally substituted (C C 8 alkylene)-R r (preferably, CH 2 -R r ), optionally substituted R r -(Ci-C 8 alkylene), optionally substituted (Ci-C 8 alkylene)- R r -(Ci-C 8 alkylene), or a moiety comprising of optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R r is 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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
  • R 5 and R 6 are independently selected from hydrogen, optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyalkyl, optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • n 0 to 15;
  • n at each occurrence, is 0 to 15;
  • o 0 to 15.
  • A, W and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -, -(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -, (CH 2 ) 0-8 -NH-CO, (CH 2 ) 0-8 -CO-NH, NH-CO- (CH 2 ) O-8 , CO-NH-(CH 2 ) O-8 , (CH 2 ) !-3 -NH-(CH 2 ) 1 3 -CO-NH, (CH 2 ) !-3 -NH-(CH 2 ) 1 3 -NH-CO, -CO-NH, CO-NH- (CH 2 ) !-3 -NH-(CH 2 ) !-3 , (CH 2 ) , 3 -NH-(CH 2 ) ,_ 3 .
  • R r is selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined hereinafter.
  • R r is selected from FORMULA Cl, C2, C3, C4, and C5 as defined hereinafter.
  • R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • the CBP/P300 ligand of the bivalent compound is attached to A in FORMULA
  • A (when A is attached to the CBP/P300 ligand) is selected from null, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -, -(CH 2 )o- 3 -CO-(CH 2 )o- 8 -, (CH 2 ) 0.8 -NH-CO, (CH 2 ) 0.8 -CO-NH, NH-CO-
  • R r is selected from Group R, and Group R is defined as in FORMULA 9;
  • the linker moiety is of FORMULA 9A:
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, optionally substituted C C 8 alkyl (preperably, C 1 -C 4 alkyl), or
  • R 1 and R 2 , R 3 and R 4 together with the atom to which they are connected form a 3-20 membered cycloalkyl (preferably, 3-5 membered cycloalkyl) or 4-20 membered heterocyclyl ring;
  • A is defined as before; and W and B are null;
  • n is 0 to 15 (preferably, m is 0, 1, or 2);
  • n at each occurrence, is 1 to 15 (preferably, n is 1);
  • o is 1 to 15(preferably, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13).
  • A is independently selected from null, or bivalent moiety selected from R -
  • R S0 2 N(R 5 )R , RN(R 5 )R , RN(R 5 )COR , RN(R 5 )CON(R 6 )R , RN(R 5 )C(S)R R and R are defined as above.
  • R and R are independently selected from null, optionally substituted (C r C 8 alkyl)-R r (preferably, CH 2 -R r ), or optionally substituted Ci-C 8 alkyl (preferably, optionally substituted Cr C 2 alkyl).
  • linker moiety i i
  • R 1 and R 2 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C i -C 8 alkyl, optionally substituted C r C 8 alkoxy, optionally substituted C r C 8 alkoxy C r C 8 alkyl, optionally substituted C
  • R 1 and R 2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or
  • a and B are independently selected from null, or bivalent moiety selected from R -R , R COR , R C0 2 R , R C(0)N(R 3 )R , R C(S)N(R 3 )R , R OR , R SR , R SOR , R S0 2 R ,
  • R and R are independently selected from null, optionally substituted (Ci-C 8 alkylene)-R r (preferably, CH 2 -R r ), optionally substituted R r -(Ci-C 8 alkylene), optionally substituted (Ci-C 8 alkylene)- R r -(Ci-C 8 alkylene), or a moiety comprising of optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene,
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -Ci 3 fused cycloalkyl, optionally substituted C 3 -Ci 3 fused heterocyclyl, optionally substituted C 3 -Ci 3 bridged cycloalkyl, optionally substituted C 3 -Ci 3 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 3 and R 4 are independently selected from hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C -C 8 alkenyl, optionally substituted C -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyalkyl, optionally substituted Ci-Cs haloalkyl, optionally substituted Ci-Cs hydroxyalkyl, optionally substituted C I -C’salkylaminoC 1 -C x alkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • each m is 0 to 15;
  • n 0 to 15.
  • a and B are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH 2 ) O-8 -, -(CH 2 ) O -3-CO-(CH 2 ) O -8-, (CH 2 ) O-8 -NH-CO, (CH 2 ) O-8 -CO-NH, NH-CO-(CH 2 )
  • R r is selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined hereinafter.
  • R r is selected from FORMULA Cl, C2, C3, C4, and C5 as defined hereinafter.
  • R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • linker moiety is of FORMULA 9C:
  • X is selected from O, NH, and NR 7 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C
  • -C x alkyl optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroary
  • a and B are independently selected from null, or bivalent moiety selected from R -R , R COR ,
  • R CO2R R C(0)N(R 8 )R , R C(S)N(R 8 )R , R OR , R SR , R SOR , R S0 2 R , R S0 2 N(R 8 )R , R N(R 8 )R RN(R 8 )COR , RN(R 8 )CON(R 9 )R , RN(R 8 )C(S)R , optionally substituted Ci-Cs alkylene, optionally substituted C -C 8 alkenylene, optionally substituted C -C 8 alkynylene, optionally substituted C
  • C x alkoxyCi-C x alkylene optionally substituted Ci-Cs haloalkylene, optionally substituted Ci-Cs hydroxyalkylene, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C 3 -Ci 3 spiro
  • heterocyclyl 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 null, optionally substituted (C C 8 alkylene)-R r (preferably, CH -R r ), optionally substituted R r -(C C x alkylene), optionally substituted (C r C 8 alkylene)- R r -(C
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -Ci 3 fused cycloalkyl, optionally substituted C 3 -Ci 3 fused heterocyclyl, optionally substituted C 3 -Ci 3 bridged cycloalkyl, optionally substituted C 3 -Ci 3 bridged heterocyclyl, optionally substituted C 3 -Ci 3 spiro cycloalkyl, optionally substituted C 3 -Ci 3 spiro
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R 7 , R 8 and R 9 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyalkyl, optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • n 0 to 15;
  • n at each occurrence, is 0 to 15;
  • o 0 to 15;
  • p 0 to 15.
  • a and B are independently selected from null, CO, NH, NH-CO, CO-NH, -
  • R r is selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined hereinafter.
  • R r is selected from FORMULA Cl, C2, C3, C4, and C5 as defined hereinafter.
  • R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • a and B are independently selected from null, CO, NH, NH-CO, CO-NH, CH 2 -NH-CO, CH 2 -CO-NH, NH-CO-CH 2 , CO-NH-CH 2 , CH 2 -NH-CH 2 -CO-NH, CH 2 - NH-CH 2 -NH-CO, -CO-NH, CO-NH- CH 2 -NH-CH 2 , CH 2 -NH-CH 2
  • o is 0 to 5.
  • the linker moiety comprises one or more rings selected from the group consisting of 3 to 13 membered rings, 3 to 13 membered fused rings, 3 to 13 membered bridged rings, and 3 to 13 membered spiro rings.
  • the linker moiety comprises one or more rings selected from the group consisting of
  • X’ and Y’ are independently selected from N, CR b ;
  • a 1 , B 1 , C 1 and D 1 are independently selected from null, O, CO, SO, SO2, NR b , CR b R c ;
  • a 2 , B 2 , C 2 , and D 2 at each occurrence, are independently selected from N, CR b ;
  • a 3 , B 3 , C 3 , D 3 , and E 3 at each occurrence, are independently selected from N, O, S, NR b , CR b ;
  • R b and R c are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C r C x alkyl optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1 -C x alkoxy, optionally substituted C
  • n 1 , o 1 and p 1 are independently selected from 0, 1, 2, 3, 4 and 5.
  • the linker moiety comprises one or more rings selected from the group consisting of
  • the linker moiety is of FORMULA 9A.
  • A, W and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -, -(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -, (CH 2 ) 0-8 -NH-CO, (CH 2 ) 0-8 -CO-NH, NH-CO-
  • R r is selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined above.
  • R r is selected from FORMULA Cl, C2, C3, C4, and C5 as defined above.
  • R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • a and B are independently defined as above, and W is null.
  • the length of the linker is 0 to 40 chain atoms.
  • the length of the linker is 3 to 20 chain atoms.
  • the length of the linker is 5 to 15 chain atoms.
  • A is selected from -(CO)-, -(CH 2 ) !-2 (CO)-NH-, -(CH 2 ) 0-8 -, -(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -, -(CH 2 )o- 3 -R r -(CH 2 ) 0-3 , - (CH 2 )o- 3 -(CO)-(CH 2 )o- 3 -R r -(CH 2 ) 0-3 , wherein
  • R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • the linker is -(CO)-(CH 2 ) 3 _7-.
  • the linker is -(CH 2 )I_ 2 (CO)-NH-(CH 2 ) 3 _7-.
  • the linker is -(CH 2 ) 0 _n-, or -(CH 2 ) 0 -3-CO-(CH 2 ) 0 -I O -.
  • the linker is -(CH 2 ) 0 -3-R r -(CH 2 ) 0 -3-, or -(CH 2 )o-3-(CO)-(CH 2 ) 0 -3-R r -(CH 2 ) 0 -3-, wherein R r is selected from the group Group R, and Group R is defined as in FORMULA 9.
  • 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.
  • the bivalent 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 a
  • the bivalent compound is 3-(7-(difluoromcthyl)-6-( I -methyl- 1 //-pyrazol-4-yl)- 3 ,4-dihydroquinolin- 1 (2H)-y ⁇ )- 1 -( 1 -(5 -((2-(2,6-dioxopiperidin-3-yl)- 1 ,3 -dioxoisoindolin-5 - yl)amino)pcntanoyl)pipcridin-4-yl)-/V-mcthyl- 1.4.6.7-tctrahydro-5//-pyrazolo
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-lH-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((6-((2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)amino)hexyl)amino)-2-oxoethyl)- 1 / -pyrazol-4-yl)-3 ,4- dihydroquinolin- 1 (2//)-yl)-/V-methyl- 1 -(tctrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((7-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)heptyl)amino)-2-oxoethyl)-l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-N-mcthyl- 1 -(tetrahydro-2//-pyran-4-yl)- 1 ,4,6,7-tetrahydro-5//-pyrazolo[4,3- c]pyridine-5 -carboxamide (P-026).
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((8-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)octyl)amino)-2-oxoethyl)-l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-/V-methyl- 1 -(tctrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((6-((2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl)- 1 / -pyrazol-4-yl)-3 ,4- dihydroquinolin- 1 (2 /)-yl)-/V-methyl- 1 -(tctrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((8-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)octyl)amino)-2-oxoethyl)-l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2 /)-yl)-/V-methyl- 1 -(tetrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 4-((6-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l-methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
  • the bivalent compound is 3 -(4-((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 /-pyrazolo
  • the bivalent compound is 3 -(4-((7-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo
  • the bivalent compound is 4-((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l -methyl - 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 / -pyrazolo
  • the bivalent compound is 4-((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l -methyl - 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
  • the bivalent compound is 3 -(5 -((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 / -pyrazolo
  • the bivalent compound is 5-((8-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l-methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 5 -((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l -methyl - 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 / -pyrazolo
  • the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
  • the bivalent compound is 3-(5-((7-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- mcthyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 4-(2-(l-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 2-(4-(l -(5 -acetyl- l-(tetrahydro-2H-pyran-4-yl)- 4.5.6.7-tctrahydro- 1 /-pyrazolo
  • the bivalent compound is 3-(3-(8-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo
  • the bivalent compound is 4-(((4-(2-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo
  • the bivalent compound is 4-(((l-(2-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo
  • the bivalent compound is 4-(3-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 4-(3-(l-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo
  • the bivalent compound is 4-(2-(l-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 4-(3-(4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 3 -(5 -((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo
  • the bivalent compound is 3 -(5 -((7-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo
  • the bivalent compound is 3-(5-((5-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 4-(2-(l-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 3-(4-((8-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 3 -(4-((9-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- mcthyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo
  • the bivalent compound is 3-(5-((8-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 3 -(5 -((9-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo
  • the bivalent compound is 3-(3-(9-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo
  • the bivalent compound is 3-(3-(10-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo
  • the bivalent compound is 3-(4-((4-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 3 -(4-((4-(2-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo
  • the bivalent compound is 3 -(4-(4-((4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l-methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo
  • composition disclosed herein comprises the bivalent compound or a pharmaceutically acceptable salt or analog thereof, and a pharmaceutically acceptable carrier or diluent.
  • a method of treating a CBP/P300-mediated disease disclosed herein comprises administering to a subject with a CBP/P300-mediated disease the bivalent compound or a pharmaceutically acceptable salt or analog thereof.
  • the CBP/P300-mediated disease results from CBP/P300 expression, mutation, deletion, or fusion.
  • the subject with the CBP/P300-mediated disease has an elevated CBP/P300 function relative to a healthy subject without the CBP/P300-mediated disease.
  • the bivalent compound is selected from the group consisting of P-001 to P-174, and CPD-1139 to CPD-1179, or analogs thereof.
  • the bivalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.
  • the method further comprises administering to the subject an additional therapeutic regimen for treating cancer, inflammatory disorders, or autoimmune diseases.
  • the additional therapeutic regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.
  • the CBP/P300-mediated cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymph
  • oligodendroglioma oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer,
  • the CBP/P300-mediated cancer is selected from the group consisting of prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and melanoma.
  • the CBP/P300-mediated inflammatory disorders or the autoimmune diseases are selected from the group consisting of 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 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, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.
  • the CBP/P300-mediated disease is a relapsed cancer.
  • the CBP/P300-mediated disease is refractory to one or more previous treatments.
  • a method for identifying a bivalent compound which mediates degradation or reduction of CBP/P300 comprises:
  • heterobifunctional test compound comprising an CBP/P300 ligand conjugated to a degradation tag through a linker
  • the cell is a cancer cell.
  • the cancer cell is a CBP/P300-dependent cancer cell.
  • FIG. 1 shows immunoblots of P300 protein expressed by LNCaP cells after treatment with 5 nM GNE-781 or heterobifunctional compounds P-001 to P-036.
  • FIG. 2 shows immunoblots of P300 protein expressed by LNCaP cells after treatment with GNE-781, P-003, P-004, P-005, P-015, P-016, or P-020 at indicated concentrations.
  • FIG. 3 shows an immunoblot of P300 protein expressed by LNCaP cells after treatment with GNE- 781, P-004, P-005, P-015, or P-020 at various timepoints.
  • FIG. 4 shows a graph of LNCaP cell viability vs. concentrations of GNE-781, P-001, P-002, and P-
  • FIG. 5 shows an immunoblot of P300 and CBP protein expressed by LNCaP cells after treatment with GNE-781 or heterobifimctional compounds P-056, P-57, P-58, P-59, P-060, P-062, P-063, P-067, P- 068 or P-069.
  • FIG. 6 shows immunoblots of P300 and CBP protein expressed by LNCaP cells after treatment with P-084 to P-093, P-096, P-097, P-100, P-102, or P-104 to P-108 at indicated concentrations.
  • FIG. 7A shows an immunoblot of P300 protein expressed by LNCaP cells after treatment with heterobifimctional compounds P-034 or P-034-neg at indicated concentrations.
  • FIG. 7B shows an immunoblot of P300 protein expressed by 22RV 1 cells after treatment with heterobifimctional compounds P-034 or P-034-neg at indicated concentrations.
  • FIG. 8 shows an immunoblot of P300 and CBP protein 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.
  • FIG. 9 shows an immunoblot of P300 and CBP protein expressed in subcutaneous 22RV1 xenograft tumors after treatment with a single dose of 40 mg/kg P-100, P-007, or P-034 via intraperitoneal injection (i.p.) or oral gavage (p.o.).
  • FIG. 10 shows immunoblots of P300 and CBP protein expressed by LNCaP cells (Fig. 10A-B) or 22RV 1 cells (Fig.10C-E) after treatment with heterobifimctional compounds P-095 or P- 109 to P- 131 at indicated concentrations.
  • FIG. 11 shows immunoblots of P300 and CBP protein expressed by LNCaP cells (Fig.l 1B-E) or 22RV1 cells (Fig.11 A) after treatment with heterobifimctional compounds P-142 to P-174 at indicated concentrations.
  • FIG. 12 shows immunoblots of CBP protein expressed in the lung tissues of ICR mice after treatment with a single dose of 40 mg/kg indicated heterobifimctional compounds via oral gavage (p.o.).
  • P300 encoded by EP300
  • CBP lysine acetyltransferases
  • HATs lysine acetyltransferases
  • the best defined substrates of P300 and CBP are histones. Acetylation of histones modulates the conformation of chromatin and generally leads to transcription activation.
  • recruiting P300 and/or CBP is essential for many transcription factors and other transcription regulators to effectively promote regional transcription (Dancy and Cole, 2015).
  • Substrates of P300 and CBP also include many non-histone proteins that have crucial physiological and pathological functions, such as p53, MYC, FOXOl, and NF-KB (Dancy and Cole, 2015). Because P300 and CBP functionally interact with a wide variety of signaling proteins, these two lysine
  • acetyltransferases act as the converge point of many signal transduction pathways (Bedford et al., 2010). Through modulating acetylation of diverse substrates and connecting a multitude of binding partners,
  • P300 and CBP are widely implicated in biological processes, such as cellular proliferation, differentiation, development, DNA repair, inflammation, metabolism, and memory.
  • P300 and CBP are indispensable for development, as mice deficient in either P300 or CBP die early during embryogenesis (Goodman and Smolik, 2000). Aberrant P300 or CBP are associated with a wide range of human diseases. Germline mutations that inactivate one of CREBBP alleles result in the Rubinstein-Taybi syndrome (Petrij et al., 1995), probably due to impaired activation of the Hedgehog family transcription factors. Both P300 and CBP are known to contribute to hematopoiesis, through interaction with hematopoietic transcription factors, such as GATA-1 (Blobel, 2000). Tumor suppressive roles of P300 and CBP have been well defined.
  • P300 has been reported to regulate immune cell functions (Liu et al., 2013). Further, P300 and CBP are important transcription co-activators for the STAT and NF- KB family transcription factors (Nadiminty et al., 2006; Wang et al., 2005; Wang et al., 2017), which have crucial functions in immune cells. Therefore, P300/CBP antagonizers may be employed to modulate activities of the immune system and the crosstalk between immune cells and cancer cells (Liu et al., 2013). Finally, it has been extensively documented that histone acetylation is crucially implicated in
  • P300 and CBP share nearly 75% similarity and 63% identity in protein sequences. Greater homology is found in functional domains that are highly conserved during evolution. Most of these domains mediate protein-protein interactions, such as the Cysteine-Histidine-rich region 1 (CHI), the CREB-interacting KIX domain, the Cysteine-Histidine-rich region (CH3), and the nuclear receptor co-activator binding domain (Wang et al., 2013a). However, these domains are less amenable to small molecule-mediated intervention. Only few inhibitors have been reported.
  • CHI Cysteine-Histidine-rich region 1
  • CH3 Cysteine-Histidine-rich region
  • nuclear receptor co-activator binding domain Wang et al., 2013a
  • KCN1 Shi et al., 2012; Yin et al., 2012
  • OHM1 Lao et al., 2014
  • HBS1 Kushal et al., 2013
  • KCN1 analogs Feguson et al., 2017
  • ICG-001 (Emami et al., 2004) was reported as selective inhibitor of CBP NRID/b -eaten in interactions.
  • YH249 and YH250 (Yusuke et al., 2016) were reported to selectivily inhibit P300-dependent transcription.
  • Recent efforts to develop small molecule probes for P300 and CBP are concentrated on the HAT domain and the bromodomain.
  • the HAT domain is responsible to catalyze transfer of acetyl groups, while the bromodomain binds to acetylated lysine residues, which promotes interaction of P300 and CBP to acetylated chromatin.
  • 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),
  • I-CBP112 Paned et al., 2015
  • TPOP146 Popp et al., 2016
  • CPI-637 Teylor et al., 2016
  • SGC- CBP30 Hammitzsch et al., 2015; Hay et al., 2014
  • CPD 11 Denny et al., 2017
  • CPD 41 Denny et al.,
  • HAT or bromodomain inhibitors have exhibited anti-cancer activities in a wide range of human cancers, including but are not limited to prostate cancer (Jin et al., 2017; Lasko et al., 2017), breast cancer (Y ang 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.,
  • P300 and CBP have multiple functional domains. Blockade of either the HAT domains or the bromodomains only lead to partial inhibition of their activities. The scaffolding functions P300 and CBP are not effectively modulated by these small molecule inhibitors. Second, the HAT domains and the bromodomains of P300 and CBP share significant homology so that most small molecule compounds do not effectively differentiate these two targets. Conversely, P300 and CBP have distinct tissue type-dependent roles. For example, in prostate cancer, P300 is the dominating co-activator of androgen receptor, while CBP has limited roles (Ianculescu et al., 2012).
  • the present disclosure is believed to be based, at least in part, on the discovery that novel heterobifimctional small molecules which degrade CBP/P300, CBP/P300 fusion proteins, and/or CBP/P300 mutant proteins (“PROteolysis TArgeting Chimeras”/“PROTACs” and “Specific and Nongenetic IAP-dependent Protein Erasers”/“SNIPERs”) are useful in the treatment of CBP/P300-mediated diseases, particularly prostate cancer (Jin et al., 2017; Lasko et al., 2017), breast cancer (Y ang 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).
  • prostate cancer Jin et al., 2017; Lasko et al., 2017
  • breast cancer Y ang e
  • Selective degradation of a target protein induced by a small molecule may be achieved by recruiting an E3 ubiquitin ligase and mimicking protein misfolding with a hydrophobic tag (Buckley and Crews, 2014).
  • PROTACs are bivalent inhibitors having one moiety that binds to an E3 ubiquitin ligase and another moiety that binds the protein target of interest (Buckley and Crews, 2014). The induced proximity leads to ubiquitination of the target followed by its degradation via proteasome-mediated proteolysis.
  • E3 ligase ligands have been identified or developed.
  • IMDs immunomodulatory drugs
  • thalidomide and pomalidomide which bind cereblon
  • CRL4CRBN cullin-RING ubiquitin ligase
  • VHL-1 a hydroxyproline-containing ligand, which binds van Hippel-Lindau protein (VHL or CRL2VHL)
  • VHL or CRL2VHL van Hippel-Lindau protein
  • the PROTAC technology has been applied to degradation of several 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).
  • a hydrophobic tagging approach which utilizes a bulky and hydrophobic adamantyl group, has been developed to mimic protein misfolding, leading to the degradation of the target protein by proteasome (Buckley and Crews, 2014).
  • This approach has been applied to selective degradation of the pseudokinase HER3 (Xie et al., 2014).
  • the inventors have not yet seen any efforts applying any of these approaches to degradation of CBP/P300, CBP/P300 mutant, CBP/P300 deletion, or CBP/P300 fusion proteins.
  • CBP/P300 inhibitors such as GNE-781, GNE-272, GNE-207, CPD 4d, CPD (S)-8, CPD (R)-2, CPD6, CPD19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD 11, CPD 41, CPD 30, CPD 5, CPD 27, CPD 29, CCS 1477 (clinical trial ID: NCT03568656), C646 (Oike et al., 2014), A-485, naphthol-AS-E (Uttarkar et al., 2015), compound 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
  • a novel approach is taken: to develop compounds that directly and selectively modulate not only the protein-protein interactions and acetyltransferase activity of CBP/P300, but also their protein levels.
  • Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, mimicking protein misfolding with hydrophobic tags, and inhibiting chaperones.
  • Such an approach based on the use of bivalent small molecule compounds, permits more flexible regulation of protein levels in vitro and in vivo compared with techniques such as gene knockout or short hairpin RNA- mediated (shRNA) knockdown.
  • shRNA short hairpin RNA- mediated
  • a small molecule approach further provides an opportunity to study dose and time dependency in a disease model through modulating the administration routes, concentrations and frequencies of administration of the corresponding small molecule.
  • the present disclosure provides bivalent compounds including a CBP/P300 ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof.
  • the CBP/P300 ligand may be conjugated to the degradation tag directly or via a linker moiety.
  • the CBP/P300 ligand may be conjugated to the degradation tag directly.
  • the CBP/P300 ligand may be conjugated to the degradation tag via a linker moiety.
  • the terms“cyclic-AMP response element binding protein and/or adenoviral E1A binding protein of 300 kDa” and“CBP/P300 ligand”, or“CBP/P300 targeting moiety” are to be construed to encompass any molecules ranging from small molecules to large proteins that associate with or bind to CBP and/or P300 proteins.
  • the CBP/P300 ligand is capable of binding to a CBP/P300 protein comprising CBP/P300, a CBP/P300 mutant, a CBP/P300 deletion, or a CBP/P300 fusion protein.
  • the CBP/P300 ligand can be, for example but not limited to, a small molecule compound (i.e., a molecule of molecular weight less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, nucleic acid or oligonucleotide, carbohydrate such as oligosaccharides, or an antibody or fragment thereof.
  • a small molecule compound i.e., a molecule of molecular weight less than about 1.5 kilodaltons (kDa)
  • a peptide or polypeptide i.e., a molecule of molecular weight less than about 1.5 kilodaltons (kDa)
  • a peptide or polypeptide i.e., a molecule of molecular weight less than about 1.5 kilodaltons (kDa)
  • a peptide or polypeptide i.e., a molecule of molecular weight less than about 1.5
  • the CBP/P300 ligand or targeting moiety can be a CBP/P300 inhibitor or a portion of CBP/P300 inhibitor.
  • the CBP/P300 inhibitor comprises one or more of (e.g., GNE-781, GNE-272, GNE-207, CPD 4d, CPD (S)-8, CPD (R)-2, CPD6, CPD19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD 11, CPD 41, CPD 30, CPD 5, CPD 27, CPD 29, CCS1477 (clinical trial ID: NCT03568656), C646 (Oike et al., 2014), A-485, naphthol-AS-E (Uttarkar et ah, 2015), compound 1-10 (Wang et ak, 2013b), MYBMIM (Ramaswamy et ak, 2018), KCN1 (Shi et ah, 2012;
  • a“CBP/P300 inhibitor” refers to an agent that restrains, retards, or otherwise causes inhibition of a physiological, chemical or enzymatic action or function and causes a decrease in binding of at least 5%.
  • An inhibitor can also or alternately refer to a drug, compound, or agent that prevents or reduces the expression, transcription, or translation of a gene or protein.
  • An inhibitor can reduce or prevent the function of a protein, e.g., by binding to or activating/inactivating another protein or receptor.
  • the CBP/P300 ligand is derived from a CBP/P300 inhibitor comprising:
  • the CBP/P300 ligand include, but are not limited to GNE-781, GNE-272, GNE-207, CPD 4d, CPD (S)-8, CPD (R)-2, CPD6, CPD19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD 11, CPD 41, CPD 30, CPD 5, CPD 27, CPD 29, CCS1477 (clinical trial ID:
  • NCT03568656 C646 (Oike et al., 2014), A-485, naphthol-AS-E (Uttarkar et al., 2015), compound 1-10 (Wang et ah, 2013b), MYBMIM (Ramaswamy et ah, 2018), KCN1 (Shi et ah, 2012; Yin et ah, 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).
  • the CBP/P300 ligand comprises a moiety of FORMULA 1:
  • linker moiety of the bivalent compound is attached to R 2 ;
  • X 1 and X 3 are independently selected from C and N, with the proviso that at least one of X 1 and X 3 is C and at most only one of X 1 and X 3 is N;
  • X 2 is selected from CR’, O, and NR’, wherein
  • R’ is selected from H, optionally substituted C r C 8 alkyl, and optionally substituted 3-10 membered carbocyclyl;
  • A is selected from null, CR 4 R 5 , CO, O, S, SO, SO2, and NR 4 , wherein
  • R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylamino, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R 1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, N0 2 , OR 6 , SR 6 , NR 6 R 7 , OCOR 6 ,
  • OCO 2 R 6 OCONR 6 R 7 , COR 6 , CO 2 R 6 , CONR 6 R 7 , SOR 6 , SO 2 R 6 , SO 2 NR 6 R 7 , NR 8 CO 2 R 6 , NR 8 COR 6 ,
  • NR 8 C(0)NR 6 R 7 ,NR 8 S0R 6 , NR 8 S0 2 R 6 , NR 8 S0 2 NR 6 R 7 optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylamino, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered
  • R 6 , R 7 , and R 8 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Cr C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 4-20 membered heterocyclyl ring;
  • R 1 is selected from hydrogen, halogen, CN, N0 2 , OR 9 , SR 9 , NR 9 R 10 , OCOR 9 , 0C0 2 R 9 , OCONR 9 R 10 , COR 9 , C0 2 R 9 , C0NR 9 R 10 , SOR 9 , S0 2 R 9 , S0 2 NR 9 R 10 , NR U C0 2 R 9 , NR U COR 9 , NR U C(0)NR 9 R 10 , NR U C(0)NR 9 R 10 , NR U S0 2 R 9 , NR U S0 2 NR 9 R 10 , optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylamino, optionally
  • R 9 , R 10 , and R 11 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci- C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • R 2 is connected to the“linker” moiety of the bivalent compound, and is selected from null, R O, R S, R NR 12 , R OC(O), R 0C(0)0, R OCONR 12 , R C(O), R C(0)0, R CONR 12 , R S(O), R S(0) 2 , R S0 2 NR 12 , R NR 13 C(0)0, R NR 13 C(0), R NR 13 C(0)NR 12 , R NR 13 S(0), R NR 13 S(0) 2 , R NR 13 S(0) 2 NR 12 , optionally substituted Ci-C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl,
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl, wherein
  • R is null, or a bivalent moiety selected from optionally substituted Ci-C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted Cr
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R 12 and R 13 are independently selected from optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyCr C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and R 3 is selected from hydrogen, COR 14 , C0 2 R 14 , CONR 14 R 15 , SOR 14 , S0 2 R 14 , S0 2 NR 14 R 15 , optionally substituted C 1 -C ( 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 are independently selected from hydrogen, optionally substituted C 1 -C ( , 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 atom to which they are connected form a 4-20 membered heterocyclyl ring.
  • X 1 is C; and X 2 and X 3 are N.
  • the FORMULA I is FORMULA 1A:
  • A-Ar-R 1 is a moiety of formulae Al :
  • a and R 1 are the same as in FORMULA 1.
  • X is selected from CR”’ and N, wherein
  • R is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C 6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 1 -C ( alkoxy, optionally substituted C 1 -C ( alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
  • R a is optionally formed a ring with A, and is selected from null, hydrogen, halogen, R b NR .
  • R b is is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-C 8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C x alkoxyCi-C x alkylene, optionally substituted C 1 - C x al k y 1 am i n o C 1 - C x al k y 1 e n e .
  • Ci-Cg haloalkylene optionally substituted C C 8 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 are independently selected from null, hydrogen, optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Cr CgalkoxyCi-Cgalkyl, optionally substituted C i - C 8 al k y 1 am i n o C i - C 8 al k y 1. 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 atom to which they are connected form a 3-20 membered cycloalkyl or heterocyclyl ring.
  • A is null.
  • A is null; Ar is a bicyclic aryl or a bicyclic heteroaryl; and A-Ar-R 1 is a moiety of FORMULAE A2 or A3:
  • R 1 is the same as in FORMULA 1.
  • A is NR 4 , wherein
  • R 4 is selected from hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • -Ar-R 1 is a moiety
  • R 1 is the same as in FORMULA 1.
  • R 1 is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.
  • R 1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • R 1 is is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
  • R 2 is selected from optionally substituted Ci-C 8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocycly, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 3 is selected from COR 14 and CONR 14 R 15 .
  • R 3 is selected from COMe and CONHMe.
  • the CBP/P300 ligand comprises a moiety of FORMULA 2:
  • X 1 and X 3 are independently selected from C and N, with the proviso that at least one of X 1 and X 3 is C and at most only one of X 1 and X 3 is N;
  • X 2 is selected from CR’, O, and NR’, wherein
  • R’ is selected from H, optionally substituted C r C 8 alkyl, and optionally substituted 3-10 membered carbocyclyl;
  • A is selected from null, CR 4 R 5 , CO, O, S, SO, S0 , and NR 4 , wherein
  • R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl amino, cyano, nitro, optionally substituted C r C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C C 8 alkoxy, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylamino, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3- 10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R 1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, N0 2 .
  • OR 6 , SR 6 , NR 6 R 7 , OCOR 6
  • OCO 2 R 6 OCONR 6 R 7 , COR 6 , CO 2 R 6 , CONR 6 R 7 , SOR 6 , SO 2 R 6 , SO 2 NR 6 R 7 , NR 8 CO 2 R 6 , NR 8 COR 6 ,
  • R 6 , R 7 , and R 8 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Cr C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 4-20 membered heterocyclyl ring;
  • R 1 is connected to the“linker” moiety of the bivalent compound, and R 1 is selected from null, R O,
  • R S R NR 9 , R OC(O), R 0C(0)0, R OCONR 9 , R C(O), R C(0)0, R CONR 9 , R S(O), R S(0) 2 ,
  • R is null, or a bivalent moiety selected from optionally substituted C C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted Cr
  • R 9 and R 10 are independently selected from optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyCr C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • R 2 is selected from hydrogen, halogen, CN, N0 2 , OR 11 , SR 11 , NR U R 12 , OCOR 11 , OC0 2 R u , OCONR u R 12 , COR 11 , C0 2 R u , CONR U R 12 , SOR 11 , S0 2 R u , S0 2 NR U R 12 , NR 13 C0 2 R u , NR 13 COR u , NR 13 C(0)NR U R 12 ,NR 13 S0R u , NR 13 S0 2 R u , NR 13 S0 2 NR U R 12 , optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylamino,
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Cr C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
  • R and R , R and R together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • R 3 is selected from hydrogen, COR 14 , C0 2 R 14 , CONR 14 R 15 , SOR 14 , S0 2 R 14 , S0 2 NR 14 R 15 , optionally substituted C -C ( alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, wherein
  • R 14 and R 15 are independently selected from hydrogen, optionally substituted C -C ( , alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, and optionally substituted 4-6 membered heterocyclyl, or
  • R 14 and R 15 together with the atom to which they are connected form a 4-6 membered heterocyclyl ring.
  • X 1 is C; and X 2 and X 3 are N.
  • the FORMULA 2 is FORMULA 2A:
  • A-Ar-R 1 is a moiety of formulae B 1 :
  • a and R 1 are the same as in FORMULA 2;
  • X is selected from CR”’ and N, wherein
  • R is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C 6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 1 -C ( alkoxy, optionally substituted C 1 -C ( alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl; and
  • R a optionally forms a ring with A, and is selected from null, 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 0C0 2 R 16 , R b OCONR 16 R 17 , R b COR 16 , R b C0 2 R 16 , R b CONR 16 R 17 , R b SOR 16 , R b S0 2 R 16 , R b S0 2 NR 16 R 17 , R b NR 18 C0 2 R 16 , R b NR 18 COR 16 , R b NR 18 C(0)NR 16 R 17 , R b NR 18 SOR 16 , R b NR 18 S0 2 R 16 , R b NR 18 S0 NR 16 R 17 , optionally substituted Ci-C 8 alkyl, optionally substituted Ci-C 8 alkylene, optionally substitute
  • R b is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-C 8 alkylene, optionally substituted C2-C 8 alkenylene, optionally substituted C2-C 8 alkynylene, optionally substituted Ci-C 8 alkoxyCi-C 8 alkylene, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkylene, optionally substituted Ci-C 8 haloalkylene, optionally substituted C r C 8 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 are independently selected from null, a bond, hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C2-C 8 alkenyl, optionally substituted C2-C 8 alkynyl, optionally substituted Ci-C 8 alkoxyCi-C 8 alkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring.
  • A is null. In another embodiment, A is null; Ar is a bicyclic aryl or a bicyclic heteroaryl; and A-Ar-R 1 is a moiety of FORMULAE B2 or B3:
  • R 1 is the same as in FORMULA 2.
  • A is NR 4 , wherein
  • R 4 is selected from hydrogen, optionally substituted C i -C x alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1 -C x alkoxyC 1 -C x alkyl. optionally substituted C i -C x alkylaminoC 1 -C x alkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • -Ar-R 1 is a moiety
  • R 1 is the same as in FORMULA 2.
  • R 1 is selected from optionally substituted 3-10 membered carbocyclylene, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • R 1 is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
  • R 2 is selected from optionally substituted C 1 -C x alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 3 is selected from COR 14 and CONR 14 R 15 .
  • R 3 is selected from COMe and CONHMe.
  • the CBP/P300 ligand is derived from any of the following:
  • the CBP/P300 ligand is derived from the following CBP/P300 inhibitors: C646, naphthol-AS-E, compound 1-10, MYBMIM, CCS 1477, ICG-001, YH249, YH250, HBS1, OHM1, and KCN1.
  • the CBP/P300 ligand is selected from the group consisting of:
  • degradation tag refers to a compound, which associates with or binds to an ubiquitin ligase for recruitment of the corresponding ubiquitination machinery to CBP/P300 or is a hydrophobic group or a tag that leads to misfolding of the CBP/P300 protein and subsequent degradation at the proteasome or loss of function.
  • the degradation tag is a moiety selected from the group consisting of
  • V, W, and X are independently selected from CR 2 and N;
  • R 1 , and R 2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
  • R 3 , and R 4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 3 and R 4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
  • R 5 and R 6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C 6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 5 and R 6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl.
  • the degradation tag is a moiety selected from the group consisting of FORMULAE 5A, 5B, 5C, and 5D:
  • V, W, and X are independently selected from CR 2 and N;
  • Z is selected from CH 2 , NH and O;
  • R 1 and R 2 are independently selected from hydrogen, halogen, cyano, nitro, and C 1-C5 alkyl.
  • the degradation tag is a moiety selected from the group consisting of
  • U, V, W, X 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 CH , NH, NC13 ⁇ 4 and O;
  • Y’, Y”, and Y”’ are independently selected from CR 3 R 4 ;
  • R 1 , and R 2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
  • R 3 , and R 4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted
  • Ci-Ce alkyl optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 3 and R 4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
  • R 5 and R 6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C 6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R 5 and R 6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
  • R’ is selected from hydrogen, optionally substituted C i -C ( alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl.
  • the degradation tag is a moiety of FORMULA 6A:
  • R 1 and R 2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C r C x alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl;
  • optionally substituted C 1 -C x alkoxyC 1 -C x alkyl optionally substituted C 1 -C x haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 aminoalkyl, optionally substituted Ci- CsalkylaminoCi-Csalkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4- 10 membered heterocyclyl; and
  • R 3 is selected from hydrogen, optionally substituted C(0)Ci-C 8 alkyl, optionally substituted C(0)Ci- CsalkoxyCi-Csalkyl, optionally substituted C(0)Ci-C 8 haloalkyl, optionally substituted C(0)Ci-C 8 hydroxyalkyl, optionally substituted C(0)Ci-C 8 aminoalkyl, optionally substituted C(0)Cr
  • CsalkylaminoCi-Csalkyl optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C 2 -C 8 alkenyl, optionally substituted C(0)C -C 8 alkynyl, optionally substituted C(0)OCi-C 8 alkoxyCi-C 8 alkyl, optionally substituted
  • C(0)OCi-C 8 haloalkyl optionally substituted C(0)OCi-C 8 hydroxyalkyl, optionally substituted C(0)OCr Cs aminoalkyl, optionally substituted C(0)OCi-C 8 alkylaminoCi-C 8 alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C 2 -C 8 alkenyl, optionally substituted C(0)0C 2 -C 8 alkynyl, optionally substituted C(0)NCi-C 8 alkoxyCi-C 8 alkyl, optionally substituted C(0)NC I -C 8 haloalkyl, optionally substituted C(0)NC I -C 8 hydroxyalkyl, optionally substituted C(0)NCi-C 8 aminoalkyl, optionally substituted C(0)NCi-C 8 alkylaminoCi-C 8 alkyl, optionally substituted C(
  • the degradation tag is a moiety of FORMULAE 6B, 6C, and 6D: FORMULA 6B, FORMULA 6C, FORMULA 6D wherein
  • R 1 and R 2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl;
  • Ci-C 8 alkoxyCi-C 8 alkyl optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 aminoalkyl, optionally substituted Cr C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4- 10 membered heterocyclyl;
  • R 3 is selected from hydrogen, optionally substituted C(0)Ci-C 8 alkyl, optionally substituted C(0)Cr C 8 alkoxyCi-C 8 alkyl, optionally substituted C(0)Ci-C 8 haloalkyl, optionally substituted C(0)Ci-C 8 hydroxyalkyl, optionally substituted C(0)Ci-C 8 aminoalkyl, optionally substituted C(0)Cr
  • C 8 alkylaminoCi-C 8 alkyl optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C 2 -C 8 alkenyl, optionally substituted C(0)C 2 -C 8 alkynyl, optionally substituted C(0)OCi-C 8 alkoxyCi-C 8 alkyl, optionally substituted
  • C(0)0Ci-C 8 haloalkyl optionally substituted C(0)0Ci-C 8 hydroxyalkyl, optionally substituted C(0)0Cr C 8 aminoalkyl, optionally substituted C(0)OCi-C 8 alkylaminoCi-C 8 alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C 2 -C 8 alkenyl, optionally substituted C(0)0C 2 -C 8 alkynyl, optionally substituted C(0)NCi-C 8 alkoxyCi-C 8 alkyl, optionally substituted C(0)NCi-C 8 haloalkyl, optionally substituted C(0)NC I -C 8 hydroxyalkyl, optionally substituted C(0)NCi-C 8 aminoalkyl, optionally substituted C(0)NCi-C 8 alkylaminoCi-C 8 alkyl, optionally substituted
  • R 4 is selected from NR 7 R 8 , , optionally substituted Ci-C 8 alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteraryl, in which
  • R 7 is selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted Ci- C 8 cycloalkyl, optionally substituted Ci-C 8 alkyl-CO, optionally substituted Ci-C 8 cycloalkyl-CO, optionally substituted Ci-C 8 cycloalkyl-Ci-C 8 alkyl-CO, optionally substituted 4-10 membered
  • heterocyclyl-CO optionally substituted 4-10 membered heterocyclyl-Ci-C 8 alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-Ci-C 8 alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-Ci-C 8 alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 8 is selected from hydrogen, optionally substituted Ci-C 8 alkyl, and optionally substituted Cr C 8 cycloalkyl;
  • R 9 is independently selected from hydrogen, halogen, cyano, optionally substituted Ci-C 8 alkyl, optionally substituted Ci-C 8 cycloalkyl, optionally substituted Ci- C 8 heterocycloalkyl, optionally substituted Ci-C 8 alkoxy, optionally substituted Ci-C 8 cycloalkoxy, halo substituted Ci-C 8 alkyl, halo substituted Ci-C 8 cycloalkyl, halo substituted Ci-C 8 alkoxl, halo substituted Ci- C 8 cycloalkoxy, and halo substituted Ci-C 8 heterocycloalkyl;
  • X is selected from CH and N;
  • n 0, 1, 2, 3, or 4;
  • R 6 is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci- C x alkyl, optionally substituted Ci-C x cycloalkyl, optionally substituted Ci-C x alkoxy, and optionally substituted Ci-C x cycloalkoxy, optionally substituted Ci-C x 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 group.
  • the degradation tag is a moiety of FORMULA 7A:
  • V, W, X, and Z are independently selected from CR 4 and N;
  • R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C r C x alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl; optionally substituted Ci-Csalkoxy, optionally substituted Ci-Csalkylamino, optionally substituted Cr CsalkoxyCi-Csalkyl, optionally substituted C 1 -C x alkvlam inoC 1 -C x alkyl.
  • the degradation tag is a moiety of FORMULA 7B:
  • R 1 , R 2 , and R 3 are independently selected from hydrogen, halogene, optionally substituted C 1 -C x alkyl, optionally substituted C 1 -C x alkoxyC 1 -C x alkyl. optionally substituted C 1 -C x haloalkyl, optionally substituted C 1 -C x hydroxyalkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl;
  • R 4 and R 5 are independently selected from hydrogen, COR 6 , CO 2 R 6 , CONR 6 R 7 , SOR 6 , SO 2 R 6 , S0 2 NR 6 R 7 , optionally substituted C 1 -C x alkyl, optionally substituted C 1 -C x alkoxyC 1 -C x alkyl. optionally substituted C 1 -C x alkylaminoC 1 -C x alkyl. optionally substituted aryl-Ci-C x alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
  • R 6 and R 7 are independently selected from hydrogen, optionally substituted C' 1 -C' x alkyl, optionally substituted C 1 -C x alkoxyC 1 -C x alkyl. optionally substituted C 1 -CxalkylaminoC 1 -Cxalkyl. optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
  • the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, and 51.
  • the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, and 5F. In another embodiment, the degradation tag is derived from any of the following:
  • the degradation tag is derived from any 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.
  • the degradation tag is selected from the group consisting of:
  • the degradation tag is selected from the group consisting of: FORMULA 8 A 8B, 8C, 8D, 8E, 8F, 8G, 8H, 81, 8J, 8K, 8L, 8M, 80, 8P, 8Q, 8R, 8AQ, 8AR, 8AS, 8AT, 8AU, 8AV, 8AW, 8 AX, 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, 8 CL, 8 CM, 8CN, 8CO, 8CP, 8CQ, 8CR, 8CS, 8CT, 8CU, 8CV, 8CW, 8CX, 8CY, 8CZ, 8DA, 8DB, 8DC, 8DD, 8
  • a“linker” or“linker moiety” is a bond, molecule, or group of molecules that binds two separate entities to one another. Linkers provide for optimal spacing of the two entities.
  • the term “linker” in some aspects refers to any agent or molecule that bridges the CBP/P300 ligand to the degradation tag.
  • sites on the CBP/P300 ligand or the degradation tag which are not necessary for the function of the PROTACs or SNIPERs of the present disclosure, are ideal sites for attaching a linker, provided that the linker, once attached to the conjugate of the present disclosures, 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 a ubiquitin ligase.
  • the length of the linker of the bivalent compound can be adjusted to minimize the molecular weight of the bivalent compounds, avoid the clash of the CBP/P300 ligand or targeting moiety with the ubiquitin ligase and/or induce CBP/P300 misfolding by the hydrophobic tag.
  • the linker comprises acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic or carbonyl groups.
  • 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.
  • the linker moiety is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl linker moiety
  • A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR , R C0 2 R , RCjOjNjR'jR ” , R CfSjNjR'jR ” , R OR , R SR , R SOR , R S0 2 R ,
  • R and R are independently selected from null, optionally substituted (Cj-C 8 alkylene)-R r (preferably, CtU-R 1 ).
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C C 8 alkoxyalkyl, optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • m 0 to 15.
  • W and m are defined as above; and A and B, at each occurrence, are
  • W and m are defined as above; and A and B, at each occurrence, are
  • R r is selected from FORMULA Cla, C2a, C3a, C4a, C5a, Cl, C2, C3, C4 and C5 as defined hereinafter.
  • R r is selected from Group R, and Group R consists of
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, hydroxyl amino, cyano, nitro, optionally substituted C
  • R 1 and R 2 , R 3 and R 4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR ” , R C0 2 R , R C(0)N(R 5 )R , R C(S)N(R 5 )R , R OR , R SR , R SOR , R S0 2 R ,
  • optionally substituted C 1 -C x haloalkylene optionally substituted Ci-C 8 hydroxyalkylene, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, 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 null, optionally substituted (C
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R 5 and R 6 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C2-C 8 alkenyl, optionally substituted C2-C 8 alkynyl, optionally substituted Ci-C 8 alkoxyalkyl, optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • n 0 to 15;
  • n at each occurrence, is 0 to 15;
  • o 0 to 15.
  • A, W and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0-8 -, -(CH 2 )o-3-CO-(CH 2 )o- 8 -, (CH 2 ) 0-8 -NH-CO, (CH 2 ) 0-8 -CO-NH, NH-CO- (CH 2 ) O -8, CO-NH-(CH 2 ) O -8, (CH 2 ) I-3 -NH-(CH 2 ) I-3 -CO-NH, (CH 2 ) I-3 -NH-(CH 2 ) I-3 -NH-CO, -CO-NH, CO-NH- (CH 2 ) 1-3 -NH-(CH 2 ) 1-3, (CH 2 ) 1-3 -NH-(CH 2 ) 1-3, -(CH 2 )o- 3 -R r -(CH 2 )o- 3 , -(CH 2 )
  • W and m are defined as above; and A and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH 2 )o-8-, -(CH 2 )o-3-CO-(CH 2 )o-8-, (CH 2 ) I.2 - NH-CO, (CH 2 ) I -2-CO-NH, NH-CO-(CH 2 ) I-2 , CO-NH-(CH 2 ) I-2 , (CH 2 ) I-2 -NH-(CH 2 ) 1-2-CO-NH, (CH 2 ) i_ 2 - NH-(CH 2 ) I -2-NH-CO, -CO-NH, CO-NH- (CH 2 ) I-2 -NH-(CH 2 ) 1-2, (CH 2 ) I-2 -NH-(CH 2 ) i_ 2 ,-(CH 2 )o-2-R (CH 2 )O-2, -(CH 2 )O
  • R r is selected from FORMULA Cla, C2a, C3a, C4a, C5a, Cl, C2, C3, C4, and C5 as defined hereinafter.
  • R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • the CBP/P300 ligand of the bivalent compound is attached to A in FORMULA
  • A (when A is attached to the CBP/P300 ligand ) is selected from null, CO,
  • R r is selected from Group R, and Group R is defined as in FORMULA 9;
  • the linker moiety is of FORMULA 9A:
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, optionally substituted Ci-Cg alkyl (preperably, C1-C4 alkyl), or
  • R 1 and R 2 , R 3 and R 4 together with the atom to which they are connected form a 3-20 membered cycloalkyl (preferably, 3-5 membered cycloalkyl) or 4-20 membered heterocyclyl ring;
  • A is defined as before; and W and B are null;
  • n is 0 to 15 (preferably, m is 0, 1, or 2);
  • n at each occurrence, is 1 to 15 (preferably, n is 1);
  • o is 1 to 15 (preferably, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13).
  • A is independently selected from null, or bivalent moiety selected from R -
  • R and R are independently selected from null, optionally substituted (Ci-Cg alkylene)-R r (preferably, CFL-R 1 ), or optionally substituted Ci-Cg alkyl (preferably, optionally substituted
  • linker moiety is of FORMULA 9B:
  • R 1 and R 2 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted Ci-Cg alkyl, optionally substituted Ci-Cg alkoxy, optionally substituted Ci-Cg alkoxy Ci-Cg alkyl, optionally substituted Ci-Cg haloalkyl, optionally substituted Ci-Cg hydroxyalkyl, optionally substituted Ci-Cg alkylamino, C 1 -C x alkylaminoC 1 -C x alkyl. optionally substituted
  • R 1 and R 2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or
  • a and B are independently selected from null, or bivalent moiety selected from
  • optionally substituted C r C 8 haloalkylene optionally substituted C C 8 hydroxyalkylene, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, 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 null, optionally substituted (C
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R r is 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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R 3 and R 4 are independently selected from hydrogen, optionally substituted Ci-C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted Ci-C 8 alkoxyalkyl, optionally substituted Ci-C 8 haloalkyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted Ci-C 8 alkylaminoCi-C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • each m is 0 to 15;
  • n 0 to 15.
  • A, W and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH 2 ) 0.8 -, -(CH 2 ) O-3 -CO-(CH 2 ) 0 -I O -, (CH 2 ) 0.8 -NH-CO, (CH 2 ) 0.8 -CO-NH, NH-CO- (CH 2 ) O-8 , CO-NH-(CH 2 ) O-8 , (CH 2 ) ,_3-NH-(CH 2 ) , 3-CO-NH.
  • R r is selected from FORMULA Cla, C2a, C3a, C4a, C5a, Cl, C2, C3, C4, and C5 as defined hereinafter.
  • R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • linker moiety is of FORMULA 9C:
  • X is selected from O, NH, and NR 7 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C
  • a and B are independently selected from null, or bivalent moiety selected from R -R , R COR ,
  • C x alkoxyCi-C x alkylene optionally substituted C' 1 -C' x haloalkylene, optionally substituted C' 1 -C' x hydroxyalkylene, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro
  • heterocyclyl 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 null, optionally substituted (Ci-C 8 alkylene)-R r (preferably, CH -R r ), optionally substituted R r -(Ci-C 8 alkylene), optionally substituted (C 1 -C 3 alkylene)- R r -(Ci-C 8 alkylene), or a moiety comprising of optionally substituted C 1 -C 3 alkyl, optionally substituted C -C 8 alkenyl, optionally substituted C -C 8 alkynyl, optionally substituted Ci-C 8 hydroxyalkyl, optionally substituted C 1 -C’salkoxyC 1 -C’salkyl.
  • optionally substituted Ci-C 8 haloalkyl optionally substituted Ci-C 8 alkylene, optionally substituted C -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 3 hydroxyalkylene, optionally substituted C i-CsalkoxyC’i-Csalkylcnc. optionally substituted C 1 -C’salkylaminoC 1 -C’salkylcnc.
  • Ci-C 8 haloalkylene optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R r is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro
  • heterocyclyl optionally substituted aryl, and optionally substituted heteroaryl
  • R , R and R are independently selected from hydrogen, optionally substituted C
  • 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 atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
  • n 0 to 15;
  • n at each occurrence, is 0 to 15;
  • o 0 to 15;
  • p 0 to 15.
  • a and B are independently selected from null, CO, NH, NH-CO, CO-NH, -
  • R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • a and B are independently selected from null, CO, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH 2 - NH-CH2-NH-CO, -CO-NH, CO-NH- CH2-NH-CH2, CH2-NH-CH2
  • o is 0 to 5.
  • the linker moiety comprises one or more rings selected from the group consisting of 3 to 13 membered rings, 3 to 13 membered fused rings, 3 to 13 membered bridged rings, and 3 to 13 membered spiro rings.
  • the linker moiety comprises one or more rings selected from the group consisting o
  • X’ and Y’ are independently selected from N, CR b ;
  • a 1 , B 1 , C 1 and D 1 are independently selected from null, O, CO, SO, SO2, NR b , CR b R c ;
  • a 2 , B 2 , C 2 , and D 2 at each occurrence, are independently selected from N, CR b ;
  • a 3 , B 3 , C 3 , D 3 , and E 3 at each occurrence, are independently selected from N, O, S, NR b , CR b ;
  • R b and R c are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C r C 8 alkyl.
  • n 1 , o 1 and p 1 are independently selected from 0, 1, 2, 3, 4 and 5.
  • the linker moiety comprises one or more rings selected from the group consisting of formulae Cl, C2, C3, C4 and C5:
  • R r is selected from FORMULA Cla, C2a, C3a, C4a, C5a, Cl, C2, C3, C4, and C5 as defined above.
  • R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • a and B are independently defined as above, and W is null.
  • the length of the linker is 0 to 40 chain atoms.
  • the length of the linker is 3 to 20 chain atoms.
  • the length of the linker is 5-15 chain atoms.
  • A when the CBP/P300 ligand of the bivalent compound attached to A, A is selected from -(CO)-, -(CH 2 ) 1.2 (CO)-NH-,-(CH 2 ) 0-8 -, -(CH 2 ) 0-3 -CO-(CH 2 ) 0-8 -, -(CH 2 ) 0-3 -R r -(CH 2 ) 0-3 , - (CH 2 )o- 3 -(CO)-(CH 2 )o- 3 -R r -(CH 2 )o_ 3 , wherein R r is selected from Group R, and Group R is defined as in FORMULA 9.
  • the linker is -(CO)-(CH 2 ) 3-7 -.
  • the linker is -(CH 2 ) I-2 (CO)-NH-(CH2) 3-7 -.
  • the linker is -(CH 2 ) 0-IO -, and -(CH 2 ) 0-3 -CO-(CH 2 ) 0-IO -,
  • the linker is -(CH 2 ) 0-3 -R r -(CH 2 ) 0-3 -, or -(CH 2 ) 0-3 -(CO)-(CH 2 )o- 3 -R r -(CH 2 ) 0-3 , wherein R r is selected from the group of Group R, and Group R is defined as in FORMULA 9.
  • R r is selected from the group of Group R
  • Group R is defined as in FORMULA 9.
  • the bivalent compounds disclosed herein can selectively affect CBP/P300-mediated disease cells compared to WT (wild type) cells (i.e., an bivalent compound able to kill or inhibit the growth of an CBP/P300-mediated disease cell while also having a relatively low ability to lyse or inhibit the growth of a WT cell), e.g., possess a GI 50 for one or more CBP/P300-mediated disease cells more than 1.5-fold lower, more than 2-fold lower, more than 2.5-fold lower, more than 3-fold lower, more than 4-fold lower, more than 5-fold lower, more than 6-fold lower, more than 7-fold lower, more than 8-fold lower, more than 9-fold lower, more than 10-fold lower, more than 15 -fold lower, or more than 20-fold lower than its GI 50 for one or more WT cells, e.g., WT cells of the same species and tissue type as the CBP/P300- mediated disease cells.
  • WT wild type
  • a method for identifying a bivalent compound which mediates degradation or reduction of CBP/P300 comprising: providing a heterobifunctional test compound comprising an CBP/P300 ligand conjugated to a degradation tag through a linker; contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and CBP/P300;
  • the cell is a cancer cell. In certain embodiments, the cancer cell is a CBP/P300-mediated cancer cell.
  • the binding affinity of novel synthesized bivalent compounds can be assessed using standard biophysical assays known in the art (e.g., isothermal titration calorimetry (ITC), surface plasmon resonance (SPR)). Cellular assays can then be used to assess the bivalent compound’s ability to induce CBP/P300 degradation and inhibit cancer cell proliferation. Besides evaluating a bivalent compound’s induced changes in the protein levels of CBP/P300, CBP/P300 mutants, or CBP/P300 fusion proteins, protein-protein interaction or acteryltransferase enzymatic activity can also be assessed.
  • ITC isothermal titration calorimetry
  • SPR surface plasmon resonance
  • Assays suitable for use in any or all of these steps are known in the art, and include, e.g., western blotting, quantitative mass spectrometry (MS) analysis, flow cytometry, enzymatic activity assay, ITC, SPR, cell growth inhibition, xenograft, orthotopic, and patient-derived xenograft models.
  • Suitable cell lines for use in any or all of these steps are known in the art and include LNCaP, 22RV1, HEL, MV4;11, RS4;11, NCI-H929, MM. IS, Pfeiffer, NCI-H520 and other cell lines.
  • Suitable mouse models for use in 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.
  • isotopic variations 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 variations of those reagents).
  • an isotopic variation 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 thus include, e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 35 S, 18 F, and 36 C1.
  • Isotopic variations e.g., isotopic variations containing 2 H
  • certain isotopic variations can be used in drug or substrate tissue distribution studies.
  • the radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • solvates of the compounds disclosed herein are contemplated.
  • a solvate can be generated, e.g., by substituting a solvent used to crystallize a compound disclosed herein with an isotopic variation (e.g., D 0 in place of H 2 0, 3 ⁇ 4-acetone in place of acetone, or ri 6 -DMSO in place of DMSO).
  • an isotopic variation e.g., D 0 in place of H 2 0, 3 ⁇ 4-acetone in place of acetone, or ri 6 -DMSO in place of DMSO.
  • a fluorinated variation is a compound in which at least one hydrogen atom is replaced by a fluoro atom. Fluorinated variations can provide therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
  • 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 hydroxyl groups or carboxylic acid groups to ester groups).
  • a prodrug refers to a compound that can be converted via some chemical or physiological process (e.g., enzymatic processes and metabolic hydrolysis) to a therapeutic agent.
  • prodrug also refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject, i.e. an ester, but is converted in vivo to an active compound, for example, by hydrolysis to the free carboxylic acid or free hydroxyl.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in an organism.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject.
  • Prodrugs of an active compound may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • LNCaP or 22RV1 cells Specific exemplary bivalent compounds were characterized in LNCaP or 22RV1 cells.
  • LNCaP or 22RV1 cells that express CBP/P300 proteins were treated with GNE-781 or the bivalent compounds disclosed herein (P-001 to P-174) for indicated hours. Cells were collected, lysed and subject to immunoblotting using an antibody specific to P300 or CBP proteins. Tubulin or vinculin was included as the loading control. DMSO was used as the negative control.
  • P300 and CBP protein levels in LNCaP or 22RV1 cells were significantly decreased ( Figure 1, 2, 5, 6, 10, and 11).
  • Selected bivalent compounds disclosed herein were found to be particularly effective in reducing CBP and P300 protein levels, as the concentrations required to reduce target protein levels by 50% (DC 50 ) for some compounds were less than 1 nM ( Figure 6).
  • LNCaP cells were treated with 20 nM P-004, P-005, P-015, or P-020 for the indicated time. Subsequently, changes in P300 protein levels were measured via immunoblotting. Tubulin was included as the loading control. Significant degradation of P300 was readily detected as early as 2 hours following administration of the compounds ( Figure 3).
  • the interaction with cereblon is critical to the ability of bivalent compounds to induce degradation of P300/CBP proteins, as a chemical modification that disrupted cereblon binding abolished P300 degradation induced by P-034 in LNCap and 22RV1 cells (Figure 7).
  • the degradation was also dependent on the ubiquitin-proteasome system, because it could be neutralized by co-administration of proteasome inhibitors, MG- 132 and bortezomib, a cullin E3 ligase inhibitor, MLN4924, or high concentration of pomalidomide that compete for cereblon binding, as exemplified by P-007, P-034, and P-100 (Figure 8).
  • bivalent compounds induce degradation of P300/CBP proteins via a mechanism specifically mediated by cereblon, cullin E3 ligases, and the proteasome.
  • athymic nude mice bearing 22RV 1 subcutaneous xenograft tumors at the right flank were intrapreitoneally or orally treated with 40 mg/kg bivalent compounds.
  • animals were sacrificed for immunoblotting of P300 and CBP in homogenized xenograft tumor masses.
  • Bivalent compounds as exemplified by P-100, P-007 and P-034, exhibited the ability of significantly reducing P300 and CBP protein levels after a single dose of drug administration (Figure 9).
  • bivalent compounds were orally treated with 40 mg/kg bivalent compounds. Six hours after drug administration, animals were sacrificed for immunoblotting of CBP in homogenized lung tissues. Bivalent compounds, as exemplified in Figure 12, exhibited the ability of significantly reducing CBP protein levels after a single dose of drug administration.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation.
  • An alkyl may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms.
  • an alkyl comprises one to fifteen carbon atoms (e.g ., C 1 -C 15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -C x alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl).
  • alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), «-propyl, 1-methylethyl (Ao-propyl), «-butyl, «-pentyl, 1,1-dimethylethyl (/-butyl), pentyl, 3-methylhexyl, 2-methylhexyl, and the like.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond.
  • An alkenyl may comprise two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms.
  • an alkenyl comprises two to twelve carbon atoms (e.g., C -Ci alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (e.g., C 2 -C x alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (e.g., C 2 -CV, alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (e.g., C 2 -C 4 alkenyl).
  • alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.
  • alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond.
  • An alkynyl may comprise two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms.
  • an alkynyl comprises two to twelve carbon atoms (e.g., C 2 -Ci 2 alkynyl).
  • an alkynyl comprises two to eight carbon atoms (e.g., C 2 -C 8 alkynyl).
  • an alkynyl has two to six carbon atoms (e.g., C 2 -CV, alkynyl). In other embodiments, an alkynyl has two to four carbon atoms (e.g., C 2 -C 4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond. Examples of such groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.
  • alkoxy means an alkyl group as defined herein witch is attached to the rest of the molecule via an oxygen atom.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
  • aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon atoms.
  • An aryl may comprise from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory.
  • an aryl comprises six to fourteen carbon atoms (CVC
  • an aryl comprises six to ten carbon atoms (CVCm aryl). Examples of such groups include, but are not limited to, phenyl, fluorenyl and naphthyl.
  • heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory.
  • a heteroaryl refers to a radical derived from a 3- to 10-membered aromatic ring radical (3-10 membered heteroaryl).
  • a heteroaryl refers to a radical derived from 5- to 7-membered aromatic ring (5-7 membered heteroaryl). Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • Examples of such groups include, but not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl
  • an heteroaryl is attached to the rest of the molecule via a ring carbon atom. In certain embodiments, an heteroaryl is attached to the rest of the molecule via a nitrogen atom (N-attached) or a carbon atom (C-attached).
  • N-attached nitrogen atom
  • C-attached carbon atom
  • a group derived from pyrrole may be pyrrol-l-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-l-yl (N-attached) or imidazol-3-yl (C-attached).
  • heterocyclyl means a non-aromatic, monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of from 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms in its ring system, and containing from 3 to 12 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.
  • a heterocyclyl group may include fused, bridged or spirocyclic ring systems.
  • a hetercyclyl group comprises 3 to 10 ring atoms (3-10 membered heterocyclyl).
  • a hetercyclyl group comprises 3 to 8 ring atoms (3-8 membered heterocyclyl). In certain embodiments, a hetercyclyl group comprises 4 to 10 ring atoms (4-10 membered heterocyclyl). In certain embodiments, a hetercyclyl group comprises 4 to 8 ring atoms (4-8 membered heterocyclyl).
  • a heterocyclyl group may contain an oxo substituent at any available atom that will result in a stable compound. For example, such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible.
  • heterocyclyl group when such a heterocyclyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone.
  • An example of a 4 membered heterocyclyl 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.
  • cycloheteroalkyl group is 4H-quinolizinyl.
  • heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,
  • tetrahydrothiopyranyl piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4//-pyranyl.
  • a heteroaryl group may be attached to the rest of molecular via a carbon atom (C-attached) or a nitrogen atom (N-attached).
  • a group derived from piperazine may be piperazin-l-yl (N-attached) or piperazin-2-yl (C-attached).
  • cycloalkyl or "carbocyclyl” means a saturated, monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of from 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms in its ring system.
  • a cycloalkyl may be fused, bridged or spirocyclic.
  • a cycloalkyl comprises 3 to 8 carbon ring atoms (3-8 membered carbocyclyl).
  • a cycloalkyl comprises 3 to 10 carbon ring atoms (3-10 membered cycloalkyl). Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, and the like.
  • cycloalkylene is a bidentate radical obtained by removing a hydrogen atom from a cycloalkyl ring as defined above.
  • groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and the like.
  • chain atom refers to atoms that is located on the main chain of the linker moiety.
  • spirocyclic as used herein has its conventional meaning, that is, any ring system containing two or more rings wherein two of the rings have one ring carbon in common.
  • Each ring of the spirocyclic ring system independently comprises 3 to 20 ring atoms. Preferably, they have 3 to 10 ring atoms.
  • Non-limiting examples of a spirocyclic system include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.
  • cyano refers to a -CoN group.
  • aldehyde refers to a -C(0)H group.
  • alkoxy refers to both an -O-alkyl, as defined herein.
  • alkoxy carbonyl refers to a -C(0)-alkoxy, as defined herein.
  • alkylaminoalkyl refers to an -alkyl-NR-alkyl group, as defined herein.
  • alkylsulfonyl refer to a -S0 2 alkyl. as defined herein.
  • amino refers to an optionally substituted -NEE.
  • aminoalkyl refers to an -alky-amino group, as defined herein.
  • aminocarbonyl refers to a -C(0)-amino, as defined herein.
  • arylalkyl refers to -alkylaryl, where alkyl and aryl are defined herein.
  • aryloxy refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.
  • aryloxy carbonyl refers to -C(0)-aryloxy, as defined herein.
  • arylsulfonyl refers to a -S0 2 aryl. as defined herein.
  • carbonyl refers to a -C(O)- group, as defined herein.
  • a “carboxylic acid” group refers to a -C(0)OH group.
  • A“cycloalkoxy” refers to a -O-cycloalkyl group, as defined herein.
  • halo or halogen group refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl group refers to an alkyl group substituted with one or more halogen atoms.
  • a "hydroxy” group refers to an -OH group.
  • a "nitro” group refers to a -N0 2 group.
  • trihalomethyl refers to a methyl substituted with three halogen atoms.
  • substituted means that the specified group or moiety bears one or more substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH 2 , -C1-C4 alkyl-NH 2 , -N(C C 4 alkyl)(Ci-C 4 alkyl), -NH(C I -C 4 alkyl), -N(C C 4 alkyl)(Ci-C 4 alkylphenyl), -NH(C I -C4 alkylphenyl), -NH(C I -C4 alkylphenyl), cyan
  • nucleic acid means the absence of an atom or moiety, and there is a bond between adjacent atoms in the structure.
  • optionally substituted means that the specified group may be either unsubstituted or substituted by one or more substituents as defined herein. It is to be understood that in the compounds of the present invention when a group is said to be“unsubstituted,” or is“substituted” with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen.
  • aryl group also called“phenyl” herein
  • aryl group also called“phenyl” herein
  • one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the G, aryl ring (6 initial positions, minus one at which the remainder of the compound of the present invention is attached to and an additional substituent, remaining 4 positions open).
  • the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies.
  • aryl group in the present compounds is said to be“disubstituted,” one of ordinary skill in the art would understand it to mean that the G, aryl has 3 carbon atoms remaining that are unsubstituted.
  • an optionally substituted radical may be a radical unsubstituted or substituted with one or more substituents selected from halogen, CN, NO2, OR m , SR m , NR n R°, COR m , C0 2 R m , CONR n R°, SOR m , S0 2 R m , S0 2 NR n R°, NR n COR°, NR m C(0)NR n R°, NR n SOR°, NR n S0 2 R°, C C 8 alkyl, C 1 -GalkoxyC 1 -Galkyl.
  • G-G haloalkyl C 1 -G hydroxyalkyl, C 1 -GalkylaminoC 1 -Galkyl.
  • FORMULA 1 As used herein, the same symbol in different FORMULA means different definition, for example, the definition of R 1 in FORMULA 1 is as defined with respect to FORMULA 1 and the definition of R 1 is as defined with respect to FORMULA 6.
  • m is 0 to 15
  • m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15
  • m is an integer from 0 to 3(i.e. m is 0, 1,2, or 3) or is any integer in the defined range.
  • (CH 2 ) a-b (a and b are integer) means a group of (CH 2 ) c , and c is an integer from a to b(i.e. c is a, a+1, a+2, . . ., b-1, or b).
  • (CH 2 ) 0 -3 means a group of null, (CH 2 ), (CH 2 ) 2 , or (CH 2 ) 3 .
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the bivalent compounds described herein is intended to encompass 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.
  • “Pharmaceutically acceptable acid addition salt” 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 that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • 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.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as alginates, gluconates, and gal
  • Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts may 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 salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, /V./V-dibcnzylcthylcncdiaminc.
  • compositions and methods described herein include the manufacture and use of pharmaceutical compositions and medicaments that include one or more bivalent compounds as disclosed herein. Also included are the pharmaceutical compositions themselves.
  • compositions disclosed herein can include other compounds, drugs, or agents used for the treatment of cancer.
  • pharmaceutical compositions disclosed herein can be combined with one or more (e.g., one, two, three, four, five, or less than ten) compounds.
  • additional compounds can include, e.g., conventional chemotherapeutic agents or any other cancer treatment known in the art.
  • bivalent compounds disclosed herein can operate in conjunction with conventional chemotherapeutic agents or any other cancer treatment known in the art to produce mechanistically additive or synergistic therapeutic effects.
  • the pH of the compositions disclosed herein can be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the bivalent compound or its delivery form.
  • compositions typically include a pharmaceutically acceptable excipient, adjuvant, or vehicle.
  • pharmaceutically acceptable refers to molecular entities and compositions that are generally believed to be physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • a pharmaceutically acceptable excipient, adjuvant, or vehicle is a substance that can be administered to a patient, together with a compound of the invention, and which does not compromise the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • Exemplary conventional nontoxic pharmaceutically acceptable excipients, adjuvants, and vehicles include, but not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • pharmaceutically acceptable excipients, adjuvants, and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric 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, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
  • Cyclodextrins such as a-, b-, and g-cyclodextrin, may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • compositions may be used.
  • pharmaceutically acceptable excipients, adjuvants, and vehicles include lactose and com starch.
  • useful diluents include lactose and dried com starch.
  • the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
  • the bivalent compounds disclosed herein are defined to include pharmaceutically acceptable derivatives or prodmgs thereof.
  • A“pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, solvate, or prodrug, e.g., carbamate, ester, phosphate ester, salt of an ester, or other derivative of a compound or agent disclosed herein, which upon administration to a recipient is capable of providing (directly or indirectly) a compound described herein, or an active metabolite or residue thereof.
  • Particularly favored derivatives and prodmgs are those that increase the bioavailability of the compounds disclosed herein when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Preferred prodmgs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the stmcture of formulae described herein. Such derivatives are recognizable to those skilled in the art without undue experimentation.
  • the bivalent compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of
  • diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, morphological forms, or deuterated derivatives thereof.
  • the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates.
  • Racemates can be accomplished, for example, by 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.
  • compounds include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds.
  • the term“compound” is intended to include all tautomeric forms of the compound.
  • the bivalent compounds disclosed herein also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • Crystal form may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • polymorphs may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • solvates including hydrates
  • unsolvated polymorphs including anhydrates
  • conformational polymorphs including anhydrates
  • amorphous forms as well as mixtures
  • “pharmaceutically acceptable salts” of the bivalent compounds also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the pharmaceutically acceptable salts, as well as mixtures thereof.
  • A“solvate” is formed by the interaction of a solvent and a compound.
  • the term“compound” is intended to include solvates of compounds.
  • “pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts.
  • Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi -hydrates.
  • the pharmaceutical compositions disclosed herein can include an effective amount of one or more bivalent compounds.
  • the terms“effective amount” and“effective to treat,” as used herein, refer to an amount or a concentration of one or more compounds or a pharmaceutical composition described herein utilized for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer).
  • pharmaceutical compositions can further include one or more additional compounds, drugs, or agents used for the treatment of cancer (e.g., conventional chemotherapeutic agents) in amounts effective for causing an intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer).
  • compositions disclosed herein can be formulated for sale in the United States, import into the United States, or export from the United States.
  • compositions disclosed herein can be formulated or adapted for administration to a subject via any route, e.g., any route approved by the Food and Drug Administration (FDA).
  • FDA Food and Drug Administration
  • Exemplary methods are described in the FDA Data Standards Manual (DSM) (available at
  • compositions can be formulated for and administered via oral, parenteral, or transdermal delivery.
  • parenteral includes subcutaneous, intracutaneous, intravenous, intramuscular, intraperitoneal, intra-articular, intra-arterial, intrasynovial, intrastemal, intrathecal, intralesional, and intracranial injection or infusion techniques.
  • compositions disclosed herein can be administered, e.g., topically, rectally, nasally (e.g., by inhalation spray or nebulizer), buccally, vaginally, subdermally (e.g., by injection or via an implanted reservoir), or ophthalmically.
  • compositions of this 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.
  • compositions of this invention can be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
  • compositions of this 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 solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, or other solubilizing or dispersing agents known in the art.
  • compositions of this 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 dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, e.g., as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed, including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically -acceptable oils, e.g., olive oil or castor oil, especially in their
  • oil solutions or suspensions can also contain a long -chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • a long -chain alcohol diluent or dispersant or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • Other commonly used surfactants such as Tweens, Spans, or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
  • an effective dose of a pharmaceutical composition of this invention can include, but is not limited to, e.g., 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 according to the requirements of the particular pharmaceutical composition.
  • both the bivalent compounds and the additional compounds may be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents can be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents can be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • compositions disclosed herein can be included in a container, pack, or dispenser together with instructions for administration.
  • the methods disclosed herein contemplate administration of an effective amount of a compound or composition to achieve the desired or stated effect.
  • the compounds or compositions of the invention will be administered from about 1 to about 6 times per day or, alternately or in addition, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations can contain from about 20% to about 80% active compound.
  • provided herein are a bivalent compound described herein for preventing or treating a disease or condition.
  • a bivalent compound described herein for treating or preventing one or more diseases or conditions disclosed herein in a subject in need thereof.
  • the disease or condition is a CBP/P300-mediated disease or condition.
  • the disease or condition is resulted from CBP/P300 expression, mutation, deletion, or fusion.
  • the disease or condition is a cancer.
  • the disease or condition comprises acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer,
  • leiomyosarcoma leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T- cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcom
  • the disease or condition is a relapsed cancer.
  • the disease or condition is an inflammatory disorder or the autoimmune disease.
  • 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 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, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's
  • the disease or condition is refractory to one or more previous treatments.
  • a bivalent compound in manufacture of a medicament for preventing or treating one or more diseases or conditions disclosed herein.
  • the methods disclosed include the administration of a therapeutically effective amount of one or more of the compounds or compositions described herein to a subject (e.g., a
  • the methods disclosed include selecting a subject and administering to the subject an effective amount of one or more of the compounds or compositions described herein, and optionally repeating administration as required for the prevention or treatment of cancer.
  • subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection.
  • the subject can be confirmed or identified, e.g. by a health care professional, as having had, having an elevated risk to have, or having a condition or disease.
  • suitable subjects include, for example, subjects who have or had a condition or disease but that resolved the disease or an aspect thereof, present reduced symptoms of disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), or that survive for extended periods of time with the condition or disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), e.g., in an asymptomatic state (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease).
  • exhibition of a positive immune response towards a condition or disease can be made from patient records, family history, or detecting an indication of a positive immune response.
  • multiple parties can be included in subject selection.
  • a first party can obtain a sample from a candidate subject and a second party can test the sample.
  • subjects can be selected or referred by a medical practitioner (e.g., a general practitioner).
  • subject selection can include obtaining a sample from a selected subject and storing the sample or using the in the methods disclosed herein. Samples can include, e.g., cells or populations of cells.
  • methods of treatment can include a single administration, multiple administrations, and repeating administration of one or more compounds disclosed herein as required for the prevention or treatment of the disease or condition disclosed herein (e.g., an CBP/P300-mediated disease).
  • methods of treatment can include assessing a level of disease in the subject prior to treatment, during treatment, or after treatment. In some aspects, treatment can continue until a decrease in the level of disease in the subject is detected.
  • subject refers to any animal. In some instances, the subject is a mammal. In some instances, the term“subject,” as used herein, refers to a human (e.g., a man, a woman, or a child).
  • administer refers to implanting, ingesting, injecting, inhaling, or otherwise absorbing a compound or composition, regardless of form.
  • methods disclosed herein include administration of an effective amount of a compound or composition to achieve the desired or stated effect.
  • treat refers to partially or completely alleviating, inhibiting, ameliorating, or relieving the disease or condition from which the subject is suffering. This means any manner in which one or more of the symptoms of a disease or disorder (e.g., cancer) are ameliorated or otherwise beneficially altered.
  • amelioration of the symptoms of a particular disorder refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with treatment by the bivalent compounds, compositions and methods of the present invention.
  • 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 prior to treatment; a decrease in the viability (e.g., the average/mean viability) of tumor cells (e.g., in a subject) relative to the viability of tumor cells prior to treatment; a decrease in the rate of growth of tumor cells; a decrease in the rate of local or distant tumor metastasis; or reductions in one or more symptoms associated with one or more tumors in a subject relative to the subject’s symptoms prior to treatment.
  • a decrease in the number of tumor cells e.g., in a subject
  • a decrease in the viability e.g., the average/mean viability
  • the rate of growth of tumor cells e.g., in a subject
  • a decrease in the rate of local or distant tumor metastasis e.g., the rate of local or distant tumor metastasis
  • the terms“prevent,”“preventing,” and“prevention,” as used herein, shall refer to a decrease in the occurrence of a disease or decrease in the risk of acquiring a disease or its associated symptoms in a subject.
  • the prevention may be complete, e.g., the total absence of disease or pathological cells in a subject.
  • the prevention may also be partial, such that the occurrence of the disease or pathological cells in a subject is less than, occurs later than, or develops more slowly than that which would have occurred without the present invention.
  • the subject has an elevated risk of 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 myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, f
  • immunodeficiency syndrome inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.
  • Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • a therapeutically effective amount of a therapeutic compound depends on the therapeutic compounds selected.
  • treatment of a subject with a therapeutically effective amount of the compounds or compositions described herein can include a single treatment or a series of treatments.
  • effective amounts can be administered at least once.
  • the compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health or age of the subject, and other diseases present.
  • the subject can be evaluated to detect, assess, or determine their level of disease.
  • treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected.
  • a maintenance dose of a compound, or composition disclosed herein can be administered, if necessary.
  • the dosage or frequency of administration, or both can be reduced, e.g., as a function of the symptoms, to a level at which the improved condition is retained.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • Linker 3 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.4 g, yield: 15% over 2 steps).
  • MS (ESI) m/z 345.1 [M+H]+
  • Linker 5 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.8 g, yield: 20% over 2 steps).
  • Linker 10 was synthesized following th same procedures as Linker 1 as described in Example 1.
  • Example 11 4-((14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (Linker 11)
  • Linker 11 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.2 g, yield: 16% over 2 steps). l NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 7.84 (s, 3H), 7.61-7.57
  • Example 12 4-((17-Amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (Linker 12)

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Abstract

Bivalent compounds composition comprises one or more of the bivalent compounds. The bivalent compound comprises a cyclic-AMP response element binding protein (CBP) and/or adenoviral E1A binding protein of 300kDa (P300) ligand (CBP/P300 ligand) conjugated to a degradation tag. The method of using the bivalent compounds is treating certain disease in a subject in need thereof. The method of identifying such bivalent compounds is disclosed.

Description

CYCLIC-AMP RESPONSE ELEMENT BINDING PROTEIN (CBP) AND/OR ADENOVIRAL E1A BINDING PROTEIN OF 300 KDA (P300) DEGRADATION COMPOUNDS AND METHODS
OF USE
BACKGROUND OF THE INVENTION
This disclosure relates to bivalent compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the bivalent compounds, and to methods of use of the bivalent compounds for the treatment of certain disease in a subject in need thereof. The disclosure also relates to methods for identifying such bivalent compounds.
SUMMARY OF THE INVENTION
According to one aspect of the present disclosure, a bivalent compound disclosed herein comprises a cyclic -AMP response element binding protein (CBP) and/or adenoviral E1A binding protein of 300 kDa (P300) ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof.
In one embodiment, the CBP/P300 ligand is capable of binding to a CBP/P300 protein comprising a CBP/P300, a CBP/P300 mutant, a CBP/P300 deletion, or a CBP/P300 fusion protein.
In one embodiment, the CBP/P300 ligand is a CBP/P300 inhibitor or a portion of CBP/P300 inhibitor.
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.
In another embodiment, the degradation tag binds to an ubiquitin ligase or is a hydrophobic group or a tag that leads to misfolding of the CBP/P300 protein.
In another embodiment, the ubiquitin ligase is an E3 ligase.
In another embodiment, the E3 ligase is selected from the group consisting of a cereblon E3 ligase, a VHL E3 ligase, an IAP ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, DCAF16 ligase, RNF4 ligase, RNF114 ligase, and AhR ligase.
In another embodiment, the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, l-((4,4,5,5,5-pentafluoropentyl)sulfmyl)nonane, nutlin- 3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, CPD36, GDC-0152, CRBN-1, CRBN-2, CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, CRBN-11, and analogs thereof.
In another embodiment, the CBP/P300 ligand is conjugated to the degradation tag via a linker moiety.
In another embodiment, the CBP/P300 ligand comprises a moiety of FORMULA 1:
Figure imgf000002_0001
wherein
the linker moiety of the bivalent compound is attached to R2;
X1 and X3 are independently selected from C and N, with the proviso that at least one of X1 and X3 is C and at most only one of X1 and X3 is N;
X2 is selected from CR’, O, and NR’, wherein R’ is selected from H, optionally substituted Ci-Cg alkyl, and optionally substituted 3-10 membered carbocyclyl;
A is selected from null, CR4R5, CO, O, S, SO, SO2, and NR4, wherein
R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, optionally substituted CrCx alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C Cs alkoxy, optionally substituted C 1 -CxalkoxyC 1 -Cxalkyl. optionally substituted Ci-C8 alkylamino, optionally substituted Ci-CsalkylaminoCi-Csalkyl, 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;
Ar and R4, Ar and R5, and/or R4 and R5 together with the atom to which they are connected form an optionally substituted 3-20 membered cycloalkyl or heterocyclyl ring;
Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, N0 , OR6, SR6, NR6R7, OCOR6,
OCO2R6, OCONR6R7, COR6, CO2R6, CONR6R7, SOR6, SO2R6, SO2NR6R7, NR8CO2R6, NR8COR6,
NR8C(0)NR6R7,NR8S0R6, NR8S02R6, NR8S02NR6R7, optionally substituted C C8 alkyl, optionally substituted C -C8 alkenyl, optionally substituted C -C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted C 1 -CxalkoxyC 1 -Cxalkyl. optionally substituted Ci-Cs alkylamino, optionally substituted C 1 -Cxalkvlam inoC 1 -Cxalkyl. 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
R6, R7, and R8 are independently selected from hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr CsalkoxyCi-Csalkyl, optionally substituted C 1 - C x al k y 1 am i n o C 1 - C xal k y 1. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R6 and R7, R6 and R8 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;
R1 is selected from hydrogen, halogen, CN, N02, OR9, SR9, NR9R10, OCOR9, 0C02R9, OCONR9R10, COR9, C02R9, C0NR9R10, SOR9, S02R9, S02NR9R10, NRUC02R9, NRUCOR9, NRUC(0)NR9R10, NRuSOR9, NRUS02R9, NRUS02NR9R10, optionally substituted C' 1 -CN alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-Cs alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted C 1 - CsalkylaminoCi-Csalkyl, 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
R9, R10, and R11 are independently selected from hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr CsalkoxyCi-Csalkyl, optionally substituted C 1 - C x al k y 1 am i n o C 1 - C xal k y 1. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R9 and R10, R9 and R11 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; R2 is connected to the“linker” moiety of the bivalent compound, and is selected from null, R O, R S, R NR12, R OC(O), R 0C(0)0, R OCONR12, R C(O), R C(0)0, R CONR12, R S(O), R S(0)2, R S02NR12, R NR13C(0)0, R NR13C(0), R NR13C(0)NR12, R NR13S(0), R NR13S(0)2, R NR13S(0)2NR12, optionally substituted C 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-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R is is null, or a bivalent moiety selected from optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Cr
C8alkoxyCi-C8alkylene, optionally substituted C C8 haloalkylene, optionally substituted C 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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R12 and R13 are independently selected from optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCr C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R12 and R13 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
R3 is selected from hydrogen, COR14, C02R14, CONR14R15, SOR14, S02R14, S02NR14R15, optionally substituted C 1 -C( alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R14 and R15 are independently selected from hydrogen, optionally substituted C 1 -C(, alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R14 and R15 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring.
In another embodiment, X1 is C; and X2 and X3 are N. The FORMULA I is FORMULA 1A:
Figure imgf000004_0001
wherein
A, Ar, R1, R2 and R3 are the same as in FORMULA 1.
In another embodiment, A-Ar-R1 is a moiety of formulae Al:
Figure imgf000005_0001
wherein
A and R1 are the same as in FORMULA 1.
X is selected from CR”’ and N, wherein
R and is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 alkoxy, optionally substituted Ci-C6 alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
Ra is optionally formed a ring with A, and is selected from null, hydrogen, halogen, RbNR . RbOR16,
Figure imgf000005_0002
RbNR18S02R16, RbNR18S02NR16R17, optionally substituted C|-Cx alkyl, optionally substituted C 1 -Cx alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkenylene, optionally substituted C -C8 alkynyl, optionally substituted C -C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
Rb is is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-Cx alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-CxalkoxyCi-Cxalkylene, optionally substituted C 1 - C x al k y 1 am i n o C 1 - C xal k y 1 e n e . optionally substituted Ci-Cs haloalkylene, optionally substituted C 1 -Cx hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R16, R17, and R18 are independently selected from null, hydrogen, optionally substituted C 1 -Cx alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr CxalkoxyCi-Cxalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R16 and R17, R16 and R18 together with the atom to which they are connected form a 3-20 membered cycloalkyl or heterocyclyl ring.
In another embodiment, A is null.
In another embodiment, A is null; Ar is a bicyclic aryl or a bicyclic heteroaryl; and A-Ar-R1 is a moiety of FORMULAE A2 or A3:
Figure imgf000005_0003
wherein
R1 is the same as in FORMULA 1.
In another embodiment, A is NR4, wherein R4 is selected from hydrogen, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C i -C8alkoxyC i -C8alkyl. optionally substituted C I -C8alkylaminoC i -C8alkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodim
Figure imgf000006_0001
wherein
R1 is the same as in FORMULA 1.
In another embodiment, R1 is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.
In another embodiment, R1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
In another embodiment, R1 is is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
In another embodiment, R2 is selected from optionally substituted C i -C8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocycly, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodiment, R3 is selected from COR14 and CONR14R15.
In another embodiment, R3 is selected from COMe and CONHMe.
In another embodiment, the CBP/P300 ligand comprises a moiety of FORMULA 2:
Figure imgf000006_0002
FORMULA 2,
wherein
the linker moiety of the bivalent compound is attached to R1; and
X1 and X3 are independently selected from C and N, with the proviso that at least one of X1 and X3 is C and at most only one of X1 and X3 is N;
X2 is selected from CR’, O, and NR’, wherein
R’ is selected from H, optionally substituted C rC8 alkyl, and optionally substituted 3-10 membered carbocyclyl;
A is selected from null, CR4R5, CO, O, S, SO, S02, and NR4, wherein
R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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;
Ar and R4, Ar and R5, and/or R4 and R5 together with the atom to which they are connected form an optionally substituted 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, N0 , OR6, SR6, NR6R7, OCOR6,
OCO2R6, OCONR6R7, COR6, CO2R6, CONR6R7, SOR6, SO2R6, SO2NR6R7, NR8CO2R6, NR8COR6,
NR8C(0)NR6R7, NR8S0R6, NR8S02R6, NR8S02NR6R7, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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
R6, R7, and R8 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R6 and R7, R6 and R8 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring; and
R1 is connected to the“linker” moiety of the bivalent compound, and R1 is selected from null, R O,
R S, R NR9, R OC(O), R 0C(0)0, R OCONR9, R C(O), R C(0)0, R CONR9, R S(O), R S(0)2,
R S02NR9, R NR10C(O)O, R NR10C(O), R NR10C(0)NR9, R NR10S(0), R NR10S(O)2, R NR10S(O)2NR9, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2- C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocycly, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R is is null, or a bivalent moiety selected from optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Cr
C8alkoxyCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted Ci-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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R9 and R10 are independently selected from optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCi- C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R9 and R10 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
R2 is selected from hydrogen, halogen, CN, N02, OR11, SR11, NRUR12, OCOR11, OC02Ru, OCONRuR12, COR11, C02Ru, CONRUR12, SOR11, S02Ru, S02NRuR12, NR13C02Ru, NR13CORu, NR13C(0)NRuR12,NR13S0Ru, NR13S02Ru, NR13S02NRUR12, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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
R11, R12, and R13 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R and R , R and R together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
R3 is selected from hydrogen, COR14, C02R14, CONR14R15, SOR14, S02R14, S02NR14R15, optionally substituted C i -C( alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, wherein
R14 and R15 are independently selected from hydrogen, optionally substituted C i -C(, alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, and optionally substituted 4-6 membered heterocyclyl, or
R14 and R15 together with the atom to which they are connected form a 4-6 membered heterocyclyl ring.
In another embodiment, X1 is C; and X2 and X3 are N. The FORMULA 2 is FORMULA 2A:
Figure imgf000008_0001
FORMULA 2A,
wherein
A, Ar, R1, R2 and R3 are the same as in FORMULA 2.
In another embodiment, A-Ar-R1 is a moiety of formulae B 1 :
Figure imgf000008_0002
FORMULAE Bl,
wherein
* indicates the connection to the linker moiety of the bivalent compound;
A and R1 are the same as in FORMULA 2;
X is selected from CR”’ and N, wherein R and is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C6 alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted C i -C( alkoxy, optionally substituted C i -C( alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl; and
Ra optionally forms a ring with A, and is selected from null, hydrogen, halogen, RbNR16, RbOR16,
Figure imgf000009_0001
RbNR18S02R16, RbNR18S02NR16R17, optionally substituted C|-C8 alkyl, optionally substituted C i -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
Rb is is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted C rC8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R16, R17, and R18 are independently selected from null, a bond, hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R16 and R17, R16 and R18 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring.
In another embodiment, A is null.
In another embodiment, A is null; Ar is a bicyclic aryl or a bicyclic heteroaryl; and A-Ar-R1 is a moiety of FORMULAE B2 or B3:
Figure imgf000009_0002
FORMULA B2 FORMULA B3,
wherein
* indicates the connection to the linker moiety of the bivalent compound; and
R1 is the same as in FORMULA 2.
In another embodiment, A is NR4, wherein
R4 is selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodiment, A is NR4; and A-Ar-R1 is a moiety of FORMULAE B4, B5 or B6:
Figure imgf000010_0001
FORMULA B4 FORMULA B5 FORMULA B6,
wherein
* indicates the connection to the linker moiety of the bivalent compound; and
R1 is the same as in FORMULA 2.
In another embodiment, R1 is selected from optionally substituted 3-10 membered carbocyclylene, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodiment, R1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
In another embodiment, R1 is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
In another embodiment, R2 is selected from optionally substituted C i -Cx alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodiment, R3 is selected from COR14 and CONR14R15.
In another embodiment, R3 is selected from COMe and CONHMe.
In another embodiment, the CBP/P300 ligand is derived from any of the following:
Figure imgf000010_0002
In another embodiment, the CBP/P300 ligand is derived from the following CBP/P300 inhibitors: C646, naphthol-AS-E, compound 1-10, MYBMIM, CCS 1477, ICG-001, YH249, YH250, HBS1, OHM1, and KCN1.
In another embodiment, the CBP/P300 ligand is selected from the group consisting of:
Figure imgf000011_0001
In another embodiment, the degradation tag is a moiety selected from the group consisting of
Figure imgf000011_0002
, wherein
V, W, and X are independently selected from CR2 and N;
Y is selected from CO, CR3R4, N=CR3, and N=N;
Z is selected from null, CO, CR5R6, NR5, O, optionally substituted Ci-Cio alkylene, optionally substituted Ci-Cio alkenylene, optionally substituted Ci-Cio alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH2, CH=CH, CºC, NH and O;
R1, and R2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R3 and R4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
R5 and R6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C( alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R5 and R6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl. In another embodiment , the degradation tag is a moiety selected from the group consisting of
Figure imgf000012_0001
,
wherein
V, W, and X are independently selected from CR2 and N;
Y is selected from CO, CH , and N=N;
Z is selected from CH2, NH and O; and
R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, and C1-C5 alkyl.
In another embodiment, the degradation tag is a moiety selected from the group consisting of FORMULAE 5E, 5F, 5G, 5H, and 51:
Figure imgf000012_0002
wherein
U, V, W, and X are independently selected from CR2 and N;
Y is selected from CR3R4, NR3 and O; preferably, Y is selected from CH2, NH, NG¾ and O;
Z is selected from null, CO, CR5R6, NR5, O, optionally substituted C1-C10 alkylene, optionally substituted C Cio alkenylene, optionally substituted C Cio alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH2, CH=CH, CºC, NH and O;
R1, and R2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R3 and R4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
R5 and R6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R5 and R6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl.
In one embodiment, the degradation tag is a moiety selected from the group consisting of FORMULAE 5J, 5K, 5L, 5M, 5N, 50, 5P, and 5Q:
wherein
Figure imgf000013_0001
U, V, W, Y, X, Z, R1, and R2 are defined as in FORMULAE 5E, 5F, 5G, 5H, or 51;
Y’, Y”, and Y”’ are independently selected from CR3R4;
X’ are independently selected from CR2 and N;
R’ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl.
In one embodiment, the degradation tag is a moiety of FORMULA 6A:
Figure imgf000013_0002
wherein
R1 and R2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted CrCx alkyl, optionally substituted C -C alkenyl, and optionally substituted C -C alkynyl, optionally substituted C -CxalkoxyC -Cxalkyl. optionally substituted C -Cx haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 aminoalkyl, optionally substituted Ci- CsalkylaminoCi-Csalkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4- 10 membered heterocyclyl.
R3 is selected from hydrogen, optionally substituted C(0)Ci-C8 alkyl, optionally substituted C(0)Cr CsalkoxyCi-Csalkyl, optionally substituted C(0)Ci-C8 haloalkyl, optionally substituted C(0)Ci-C8 hydroxyalkyl, optionally substituted C(0)Ci-C8 aminoalkyl, optionally substituted C(0)Cr
CsalkylaminoCi-Csalkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C2-C8 alkenyl, optionally substituted C(0)C2-C8 alkynyl, optionally substituted C(0)OCi-C8alkoxyCi-C8alkyl, optionally substituted C(0)0Ci-C8 haloalkyl, optionally substituted C(0)0Ci-C8 hydroxyalkyl, optionally substituted C(0)0Cr C8 aminoalkyl, optionally substituted C(0)OCi-C8alkylaminoCi-C8alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C -C8 alkenyl, optionally substituted C(0)0C2-C8 alkynyl, optionally substituted C(0)NCi-C8alkoxyCi-C8alkyl, optionally substituted C(0)NCi-C8 haloalkyl, optionally substituted C(0)NCI-C8 hydroxyalkyl, optionally substituted C(0)NCi-C8 aminoalkyl, optionally substituted C(0)NCi-C8alkylaminoCi-C8alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(0)NC2-C8 alkenyl, optionally substituted C(0)NC2-C8 alkynyl, optionally substituted P(0)(0H)2, optionally substituted P(0)(0Ci-C8 alkyl)2, and optionally substituted P(0)(0Ci-C8 aryl)2.
In another embodiment, the degradation tag is a moiety of FORMULAE 6B, 6C, and 6D:
Figure imgf000014_0001
wherein
R1 and R2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl;
optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 aminoalkyl, optionally substituted Cr
C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4- 10 membered heterocyclyl;
R3 is selected from hydrogen, optionally substituted C(0)Ci-C8 alkyl, optionally substituted C(0)Cr C8alkoxyCi-C8alkyl, optionally substituted C(0)Ci-C8 haloalkyl, optionally substituted C(0)Ci-C8 hydroxyalkyl, optionally substituted C(0)Ci-C8 aminoalkyl, optionally substituted C(0)Cr
C8alkylaminoCi-C8alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C2-C8 alkenyl, optionally substituted C(0)C2-C8 alkynyl, optionally substituted C(0)OCi-C8alkoxyCi-C8alkyl, optionally substituted
C(0)OCi-C8 haloalkyl, optionally substituted C(0)OCi-C8 hydroxyalkyl, optionally substituted C(0)OCr C8 aminoalkyl, optionally substituted C(0)OCi-C8alkylaminoCi-C8alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C2-C8 alkenyl, optionally substituted C(0)0C2-C8 alkynyl, optionally substituted C(0)NCi-C8alkoxyCi-C8alkyl, optionally substituted C(0)NCi-C8 haloalkyl, optionally substituted C(0)NCI-C8 hydroxyalkyl, optionally substituted C(0)NCi-C8 aminoalkyl, optionally substituted C(0)NCi-C8alkylaminoCi-C8alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(0)NC2-C8 alkenyl, optionally substituted C(0)NC2-C8 alkynyl, optionally substituted P(0)(OH)2, optionally substituted P(0)(OCi-C8 alkyl)2, and optionally substituted P(0)(OCi-C8 aryl)2, and
0
R4 is selected from NR7R8
Figure imgf000014_0002
, optionally substituted Ci-C8alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteraryl, in which
R is selected from hydrogen, optionally substituted Ci-C8alkyl, optionally substituted C r
C8cycloalkyl, optionally substituted Ci-C8alkyl-CO, optionally substituted Ci-C8cycloalkyl-CO optionally substituted Ci-C8cycloalkyl-Ci-C8alkyl-CO, optionally substituted 4-10 membered heterocyclyl-CO, optionally substituted 4-10 membered heterocyclyl-Ci-C8alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-Ci-C8alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-Ci-C8alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;
R8 is selected from hydrogen, optionally substituted Ci-C8alkyl, and optionally substituted Cr C8cycloalkyl;
R9, at each occurance, is independently selected from hydrogen, halogen, cyano, optionally substituted Ci-C8alkyl, optionally substituted Ci-C8cycloalkyl, optionally substituted Ci- C8heterocycloalkyl, optionally substituted Ci-C8alkoxy, optionally substituted Ci-C8cycloalkoxy, halo substituted Ci-C8alkyl, halo substituted Ci-C8cycloalkyl, halo substituted Ci-C8alkoxl, halo substituted Ci- C8cycloalkoxy, and halo substituted Ci-C8heterocycloalkyl;
X is selected from CH and N; and
n is 0, 1, 2, 3, or 4;
R6 is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci- C8alkyl, optionally substituted Ci-C8cycloalkyl, optionally substituted Ci-C8alkoxy, and optionally substituted Ci-C8cycloalkoxy, optionally substituted Ci-C8heterocycloalkyl, 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 group.
In another embodiment, the degradation tag is a moiety of FORMULA 7A:
Figure imgf000015_0001
wherein
V, W, X, and Z are independently selected from CR4 and N; and
R1, R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxy, optionally substituted Cr C8alkylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.
In another embodiment, the degradation tag is a moiety of FORMULA 7B:
Figure imgf000015_0002
substituted Ci-Cg hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl;
R4 and R5 are independently selected from hydrogen, COR6, CO2R6, CONR6R7, SOR6, SO2R6, S0 NR6R7, optionally substituted Ci-C8 alkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted C 1 -C^alkylaminoC 1 -Cxalkyl. optionally substituted aryl-Ci-Csalkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R6 and R7 are independently selected from hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C 1 -CxalkoxyC 1 -Cxalkyl. optionally substituted C 1 -C^alkylaminoC 1 -Cxalkyl. optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R6 and R7 together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.
In another embodiment, the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, and 51.
In another embodiment, the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, and 5F.
In another embodiment, the degradation tag is derived from any of the following:
Figure imgf000016_0001
In another embodiment, the degradation tag is derived from any 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.
In another embodiment, the degradation tag is selected from the group consisting of:
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
In another embodiment, the degradation tag is selected from the group consisting of: FORMULA 8 A 8B, 8C, 8D, 8E, 8F, 8G, 8H, 81, 8J, 8K, 8L, 8M, 80, 8P, 8Q, 8R, 8AQ, 8AR, 8AS, 8AT, 8AU, 8AV, 8AW, 8 AX, 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, 8 CM, 8CN, 8CO, 8CP, 8CQ, 8CR, 8CS, 8CT, 8CU, 8CV, 8CW, 8CX, 8CY, 8CZ, 8DA, 8DB, 8DC, 8DD, 8DE, 8DF, 8DG, 8DH, 8DI, 8DJ, 8DK, 8DL, 8DM, 8DN, 8DO, 8DP, 8DQ, 8DR, 8DS, 8DT, 8DU, 8DV, 8DW 8DX, 8DY, 8DZ, 8EA, 8EB, 8EC, 8ED, 8EE, 8EF, 8EG, 8EH, 8EI, 8EJ, 8EK, 8EL, 8EM, 8EN, 8EO, 8EP, 8EO, 8GU, 8GV, 8GW, 8GX, 8GY, 8GZ, 8HA, 8HB, 8HC, 8HD, 8HE, 8HF, 8HG, 8HH, 8HI, 8HJ 8HK, 8HL, 8HM, 8HN, 8HO, 8HP, 8HQ, 8HR, 8HS, 8HT, 8HU, 8HV, 8HW, 8HX, 8HY, 8HZ, 8IA, 8IB 8IC, 8 ID, 8 IE, 8IF, 8IG, 8IH, 8II, 8IJ, 8IK, 8IL, 8IM, 8IN, 8IO, 8IP, 8IQ, 8IR, 8IS, 8IT, 8IU, 8IV, 8IW,
8 IX, 8IY, 8IZ, 8JA, 8JB, 8JC, 8JD, 8JE, 8JF, 8JG, 8JH, 8JI, 8JJ, 8JK, 8JL, 8JM, 8JN, 8JO, 8JP, 8JQ, 8JR; 8JS, and 8JT.
In some embodiments, the linker moiety
Figure imgf000022_0001
wherein
A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR”, R C02R , R C(0)N(R1)R , R C(S)N(R1)R , R OR , R SR , R SOR , R S02R ,
R SO N^R , R N(R')R . R N(R')C0R . RN(R1)CON(R2)R , RN(R1)C(S)R , optionally substituted C|-C’s alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted CrC8 haloalkylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, 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 null, optionally substituted (C C8 alkylene)-Rr (preferably, CH2-Rr), optionally substituted Rr-(Ci-C8 alkylene), optionally substituted (Ci-C8 alkylene)- Rr-(Ci-C8 alkyl), or a moiety comprising of optionally substituted Ci-C8 alkyl, optionally substituted C2- C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is 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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R1 and R2 are independently selected from hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C -C alkenyl, optionally substituted C -C alkynyl, optionally substituted C -Cx alkoxyalkyl, optionally substituted C Cs haloalkyl, optionally substituted Ci-Cs hydroxyalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R1 and R2, R and R1, R and R2, R and R1, R and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
m is 0 to 15.
In another embodiment, W and m are defined as above; and A and B, at each occurrence, are
Figure imgf000023_0001
In another embodiment, Rr is selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined hereinafter.
In another embodiment, Rr is selected from FORMULA Cl, C2, C3, C4, and C5 as defined hereinafter.
In another embodiment, Rris selected from Group R, and Group R consists of
In one embodiment, the linker moiety is of FORMULA 9A:
Figure imgf000024_0001
wherein
R1, R2, R3 and R4, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl amino, cyano, nitro, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted CrC8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 alkylamino, and optionally substituted Ci-C8 alkylaminoCi-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 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R1 and R2, R3 and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR , R C02R , R C(0)N(R5)R , R C(S)N(R5)R , R OR , R SR , R SOR , R S02R
R S02N(R5)R , RN(R5)R , RN(R5)COR , RN(R5)CON(R6)R , RN(R5)C(S)R , optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted CrC8 haloalkylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, 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 null, optionally substituted (C C8 alkylene)-Rr (preferably, CH2-Rr), optionally substituted Rr-(Ci-C8 alkylene), optionally substituted (Ci-C8 alkylene)- Rr-(Ci-C8 alkylene), or a moiety comprising of optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is 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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R5 and R6 are independently selected from hydrogen, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R5 and R6, R and R5, R and R6, R and R5, R and R6 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
m is 0 to 15;
n, at each occurrence, is 0 to 15; and
o is 0 to 15.
In another embodiment, A, W and B, at each occurrence, are independently selected from null, 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) O-8, CO-NH-(CH2) O-8, (CH2) !-3-NH-(CH2) 1 3-CO-NH, (CH2) !-3-NH-(CH2) 1 3-NH-CO, -CO-NH, CO-NH- (CH2) !-3-NH-(CH2) !-3, (CH2) , 3-NH-(CH2) ,_3. -(CH2)0-3-Rr-(CH2)0-3, -(CH2)0-3-(CO)-(CH2)0-3-Rr- (CH2)O-3-, -(CH2)o-3-(CO-NH)-(CH2)o-3-Rr-(CH2)o_3-, -(CH2)0-3-(NH-CO)-(CH2)0-3-Rr-(CH2)0-3-, and - (CH2)o-3-(NH)-(CH2)o-3-Rr-(CH2)o-3-.
In another embodiment, Rr is selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined hereinafter.
In another embodiment, Rr is selected from FORMULA Cl, C2, C3, C4, and C5 as defined hereinafter.
In another embodiment, Rris selected from Group R, and Group R is defined as in FORMULA 9.
In one embodiment, the CBP/P300 ligand of the bivalent compound is attached to A in FORMULA
9A.
In another embodiment, A (when A is attached to the CBP/P300 ligand) is selected from null, CO, NH, NH-CO, CO-NH, -(CH2)0-8-, -(CH2)o-3-CO-(CH2)o-8-, (CH2)0.8-NH-CO, (CH2)0.8-CO-NH, NH-CO-
(CH2) O-8, CO-NH-(CH2) O-8, (CH2) O-8-NH-(CH2) O-8-CO-NH, (CH2) !.3-NH-(CH2) 1 3-NH-CO, CO-NH- (CH2) !-3-NH-(CH2) !-3, (CH2) !-3-NH-(CH2) !-3, -(CH2)o-3-Rr-(CH2)0-3, -(CH2)0-3-(CO)-(CH2)0-3-Rr-(CH2)0-3-, -(CH2)o-3-(CO-NH)-(CH2)o-3-Rr-(CH2)o-3-, -(CH2)0-3-(NH-CO)-(CH2)0-3-Rr-(CH2)0-3-, -(CH2)0.3-(NH)- (CH2)o-3-Rr-(CH2)o-3-., wherein
Rris selected from Group R, and Group R is defined as in FORMULA 9; and
W and B is null.
In one embodiment, the linker moiety is of FORMULA 9A:
wherein
R1, R2, R3 and R4, at each occurrence, are independently selected from hydrogen, optionally substituted C C8 alkyl (preperably, C1-C4 alkyl), or
R1 and R2, R3 and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl (preferably, 3-5 membered cycloalkyl) or 4-20 membered heterocyclyl ring;
A is defined as before; and W and B are null;
m is 0 to 15 (preferably, m is 0, 1, or 2);
n, at each occurrence, is 1 to 15 (preferably, n is 1); and
o is 1 to 15(preferably, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13).
In another embodiment, A is independently selected from null, or bivalent moiety selected from R -
R , R COR , R C02R , R C(0)N(R5)R , R C(S)N(R 55\)rR> , R OR , R SR , R SOR , R S02R
R S02N(R5)R , RN(R5)R , RN(R5)COR , RN(R5)CON(R6)R , RN(R5)C(S)R R and R are defined as above. In another embodiment, R and R are independently selected from null, optionally substituted (CrC8 alkyl)-Rr (preferably, CH2-Rr), or optionally substituted Ci-C8 alkyl (preferably, optionally substituted Cr C2 alkyl).
In another embodiment, the linker moiety i
Figure imgf000026_0001
wherein
R1 and R2, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C i -C8 alkyl, optionally substituted CrC8 alkoxy, optionally substituted CrC8 alkoxy CrC8 alkyl, optionally substituted C|-C8 haloalkyl, optionally substituted C i -C8 hydroxyalkyl, optionally substituted Ci-C8 alkylamino, Ci-C8alkylaminoCi-C8alkyl, 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
R1 and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or
4-20 membered heterocyclyl ring;
A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR , R C02R , R C(0)N(R3)R , R C(S)N(R3)R , R OR , R SR , R SOR , R S02R ,
R S02N(R3)R , RN(R3)R , RN(R3)COR , RN(R3)CON(R4)R , RN(R3)C(S)R , optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted CrC8 hydroxyalkylene, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro heterocyclyl, 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 null, optionally substituted (Ci-C8 alkylene)-Rr (preferably, CH2-Rr), optionally substituted Rr-(Ci-C8 alkylene), optionally substituted (Ci-C8 alkylene)- Rr-(Ci-C8 alkylene), or a moiety comprising of optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted CrC8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R3 and R4 are independently selected from hydrogen, optionally substituted Ci-Cs alkyl, optionally substituted C -C8 alkenyl, optionally substituted C -C8 alkynyl, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted Ci-Cs haloalkyl, optionally substituted Ci-Cs hydroxyalkyl, optionally substituted C I -C’salkylaminoC 1 -Cxalkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R3 and R4, R and R3, R and R4, R and R3, R and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
each m is 0 to 15; and
n is 0 to 15.
In another embodiment, A and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH2)O-8-, -(CH2)O-3-CO-(CH2)O-8-, (CH2)O-8-NH-CO, (CH2)O-8-CO-NH, NH-CO-(CH2)
8, CO-NH-(CH2) 0-8, (CH2) I_3-NH-(CH2) 1-3-CO-NH, (CH2) I_3-NH-(CH2) 1-3-NH-CO, CO-NH-(CH2) 1-3- NH-(CH2)1_3, (CH2) 1_3-NH-(CH2) 3 -(CH2)o-3-Rr-(CH2)o-3, -(CH2)o-3-(CO)-(CH2)o-3-Rr-(CH2)o-3-, -(CH2)0. 3-(CO-NH)-(CH2)o-3-Rr-(CH2)o-3-, -(CH2)o-3-(NH-CO)-(CH2)o-3-Rr-(CH2)o-3-, -(CH2)o-3-(NH)-(CH2)o-3-Rr-
(CH2V3-.
In another embodiment, Rr is selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined hereinafter.
In another embodiment, Rr is selected from FORMULA Cl, C2, C3, C4, and C5 as defined hereinafter.
In another embodiment, Rris selected from Group R, and Group R is defined as in FORMULA 9.
In another embodiment, the linker moiety is of FORMULA 9C:
Figure imgf000027_0001
wherein
X is selected from O, NH, and NR7;
R1, R2, R3, R4, R5, and R6, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C|-Cx alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-Cs alkoxy, optionally substituted Ci-Cs alkoxy Ci-Cs alkyl, optionally substituted Ci-Cs haloalkyl, optionally substituted Ci-Cs hydroxyalkyl, optionally substituted Ci-Cs alkylamino, optionally substituted C|-Cx alkylaminoC|-Cx alkyl optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
A and B are independently selected from null, or bivalent moiety selected from R -R , R COR ,
R CO2R , R C(0)N(R8)R , R C(S)N(R8)R , R OR , R SR , R SOR , R S02R , R S02N(R8)R , R N(R8)R RN(R8)COR , RN(R8)CON(R9)R , RN(R8)C(S)R , optionally substituted Ci-Cs alkylene, optionally substituted C -C8 alkenylene, optionally substituted C -C8 alkynylene, optionally substituted C
CxalkoxyCi-Cxalkylene, optionally substituted Ci-Cs haloalkylene, optionally substituted Ci-Cs hydroxyalkylene, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-Ci3 spiro
heterocyclyl, 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 null, optionally substituted (C C8 alkylene)-Rr (preferably, CH -Rr), optionally substituted Rr-(C Cx alkylene), optionally substituted (C rC8 alkylene)- Rr-(C|-C’x alkylene), or a moiety comprising of optionally substituted C|-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted C C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R7, R8 and R9 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R8 and R9, R and R8, R and R9, R and R8, R and R9 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
m, at each occurrence, is 0 to 15;
n, at each occurrence, is 0 to 15;
o is 0 to 15; and
p is 0 to 15.
In another embodiment, A and B are independently selected from null, CO, NH, NH-CO, CO-NH, -
Figure imgf000028_0001
In another embodiment, Rr is selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined hereinafter.
In another embodiment, Rr is selected from FORMULA Cl, C2, C3, C4, and C5 as defined hereinafter.
In another embodiment, Rris selected from Group R, and Group R is defined as in FORMULA 9.
In another embodiment, A and B, at each occurrence, are independently selected from null, 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 In another embodiment, o is 0 to 5.
In another embodiment, the linker moiety comprises one or more rings selected from the group consisting of 3 to 13 membered rings, 3 to 13 membered fused rings, 3 to 13 membered bridged rings, and 3 to 13 membered spiro rings.
In another embodiment, the linker moiety comprises one or more rings selected from the group consisting
Figure imgf000029_0001
FORM ULA Cla
Figure imgf000029_0002
Figure imgf000029_0003
FORM ULA C4a FORM U LA C5a
wherein
X’ and Y’ are independently selected from N, CRb;
A1, B1, C1 and D1, at each occurrence, are independently selected from null, O, CO, SO, SO2, NRb, CRbRc;
A2, B2, C2, and D2, at each occurrence, are independently selected from N, CRb ;
A3, B3, C3, D3, and E3, at each occurrence, are independently selected from N, O, S, NRb, CRb;
Rb and Rc, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C rCx alkyl optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1 -Cx alkoxy, optionally substituted C|-Cx alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 alkylamino, and optionally substituted C 1 -Cx alkylaminoCi-Cx alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
m1, n1, o1 and p1 are independently selected from 0, 1, 2, 3, 4 and 5.
In another embodiment, the linker moiety comprises one or more rings selected from the group consisting
Figure imgf000029_0004
FORMULA Cl, FORMULA C2, FORMULA C3,
Figure imgf000030_0001
D
A si CH, alkyl), wN A ss 0, CH, C|C ¾ alkyl), N, NH, (C^ alkyl), O, S
8 *: CH, C{Ct 3 or N 8 « C, CH, Cfc s alky!}. N, NH, NiC^ alkyl), Q, S
C ~ CH, C(G,,* alkyl), orH C . C, CH CIC^ alkyl), N. NH, N(Cf ¾ alkyl), O, S
0 « CH, CiC^ aikyl), or N D * C, CH, CiC^ alkyl), N, NH, NfC^ alkyl), O, S
Figure imgf000030_0002
E ~ C, CH, C(C I -3 alkyl), N, NH, N<Cl -3alkyi). O, S
FORMULA C4, FORMULA C5
In another embodiment, the linker moiety is of FORMULA 9A.
In another embodiment, A, W and B, at each occurrence, are independently selected from null, 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) !-3-NH-(CH2) !-3-CO-NH, (CH2) !-3-NH-(CH2) !-3-NH-CO, CO-NH- (CH2) ,-3-NH-(CH2) !_3, (CH2) 1-3-NH-(CH2) !-3, -(CH2)o-3-Rr-(CH2)o-3, -(CH2)o-3-(CO)-(CH2)o-3-Rr-(CH2)o-3-, -(CH2)o-3-(CO-NH)-(CH2)o-3-Rr-(CH2)0-3-, -(CH2)0-3-(NH-CO)-(CH2)o-3-Rr-(CH2)o-3-, and -(CH2)0-3-(NH)- (CH2)o-3-Rr-(CH2)0-3-;
In another embodiment, Rris selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined above.
In another embodiment, Rris selected from FORMULA Cl, C2, C3, C4, and C5 as defined above.
In another embodiment, Rris selected from Group R, and Group R is defined as in FORMULA 9.
In another embodiment, in FORMULA 9A, A and B are independently defined as above, and W is null.
In another embodiment, the length of the linker is 0 to 40 chain atoms.
In another embodiment, the length of the linker is 3 to 20 chain atoms.
In another embodiment, the length of the linker is 5 to 15 chain atoms.
In another embodiment, when the CBP/P300 ligand of the bivalent compound attached to A, A is selected from -(CO)-, -(CH2)!-2(CO)-NH-, -(CH2)0-8-, -(CH2)0-3-CO-(CH2)0-8-, -(CH2)o-3-Rr-(CH2)0-3, - (CH2)o-3-(CO)-(CH2)o-3-Rr-(CH2)0-3, wherein
Rr is selected from Group R, and Group R is defined as in FORMULA 9.
In another embodiment, the linker is -(CO)-(CH2)3_7-.
In another embodiment, the linker is -(CH2)I_2(CO)-NH-(CH2)3_7-.
In another embodiment, the linker is -(CH2)0_n-, or -(CH2)0-3-CO-(CH2)0-IO-.
In another embodiment, the linker is -(CH2)0-3-Rr-(CH2)0-3-, or -(CH2)o-3-(CO)-(CH2)0-3-Rr-(CH2)0-3-, wherein Rr is selected from the group Group R, and Group R is defined as in FORMULA 9.
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.
In some embodiments, the bivalent 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 a
pharmaceutically acceptable salt or analog thereof.
In one embodiment, the bivalent compound is 3-(7-(difluoromcthyl)-6-( I -methyl- 1 //-pyrazol-4-yl)- 3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(5 -((2-(2,6-dioxopiperidin-3-yl)- 1 ,3 -dioxoisoindolin-5 - yl)amino)pcntanoyl)pipcridin-4-yl)-/V-mcthyl- 1.4.6.7-tctrahydro-5//-pyrazolo|4.3-c |pyridinc-5- carboxamide (P-004). In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)-\ -( 1 -(6-((2-(2,6-dioxopiperidin-3-yl)- 1 ,3 -dioxoisoindolin-5 - yl)amino)hexanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5- carboxamide (P-005).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-lH-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-yl)- 1 -( 1 -(7-((2-(2,6-dioxopiperidin-3 -yl)- l,3-dioxoisoindolin-5- yl)amino)heptanoyl)piperidin-4-yl)-N-methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxamide (P-006).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3,4-dihydroquinolin- 1 (2H)-y\)-\ -( 1 -(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)octanoyl)pipcridin-4-yl)-/V-mcthyl- 1.4.6.7-tetrahydro-5//-pyrazolo|4.3-c |pyridine-5- carboxamide (P-007).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(4-((2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4- yl)amino)butanoyl)pipcridin-4-yl)-/V-mcthyl- 1.4.6.7-tetrahydro-5//-pyrazolo|4.3-c|pyridine-5- carboxamide (P-015).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((6-((2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)amino)hexyl)amino)-2-oxoethyl)- 1 / -pyrazol-4-yl)-3 ,4- dihydroquinolin- 1 (2//)-yl)-/V-methyl- 1 -(tctrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3- c]pyridine-5 -carboxamide (P-020).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((7-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)heptyl)amino)-2-oxoethyl)-l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-N-mcthyl- 1 -(tetrahydro-2//-pyran-4-yl)- 1 ,4,6,7-tetrahydro-5//-pyrazolo[4,3- c]pyridine-5 -carboxamide (P-026).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((8-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)octyl)amino)-2-oxoethyl)-l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-/V-methyl- 1 -(tctrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3- c]pyridine-5 -carboxamide (P-027).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(5 -((2-(2,6-dioxopiperidin-3-yl)- 1 ,3 -dioxoisoindolin-4- yl)amino)pentanoyl)piperidin-4-yl)-/V-methyl- 1.4.6.7-tctrahydro-5//-pyrazolo|4.3-c |pyridinc-5- carboxamide (P-033).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(6-((2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4- yl)amino)hexanoyl)piperidin-4-yl)-A/-methyl- 1,4,6, 7-tetrahydro-5//-pyrazolo [4,3 -c]pyridine-5- carboxamide (P-034).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 {2H)-y\)-\ -( 1 -(7-((2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4- yl)amino)hcptanoyl)pipcridin-4-yl)-/V-mcthyl- 1.4.6.7-tetrahydro-5//-pyrazolo|4.3-c |pyridine-5- carboxamide (P-035).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(8-((2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4- yl)amino)octanoyl)pipcridin-4-yl)-/V-mcthyl- 1.4.6.7-tetrahydro-5//-pyrazolo|4.3-c |pyridine-5- carboxamide (P-036). In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((6-((2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl)- 1 / -pyrazol-4-yl)-3 ,4- dihydroquinolin- 1 (2 /)-yl)-/V-methyl- 1 -(tctrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3- c]pyridine-5 -carboxamide (P-041).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-(2-((8-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)octyl)amino)-2-oxoethyl)-l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2 /)-yl)-/V-methyl- 1 -(tetrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3- c]pyridine-5 -carboxamide (P-043).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)-\ -( 1 -(7-(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3-dioxoisoindolin-4- yl)hcptanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5-carboxamidc (P- 085).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(6-((2-(2,6-dioxopiperidin-3 -yl)- 1 -oxoisoindolin-4- yl)oxy)hcxanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5-carboxamidc (P-088).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(6-((2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4- yl)amino)hcxyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5-carboxamidc (P-090).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(6-((2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4- yl)oxy)hcxyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5-carboxamidc (P- 091).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(7-(2-(2,6-dioxopiperidin-3 -yl)- 1 -oxoisoindolin-4-yl)hept-6- ynoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5-carboxamidc (P-093).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(6-((2-(2,6-dioxopiperidin-3 -yl)-3 -oxoisoindolin-4- yl)amino)hexanoyl)piperidin-4-yl)-A/-methyl- 1,4,6, 7-tetrahydro-5//-pyrazolo [4,3 -c]pyridine-5- carboxamide (P-096).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(7-(2-(2,6-dioxopiperidin-3 -yl)- 1 ,3-dioxoisoindolin-4- yl)hcptyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5-carboxamidc (P-097).
In one embodiment, the bivalent compound is 4-((6-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l-methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r |pyridin- 1 - yl)piperidin-l-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-100).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4- yl)cthyl)pipcridin- 1 -yl)acctyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5- carboxamide (P-104).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(7-(3 -(2,6-dioxopiperidin-3 -yl)-2-oxo-2.3-dihydro- 1 H- bcnzo|d|imidazol- 1 -yl)hcptanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3- c]pyridine-5 -carboxamide (P-106). In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2H)-\\)- 1 -( 1 -(6-(( 1 -(2,6-dioxopiperidin-3 -yl)-3 -methyl-2-oxo-2, 3 -dihydro- 1 H- bcnzo|c/|imidazol-4-yl)amino)hcxanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3- c]pyridine-5 -carboxamide (P-109).
In one embodiment, the bivalent compound is 3 -(4-((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 /-pyrazolo|4.3-r|pyridin- 1 - yl)pipcridin- 1 -yl )-6-oxohcxyl)amino)-3 -methyl -2-OXO-2.3 -dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)pipcridinc-
2,6-dione (P-110).
In one embodiment, the bivalent compound is 3 -(4-((7-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo|4.3-r|pyridin- 1 - yl)piperidin- 1 -yl)-7 -oxoheptyl)amino)-3 -methyl-2-oxo-2, 3 -dihydro- l//-benzo |c/|imidazol- 1 -yl)piperidine-
2,6-dione (P-111).
In one embodiment, the bivalent compound is 4-((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l -methyl - 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 / -pyrazolo|4.3-r |pyridin- 1 - yl)piperidin-l-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-112).
In one embodiment, the bivalent compound is 4-((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l -methyl - 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r |pyridin- 1 - yl)piperidin-l-yl)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-113).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2//)-yl)- 1 -( 1 -(6-(( 1 -(2,6-dioxopiperidin-3 -yl)-3 -methyl-2-oxo-2, 3 -dihydro- 1 H- bcnzo|c/|imidazol-5-yl)amino)hcxanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3- c]pyridine-5 -carboxamide (P-115).
In one embodiment, the bivalent compound is 3 -(5 -((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 / -pyrazolo|4.3-r |pyridin- 1 - yl)pipcridin- 1 -yl )-6-oxohcxyl)amino)-3 -methyl -2-OXO-2.3 -dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)pipcridinc-
2,6-dione (P-116).
In one embodiment, the bivalent compound is 5-((8-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l-methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r |pyridin- 1 - yl)piperidin- 1 -yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P-119).
In one embodiment, the bivalent compound is 5 -((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l -methyl - 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 / -pyrazolo|4.3-r |pyridin- 1 - yl)piperidin-l-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-120).
In one embodiment, the bivalent compound is 3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-
3 ,4-dihydroquinolin- 1 (2//)-yl)- 1 -( 1 -(7-(( 1 -(2,6-dioxopiperidin-3 -yl)-3 -methyl-2-oxo-2, 3 -dihydro- 1 H- bcnzo|c/|imidazol-5-yl)amino)hcptanoyl)pipcridin-4-yl)-/V-mcthyl- 1.4.6.7-tctrahydro-5//-pyrazolo|4.3- c]pyridine-5 -carboxamide (P-129).
In one embodiment, the bivalent compound is 3-(5-((7-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- mcthyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r |pyridin- 1 - yl)piperidin- 1 -yl)-7 -oxoheptyl)amino)-3 -methyl-2-oxo-2, 3 -dihydro- l//-benzo |c/|imidazol- 1 -yl)piperidine-
2,6-dione (P-130).
In one embodiment, the bivalent compound is 4-(2-(l-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r |pyridin- 1 - yl)piperidin- 1 -yl)-2-oxoethyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P- 131). In one embodiment, the bivalent compound is 2-(4-(l -(5 -acetyl- l-(tetrahydro-2H-pyran-4-yl)- 4.5.6.7-tctrahydro- 1 /-pyrazolo|4.3-r |pyridin-3-yl)-7-(difluoromethyl)- 1.2.3.4-tctrahydroquinolin-6-yl)- 1 //-pyrazol- 1 -yl)-/V-(7-((2-(2.6-dioxopipcridin-3-yl)- 1.3-dioxoisoindolin-5-yl)amino)hcptyl)acctamidc (P- 133).
In one embodiment, the bivalent compound is 3-(3-(8-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo|4.3-r|pyridin- 1 - yl)piperidin- 1 -yl)-8-oxooctyl)-2-oxo-2.3-dihydro- 1 //-benzo|c/|imidazol- 1 -yl)piperidine-2,6-dione (P-135).
In one embodiment, the bivalent compound is 4-(((4-(2-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo|4.3-r|pyridin- 1 - yl)piperidin-l-yl)-2-oxoethyl)morpholin-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione (P-142).
In one embodiment, the bivalent compound is 4-(((l-(2-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo|4.3-r|pyridin- 1 - yl)piperidin-l-yl)ethyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P- 143).
In one embodiment, the bivalent compound is 4-(3-(4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 - yl)piperidin- 1 -yl)-4-oxobutyl)azetidin- 1 -yl)-2-(2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P- 146).
In one embodiment, the bivalent compound is 4-(3-(l-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 - yl)piperidin- 1 -yl)-2-oxoethyl)piperidin-4-yl)propyl)-2-(2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P-
147).
In one embodiment, the bivalent compound is 4-(2-(l-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 - yl)piperidin-l-yl)-3-oxopropyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-
148).
In one embodiment, the bivalent compound is 4-(3-(4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 - yl)piperidin- 1 -yl)methyl)piperidin- 1 -yl)propyl)-2-(2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P- 149).
In one embodiment, the bivalent compound is 3 -(5 -((6-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 - yl)piperidin- 1 -yl)-6-oxohexyl)amino)-4-oxobenzo |c/| [ 1 ,2,3]triazin-3 (4//)-yl)piperidine-2.6-dione (P-151).
In one embodiment, the bivalent compound is 3 -(5 -((7-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 - yl)piperidin- 1 -yl)-7 -oxoheptyl)amino)-4-oxobenzo |c/| [ 1.2.3 |triazin-3(4//)-yl)piperidine-2.6-dione (P-153).
In one embodiment, the bivalent compound is 3-(5-((5-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 - yl)piperidin- 1 -yl)-5 -oxopentyl)amino)-4-oxobenzo |c/| [ 1.2.3 |triazin-3(4//)-yl)piperidine-2.6-dione (P-155).
In one embodiment, the bivalent compound is 4-(2-(l-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 - yl)piperidin-l-yl)ethyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-157).
In one embodiment, the bivalent compound is 3-(4-((8-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 - yl)pipcridin- 1 -yl)-8-oxooctyl)amino)-3-mcthyl-2-oxo-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)piperidine- 2,6-dione (P-159). In one embodiment, the bivalent compound is 3 -(4-((9-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- mcthyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 - yl)pipcridin- 1 -yl)-9-oxononyl)amino)-3-mcthyl-2-oxo-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yljpipcridinc-
2,6-dione (P-160).
In one embodiment, the bivalent compound is 3-(5-((8-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 - yljpiperidin- 1 -yl)-8-oxooctyl)amino)-3-methyl-2-oxo-2.3-dihydro- 1 //-benzo|c/|imidazol- 1 -yljpipcridinc-
2,6-dione (P-161).
In one embodiment, the bivalent compound is 3 -(5 -((9-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 - yl)pipcridin- 1 -yl)-9-oxononyl)amino)-3-mcthyl-2-oxo-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yljpipcridinc-
2,6-dione (P-162).
In one embodiment, the bivalent compound is 3-(3-(9-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 - yljpiperidin- l -yl)-9-oxononyl)-2-oxo-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)pipcridinc-2.6-dionc (P-
163).
In one embodiment, the bivalent compound is 3-(3-(10-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 - yljpiperidin- 1 -yl)- 10-oxodccyl)-2-oxo-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)piperidine-2.6-dione (P-
164).
In one embodiment, the bivalent compound is 3-(4-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 - yl)piperidin- 1 -yl)methyl)benzyl)oxy)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dione (P- 166).
In one embodiment, the bivalent compound is 3 -(4-((4-(2-(4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 - yl)piperidin-l-yl)ethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (P-173).
In one embodiment, the bivalent compound is 3 -(4-(4-((4-(5 -acetyl-3 -(7-(difluoromethyl)-6-(l-methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 - yl)piperidin- 1 -yl)methyl)phenethoxy)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dione (P-174).
According to one aspect of the present disclosure, a composition disclosed herein comprises the bivalent compound or a pharmaceutically acceptable salt or analog thereof, and a pharmaceutically acceptable carrier or diluent.
According to one aspect of the present disclosure, a method of treating a CBP/P300-mediated disease disclosed herein comprises administering to a subject with a CBP/P300-mediated disease the bivalent compound or a pharmaceutically acceptable salt or analog thereof.
In one embodiment, the CBP/P300-mediated disease results from CBP/P300 expression, mutation, deletion, or fusion.
In one embodiment, the subject with the CBP/P300-mediated disease has an elevated CBP/P300 function relative to a healthy subject without the CBP/P300-mediated disease.
In one embodiment, the bivalent compound is selected from the group consisting of P-001 to P-174, and CPD-1139 to CPD-1179, or analogs thereof.
In one embodiment, the bivalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.
In one embodiment, the method further comprises administering to the subject an additional therapeutic regimen for treating cancer, inflammatory disorders, or autoimmune diseases. In one embodiment, the additional therapeutic regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.
In one embodiment, the CBP/P300-mediated cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T- cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer,
oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer,
Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.
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.
In one embodiment, the CBP/P300-mediated inflammatory disorders or the autoimmune diseases are selected from the group consisting of 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 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, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.
In one embodiment, the CBP/P300-mediated disease is a relapsed cancer.
In one embodiment, the CBP/P300-mediated disease is refractory to one or more previous treatments.
According to one aspect of the present disclosure, a method for identifying a bivalent compound which mediates degradation or reduction of CBP/P300 is disclosed. The method comprises:
providing a heterobifunctional test compound comprising an CBP/P300 ligand conjugated to a degradation tag through a linker;
contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and CBP/P300;
determining whether CBP/P300 level is decreased in the cell; and
identifying the heterobifunctional test compound as a bivalent compound which mediates degradation or reduction of CBP/P300. In one embodiment, the cell is a cancer cell.
In one embodiment, the cancer cell is a CBP/P300-dependent cancer cell.
INCORPORATION BY REFERENCE
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
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
FIG. 1 shows immunoblots of P300 protein expressed by LNCaP cells after treatment with 5 nM GNE-781 or heterobifunctional compounds P-001 to P-036.
FIG. 2 shows immunoblots of P300 protein expressed by LNCaP cells after treatment with GNE-781, P-003, P-004, P-005, P-015, P-016, or P-020 at indicated concentrations.
FIG. 3 shows an immunoblot of P300 protein expressed by LNCaP cells after treatment with GNE- 781, P-004, P-005, P-015, or P-020 at various timepoints.
FIG. 4 shows a graph of LNCaP cell viability vs. concentrations of GNE-781, P-001, P-002, and P-
019.
FIG. 5 shows an immunoblot of P300 and CBP protein expressed by LNCaP cells after treatment with GNE-781 or heterobifimctional compounds P-056, P-57, P-58, P-59, P-060, P-062, P-063, P-067, P- 068 or P-069.
FIG. 6 shows immunoblots of P300 and CBP protein expressed by LNCaP cells after treatment with P-084 to P-093, P-096, P-097, P-100, P-102, or P-104 to P-108 at indicated concentrations.
FIG. 7A shows an immunoblot of P300 protein expressed by LNCaP cells after treatment with heterobifimctional compounds P-034 or P-034-neg at indicated concentrations.
FIG. 7B shows an immunoblot of P300 protein expressed by 22RV 1 cells after treatment with heterobifimctional compounds P-034 or P-034-neg at indicated concentrations.
FIG. 8 shows an immunoblot of P300 and CBP protein 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.
FIG. 9 shows an immunoblot of P300 and CBP protein expressed in subcutaneous 22RV1 xenograft tumors after treatment with a single dose of 40 mg/kg P-100, P-007, or P-034 via intraperitoneal injection (i.p.) or oral gavage (p.o.).
FIG. 10 shows immunoblots of P300 and CBP protein expressed by LNCaP cells (Fig. 10A-B) or 22RV 1 cells (Fig.10C-E) after treatment with heterobifimctional compounds P-095 or P- 109 to P- 131 at indicated concentrations.
FIG. 11 shows immunoblots of P300 and CBP protein expressed by LNCaP cells (Fig.l 1B-E) or 22RV1 cells (Fig.11 A) after treatment with heterobifimctional compounds P-142 to P-174 at indicated concentrations.
FIG. 12 shows immunoblots of CBP protein expressed in the lung tissues of ICR mice after treatment with a single dose of 40 mg/kg indicated heterobifimctional compounds via oral gavage (p.o.). DETAILED DESCRIPTION OF THE INVENTION
Posttranslational modifications of proteins, such as phosphorylation, acetylation, methylation, and ubiquitination, greatly contribute to the diversity and regulation of proteins. P300 (encoded by EP300) and the closely related CBP (encode by CREBBP) are two extensively studied lysine acetyltransferases (HATs) that catalyze transfer of acetyl groups to lysine residues of proteins. The best defined substrates of P300 and CBP are histones. Acetylation of histones modulates the conformation of chromatin and generally leads to transcription activation. Recruiting P300 and/or CBP is essential for many transcription factors and other transcription regulators to effectively promote regional transcription (Dancy and Cole, 2015). Substrates of P300 and CBP also include many non-histone proteins that have crucial physiological and pathological functions, such as p53, MYC, FOXOl, and NF-KB (Dancy and Cole, 2015). Because P300 and CBP functionally interact with a wide variety of signaling proteins, these two lysine
acetyltransferases act as the converge point of many signal transduction pathways (Bedford et al., 2010). Through modulating acetylation of diverse substrates and connecting a multitude of binding partners,
P300 and CBP are widely implicated in biological processes, such as cellular proliferation, differentiation, development, DNA repair, inflammation, metabolism, and memory.
Both P300 and CBP are indispensable for development, as mice deficient in either P300 or CBP die early during embryogenesis (Goodman and Smolik, 2000). Aberrant P300 or CBP are associated with a wide range of human diseases. Germline mutations that inactivate one of CREBBP alleles result in the Rubinstein-Taybi syndrome (Petrij et al., 1995), probably due to impaired activation of the Hedgehog family transcription factors. Both P300 and CBP are known to contribute to hematopoiesis, through interaction with hematopoietic transcription factors, such as GATA-1 (Blobel, 2000). Tumor suppressive roles of P300 and CBP have been well defined. Patients with Rubinstein-Taybi syndrome have higher cancer prevalence. Inactivating mutations of P300 and CBP are frequently found in human cancers (Giles et al., 1998). However, these two HATs also promote oncogenesis via different mechanisms. In a subset of acute myeloid leukemia, recurrent chromosomal translocations t(8;16)(pl 1 ;p 13) produce in-frame fusions of the MOZ gene and the CREBBP gene that direct expression of oncogenic MOZ-CBP fusion proteins (Rozman et al., 2004). CBP, and less frequently P300, are also found to fuse with MLL in chemoresistant leukemia (Sobulo et al., 1997). Accumulating evidence show that P300 and CBP are recruited as co-activators by the majority of oncogenic transcription factors, such as MYC (Faiola et al., 2005; Vervoorts et al., 2003), NF-KB (Vanden Berghe et al., 1999), b-catenin (Sun et al., 2000), E2F1 (Ianari et al., 2004; Martinez-Balbas et al., 2000), and nuclear receptors (Chakravarti et al., 1996). Hence, depleting P300 and/or CBP may compromise tumor growth through impairing the functions of these oncogenic transcription factors. Additionally, P300 has been reported to regulate immune cell functions (Liu et al., 2013). Further, P300 and CBP are important transcription co-activators for the STAT and NF- KB family transcription factors (Nadiminty et al., 2006; Wang et al., 2005; Wang et al., 2017), which have crucial functions in immune cells. Therefore, P300/CBP antagonizers may be employed to modulate activities of the immune system and the crosstalk between immune cells and cancer cells (Liu et al., 2013). Finally, it has been extensively documented that histone acetylation is crucially implicated in
neurodegenerative diseases (Saha and Pahan, 2006; Valor et al., 2013). Taken together, developing novel therapeutic agents targeting P300 and CBP represents novel opportunities for the treatment of cancer, inflammatory diseases, neurological indications, and other indications.
P300 and CBP share nearly 75% similarity and 63% identity in protein sequences. Greater homology is found in functional domains that are highly conserved during evolution. Most of these domains mediate protein-protein interactions, such as the Cysteine-Histidine-rich region 1 (CHI), the CREB-interacting KIX domain, the Cysteine-Histidine-rich region (CH3), and the nuclear receptor co-activator binding domain (Wang et al., 2013a). However, these domains are less amenable to small molecule-mediated intervention. Only few inhibitors have been reported. For example, naphthol-AS-E (Uttarkar et al., 2015), compound 1-10 (Wang et al., 2013b), and MYBMIM (Ramaswamy et al., 2018) are 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 analogs (Ferguson et al., 2017) were discovered as disruptors of TAZl/HIF-la protein protein interactions. ICG-001 (Emami et al., 2004) was reported as selective inhibitor of CBP NRID/b -eaten in interactions. In addition, YH249 and YH250 (Yusuke et al., 2016) were reported to selectivily inhibit P300-dependent transcription. Recent efforts to develop small molecule probes for P300 and CBP are concentrated on the HAT domain and the bromodomain. The HAT domain is responsible to catalyze transfer of acetyl groups, while the bromodomain binds to acetylated lysine residues, which promotes interaction of P300 and CBP to acetylated chromatin. A variety of 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), CPD 19 (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), CPD 30 (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 ID: NCT03568656), have been described to target the bromodomain of P300 and CBP HAT domain targeting P300/CBP inhibitors, C646 (Oike et al., 2014) and A-485 (Lasko et al., 2017), were reported. Transcription dependent on P300 or CBP is partially compromised by these compounds (Wei et al., 2018). These HAT or bromodomain inhibitors have exhibited anti-cancer activities in a wide range of human cancers, including but are not limited to prostate cancer (Jin et al., 2017; Lasko et al., 2017), breast cancer (Y ang et al., 2013), lung cancer (Ogiwara et al., 2016; Oike et al., 2014), acute myeloid leukemia (Giotopoulos et al., 2016), and melanoma (Wang et al.,
2018). However, there are significant caveats using these small molecule inhibitors to modulate the activities of P300 and CBP. First, P300 and CBP have multiple functional domains. Blockade of either the HAT domains or the bromodomains only lead to partial inhibition of their activities. The scaffolding functions P300 and CBP are not effectively modulated by these small molecule inhibitors. Second, the HAT domains and the bromodomains of P300 and CBP share significant homology so that most small molecule compounds do not effectively differentiate these two targets. Conversely, P300 and CBP have distinct tissue type-dependent roles. For example, in prostate cancer, P300 is the dominating co-activator of androgen receptor, while CBP has limited roles (Ianculescu et al., 2012). Thus, simultaneously targeting both P300 and CBP is not always necessary and may result in more significant adverse effects than selectively targeting one of them. Not to mention many P300/CBP inhibitors have off-target effects that have been poorly defined. To improve the selectivity and activity of anti-P300/CBP therapy, approaches that selectively degrade the target protein(s) are expected to have substantial advantages.
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 heterobifimctional small molecules which degrade CBP/P300, CBP/P300 fusion proteins, and/or CBP/P300 mutant proteins (“PROteolysis TArgeting Chimeras”/“PROTACs” and “Specific and Nongenetic IAP-dependent Protein Erasers”/“SNIPERs”) are useful in the treatment of CBP/P300-mediated diseases, particularly prostate cancer (Jin et al., 2017; Lasko et al., 2017), breast cancer (Y ang 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).
Selective degradation of a target protein induced by a small molecule may be achieved by recruiting an E3 ubiquitin ligase and mimicking protein misfolding with a hydrophobic tag (Buckley and Crews, 2014). Additionally, PROTACs are bivalent inhibitors having one moiety that binds to an E3 ubiquitin ligase and another moiety that binds the protein target of interest (Buckley and Crews, 2014). The induced proximity leads to ubiquitination of the target followed by its degradation via proteasome-mediated proteolysis. 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 cereblon (CRBN or CRL4CRBN), a component of a 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); (2) VHL-1, a hydroxyproline-containing ligand, which binds van Hippel-Lindau protein (VHL or CRL2VHL), a component of another 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 KEAP1, a component of a CRL3 complex(Davies et al., 2016); (4) AMG232, which selectively binds MDM2, a heterodimeric RING E3 ligase(Sun et al., 2014); and (5) LCL161, which selectively binds IAP, a homodimeric RING E3 ligase (Ohoka et al., 2017; Okuhira et al., 2011; Shibata et al., 2017). The PROTAC technology has been applied to degradation of several protein targets (Bondeson et al., 2015; Buckley et al., 2015; Lai et al., 2016; Lu et al., 2015; Winter et al., 2015; Zengerle et al., 2015). In addition, a hydrophobic tagging approach, which utilizes a bulky and hydrophobic adamantyl group, has been developed to mimic protein misfolding, leading to the degradation of the target protein by proteasome (Buckley and Crews, 2014). This approach has been applied to selective degradation of the pseudokinase HER3 (Xie et al., 2014). The inventors have not yet seen any efforts applying any of these approaches to degradation of CBP/P300, CBP/P300 mutant, CBP/P300 deletion, or CBP/P300 fusion proteins.
Currently available small molecules targeting CBP/P300 focus on inhibition of the protein interactions or acetryltransferase activities of CBP/P300. A number of selective small-molecule
CBP/P300 inhibitors, such as GNE-781, GNE-272, GNE-207, CPD 4d, CPD (S)-8, CPD (R)-2, CPD6, CPD19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD 11, CPD 41, CPD 30, CPD 5, CPD 27, CPD 29, CCS 1477 (clinical trial ID: NCT03568656), C646 (Oike et al., 2014), A-485, naphthol-AS-E (Uttarkar et al., 2015), compound 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 (Y usuke et al., 2016) have been reported.
In the present disclosure, a novel approach is taken: to develop compounds that directly and selectively modulate not only the protein-protein interactions and acetyltransferase activity of CBP/P300, but also their protein levels. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, mimicking protein misfolding with hydrophobic tags, and inhibiting chaperones. Such an approach, based on the use of bivalent small molecule compounds, permits more flexible regulation of protein levels in vitro and in vivo compared with techniques such as gene knockout or short hairpin RNA- mediated (shRNA) knockdown. Unlike gene knockout or shRNA knockdown, a small molecule approach further provides an opportunity to study dose and time dependency in a disease model through modulating the administration routes, concentrations and frequencies of administration of the corresponding small molecule.
Bivalent Compounds
In some aspects, the present disclosure provides bivalent compounds including a CBP/P300 ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof. The CBP/P300 ligand may be conjugated to the degradation tag directly or via a linker moiety. In certain embodiments, the CBP/P300 ligand may be conjugated to the degradation tag directly. In certain embodiments, the CBP/P300 ligand may be conjugated to the degradation tag via a linker moiety.
As used herein, the terms“cyclic-AMP response element binding protein and/or adenoviral E1A binding protein of 300 kDa” and“CBP/P300 ligand”, or“CBP/P300 targeting moiety” are to be construed to encompass any molecules ranging from small molecules to large proteins that associate with or bind to CBP and/or P300 proteins. In certain embodiments, the CBP/P300 ligand is capable of binding to a CBP/P300 protein comprising CBP/P300, a CBP/P300 mutant, a CBP/P300 deletion, or a CBP/P300 fusion protein. The CBP/P300 ligand can be, for example but not limited to, a small molecule compound (i.e., a molecule of molecular weight less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, nucleic acid or oligonucleotide, carbohydrate such as oligosaccharides, or an antibody or fragment thereof.
CBP/P300 Ligand
The CBP/P300 ligand or targeting moiety can be a CBP/P300 inhibitor or a portion of CBP/P300 inhibitor. In certain embodiments, the CBP/P300 inhibitor comprises one or more of (e.g., GNE-781, GNE-272, GNE-207, CPD 4d, CPD (S)-8, CPD (R)-2, CPD6, CPD19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD 11, CPD 41, CPD 30, CPD 5, CPD 27, CPD 29, CCS1477 (clinical trial ID: NCT03568656), C646 (Oike et al., 2014), A-485, naphthol-AS-E (Uttarkar et ah, 2015), compound 1-10 (Wang et ak, 2013b), MYBMIM (Ramaswamy et ak, 2018), KCN1 (Shi et ah, 2012; Yin et ah, 2012), OHM1 (Lao et ah, 2014), HBS1 (Kushal et ah, 2013), and KCN1 analogs (Ferguson et ah, 2017), ICG- 001 (Emami et ah, 2004), YH249 (Y usuke et ah, 2016) and YH250 (Y usuke et ah, 2016), and analogs thereof), which is capable of inhibiting the protein-protein interaction or acetyltransferase activity of CBP/P300. As used herein, a“CBP/P300 inhibitor” refers to an agent that restrains, retards, or otherwise causes inhibition of a physiological, chemical or enzymatic action or function and causes a decrease in binding of at least 5%. An inhibitor can also or alternately refer to a drug, compound, or agent that prevents or reduces the expression, transcription, or translation of a gene or protein. An inhibitor can reduce or prevent the function of a protein, e.g., by binding to or activating/inactivating another protein or receptor.
In certain embodiments, the CBP/P300 ligand is derived from a CBP/P300 inhibitor comprising:
Figure imgf000041_0001
In certain embodiments, the CBP/P300 ligand include, but are not limited to GNE-781, GNE-272, GNE-207, CPD 4d, CPD (S)-8, CPD (R)-2, CPD6, CPD19, XDM-CBP, I-CBP112, TPOP146, CPI-637, SGC-CBP30, CPD 11, CPD 41, CPD 30, CPD 5, CPD 27, CPD 29, CCS1477 (clinical trial ID:
NCT03568656), C646 (Oike et al., 2014), A-485, naphthol-AS-E (Uttarkar et al., 2015), compound 1-10 (Wang et ah, 2013b), MYBMIM (Ramaswamy et ah, 2018), KCN1 (Shi et ah, 2012; Yin et ah, 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).
In another embodiment, the CBP/P300 ligand comprises a moiety of FORMULA 1:
Figure imgf000042_0001
FORMULA 1,
wherein
the linker moiety of the bivalent compound is attached to R2;
X1 and X3 are independently selected from C and N, with the proviso that at least one of X1 and X3 is C and at most only one of X1 and X3 is N;
X2 is selected from CR’, O, and NR’, wherein
R’ is selected from H, optionally substituted CrC8 alkyl, and optionally substituted 3-10 membered carbocyclyl;
A is selected from null, CR4R5, CO, O, S, SO, SO2, and NR4, wherein
R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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;
Ar and R4, Ar and R5, and/or R4 and R5 together with the atom to which they are connected form an optionally substituted 3-20 membered cycloalkyl or heterocyclyl ring;
Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, N02, OR6, SR6, NR6R7, OCOR6,
OCO2R6, OCONR6R7, COR6, CO2R6, CONR6R7, SOR6, SO2R6, SO2NR6R7, NR8CO2R6, NR8COR6,
NR8C(0)NR6R7,NR8S0R6, NR8S02R6, NR8S02NR6R7, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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
R6, R7, and R8 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R6 and R7, R6 and R8 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;
R1 is selected from hydrogen, halogen, CN, N02, OR9, SR9, NR9R10, OCOR9, 0C02R9, OCONR9R10, COR9, C02R9, C0NR9R10, SOR9, S02R9, S02NR9R10, NRUC02R9, NRUCOR9, NRUC(0)NR9R10, NRuSOR9, NRUS02R9, NRUS02NR9R10, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted Cr
C8alkylaminoCi-C8alkyl, 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
R9, R10, and R11 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci- C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R9 and R10, R9 and R11 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
R2 is connected to the“linker” moiety of the bivalent compound, and is selected from null, R O, R S, R NR12, R OC(O), R 0C(0)0, R OCONR12, R C(O), R C(0)0, R CONR12, R S(O), R S(0)2, R S02NR12, R NR13C(0)0, R NR13C(0), R NR13C(0)NR12, R NR13S(0), R NR13S(0)2, R NR13S(0)2NR12, optionally substituted Ci-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-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R is is null, or a bivalent moiety selected from optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Cr
C8alkoxyCi-C8alkylene, optionally substituted C C8 haloalkylene, optionally substituted C C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R12 and R13 are independently selected from optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCr C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R12 and R13 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and R3 is selected from hydrogen, COR14, C02R14, CONR14R15, SOR14, S02R14, S02NR14R15, optionally substituted C 1 -C( 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
R14 and R15 are independently selected from hydrogen, optionally substituted C 1 -C(, 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
R14 and R15 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring.
In another embodiment, X1 is C; and X2 and X3 are N. The FORMULA I is FORMULA 1A:
Figure imgf000044_0001
FORMULA 1A,
wherein
A, Ar, R1, R2 and R3 are the same as in FORMULA 1.
In another embodiment, A-Ar-R1 is a moiety of formulae Al :
Figure imgf000044_0002
wherein
A and R1 are the same as in FORMULA 1.
X is selected from CR”’ and N, wherein
R and is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 1 -C( alkoxy, optionally substituted C 1 -C( alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
Ra is optionally formed a ring with A, and is selected from null, hydrogen, halogen, RbNR . RbOR16, RbSR16, RbNR16R17, RbOCOR16, Rb0C02R16, RbOCONR16R17, RbCOR16, RbC02R16, RbCONR16R17, RbSOR16, RbS02R16, RbS02NR16R17, RbNR18C02R16, RbNR18COR16, RbNR18C(0)NR16R17, RbNR18SOR16, RbNR18S02R16, RbNR18S02NR16R17, optionally substituted C|-Cx alkyl, optionally substituted C 1 -Cx alkylene, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkenylene, optionally substituted C -C8 alkynyl, optionally substituted C -C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
Rb is is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-CxalkoxyCi-Cxalkylene, optionally substituted C 1 - C x al k y 1 am i n o C 1 - C xal k y 1 e n e . optionally substituted Ci-Cg haloalkylene, optionally substituted C C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R16, R17, and R18 are independently selected from null, hydrogen, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr CgalkoxyCi-Cgalkyl, optionally substituted C i - C 8 al k y 1 am i n o C i - C 8al k y 1. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R16 and R17, R16 and R18 together with the atom to which they are connected form a 3-20 membered cycloalkyl or heterocyclyl ring.
In another embodiment, A is null.
In another embodiment, A is null; Ar is a bicyclic aryl or a bicyclic heteroaryl; and A-Ar-R1 is a moiety of FORMULAE A2 or A3:
Figure imgf000045_0001
wherein
R1 is the same as in FORMULA 1.
In another embodiment, A is NR4, wherein
R4 is selected from hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodiment, -Ar-R1 is a moiety
Figure imgf000045_0004
Figure imgf000045_0002
FO
Figure imgf000045_0003
FORMULA A5 FORMULA A6,
wherein
R1 is the same as in FORMULA 1.
In another embodiment, R1 is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.
In another embodiment, R1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
In another embodiment, R1 is is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
In another embodiment, R2 is selected from optionally substituted Ci-C8 alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocycly, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodiment, R3 is selected from COR14 and CONR14R15.
In another embodiment, R3 is selected from COMe and CONHMe.
In another embodiment, the CBP/P300 ligand comprises a moiety of FORMULA 2:
Figure imgf000046_0001
FORMULA 2,
wherein
the linker moiety of the bivalent compound is attached to R1; and
X1 and X3 are independently selected from C and N, with the proviso that at least one of X1 and X3 is C and at most only one of X1 and X3 is N;
X2 is selected from CR’, O, and NR’, wherein
R’ is selected from H, optionally substituted C rC8 alkyl, and optionally substituted 3-10 membered carbocyclyl;
A is selected from null, CR4R5, CO, O, S, SO, S0 , and NR4, wherein
R4 and R5 are independently selected from hydrogen, halogen, hydroxyl amino, cyano, nitro, optionally substituted C rC8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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;
Ar and R4, Ar and R5, and/or R4 and R5 together with the atom to which they are connected form an optionally substituted 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, N02. OR6, SR6, NR6R7, OCOR6,
OCO2R6, OCONR6R7, COR6, CO2R6, CONR6R7, SOR6, SO2R6, SO2NR6R7, NR8CO2R6, NR8COR6,
NR8C(0)NR6R7, NR8S0R6, NR8S02R6, NR8S02NR6R7, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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
R6, R7, and R8 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R6 and R7, R6 and R8 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring; and
R1 is connected to the“linker” moiety of the bivalent compound, and R1 is selected from null, R O,
R S, R NR9, R OC(O), R 0C(0)0, R OCONR9, R C(O), R C(0)0, R CONR9, R S(O), R S(0)2,
R S02NR9, R NR10C(O)O, R NR10C(O), R NR10C(0)NR9, R NR10S(0), R NR10S(O)2, R NR10S(O)2NR9, optionally substituted C C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2- C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocycly, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R is is null, or a bivalent moiety selected from optionally substituted C C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Cr
C8alkoxyCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted Ci-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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R9 and R10 are independently selected from optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCr C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R9 and R10 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
R2 is selected from hydrogen, halogen, CN, N02, OR11, SR11, NRUR12, OCOR11, OC02Ru, OCONRuR12, COR11, C02Ru, CONRUR12, SOR11, S02Ru, S02NRUR12, NR13C02Ru, NR13CORu, NR13C(0)NRUR12,NR13S0Ru, NR13S02Ru, NR13S02NRUR12, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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
R11, R12, and R13 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R and R , R and R together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
R3 is selected from hydrogen, COR14, C02R14, CONR14R15, SOR14, S02R14, S02NR14R15, optionally substituted C -C( alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, wherein
R14 and R15 are independently selected from hydrogen, optionally substituted C -C(, alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, and optionally substituted 4-6 membered heterocyclyl, or
R14 and R15 together with the atom to which they are connected form a 4-6 membered heterocyclyl ring.
In another embodiment, X1 is C; and X2 and X3 are N. The FORMULA 2 is FORMULA 2A:
Figure imgf000048_0001
FORMULA 2A,
wherein
A, Ar, R1, R2 and R3 are the same as in FORMULA 2.
In another embodiment, A-Ar-R1 is a moiety of formulae B 1 :
Figure imgf000048_0002
FORMULAE Bl,
wherein
* indicates the connection to the linker moiety of the bivalent compound;
A and R1 are the same as in FORMULA 2;
X is selected from CR”’ and N, wherein
R and is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C 1 -C( alkoxy, optionally substituted C 1 -C( alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl; and
Ra optionally forms a ring with A, and is selected from null, hydrogen, halogen, RbNR16, RbOR16, RbSR16, RbNR16R17, RbOCOR16, Rb0C02R16, RbOCONR16R17, RbCOR16, RbC02R16, RbCONR16R17, RbSOR16, RbS02R16, RbS02NR16R17, RbNR18C02R16, RbNR18COR16, RbNR18C(0)NR16R17, RbNR18SOR16, RbNR18S02R16, RbNR18S0 NR16R17, optionally substituted Ci-C8 alkyl, optionally substituted Ci-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
Rb is is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted C rC8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R16, R17, and R18 are independently selected from null, a bond, hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R16 and R17, R16 and R18 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring.
In another embodiment, A is null. In another embodiment, A is null; Ar is a bicyclic aryl or a bicyclic heteroaryl; and A-Ar-R1 is a moiety of FORMULAE B2 or B3:
Figure imgf000049_0001
FORMULA B2 FORMULA B3,
wherein
* indicates the connection to the linker moiety of the bivalent compound; and
R1 is the same as in FORMULA 2.
In another embodiment, A is NR4, wherein
R4 is selected from hydrogen, optionally substituted C i -Cx alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1 -CxalkoxyC 1 -Cxalkyl. optionally substituted C i -CxalkylaminoC 1 -Cxalkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodiment, -Ar-R1 is a moiety
Figure imgf000049_0002
Figure imgf000049_0004
Figure imgf000049_0003
FORMULA B4 FORMULA B5 FORMULA B6,
wherein
* indicates the connection to the linker moiety of the bivalent compound; and
R1 is the same as in FORMULA 2.
In another embodiment, R1 is selected from optionally substituted 3-10 membered carbocyclylene, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodiment, R1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
In another embodiment, R1 is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
In another embodiment, R2 is selected from optionally substituted C 1 -Cx alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
In another embodiment, R3 is selected from COR14 and CONR14R15.
In another embodiment, R3 is selected from COMe and CONHMe.
In another embodiment, the CBP/P300 ligand is derived from any of the following:
Figure imgf000050_0001
In another embodiment, the CBP/P300 ligand is derived from the following CBP/P300 inhibitors: C646, naphthol-AS-E, compound 1-10, MYBMIM, CCS 1477, ICG-001, YH249, YH250, HBS1, OHM1, and KCN1.
In another embodiment, the CBP/P300 ligand is selected from the group consisting of:
Figure imgf000050_0002
Degradation Tag
As used herein, the term“degradation tag” refers to a compound, which associates with or binds to an ubiquitin ligase for recruitment of the corresponding ubiquitination machinery to CBP/P300 or is a hydrophobic group or a tag that leads to misfolding of the CBP/P300 protein and subsequent degradation at the proteasome or loss of function.
In some embodiments, the degradation tag is a moiety selected from the group consisting of
Figure imgf000051_0001
, wherein
V, W, and X are independently selected from CR2 and N;
Y is selected from CO, CR3R4, N=CR3, and N=N;
Z is selected from null, CO, CR5R6, NR5, O, optionally substituted Ci-Cio alkylene, optionally substituted Ci-Cio alkenylene, optionally substituted Ci-Cio alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH , CH=CH, CºC, NH and O;
R1, and R2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R3 and R4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
R5 and R6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R5 and R6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl.
In some embodiments, the degradation tag is a moiety selected from the group consisting of FORMULAE 5A, 5B, 5C, and 5D:
Figure imgf000051_0002
, wherein
V, W, and X are independently selected from CR2 and N;
Y is selected from CO, CH2, and N=N;
Z is selected from CH2, NH and O; and
R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, and C 1-C5 alkyl.
In some embodiments, the degradation tag is a moiety selected from the group consisting of
FORMULAE 5E, 5F, 5G, 5H, 51, 5J, 5K, 5L, 5M, 5N, 50, 5P, and 5Q:
Figure imgf000052_0001
wherein
U, V, W, X and X’ are independently selected from CR2 and N;
Y is selected from CR3R4, NR3 and O; preferably, Y is selected from CH , NH, NC1¾ and O;
Y’, Y”, and Y”’ are independently selected from CR3R4;
Z is selected from null, CO, CR5R6, NR5, O, optionally substituted Ci-Cio alkylene, optionally substituted Ci-Cio alkenylene, optionally substituted Ci-Cio alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH2, CH=CH, CºC, NH and O;
R1, and R2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted
Ci-Ce alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R3 and R4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
R5 and R6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R5 and R6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
R’ is selected from hydrogen, optionally substituted C i -C( alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl.
In one embodiment, the degradation tag is a moiety of FORMULA 6A:
Figure imgf000053_0001
wherein
R1 and R2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C rCx alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl;
optionally substituted C 1 -CxalkoxyC 1 -Cxalkyl. optionally substituted C 1 -Cx haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 aminoalkyl, optionally substituted Ci- CsalkylaminoCi-Csalkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4- 10 membered heterocyclyl; and
R3 is selected from hydrogen, optionally substituted C(0)Ci-C8 alkyl, optionally substituted C(0)Ci- CsalkoxyCi-Csalkyl, optionally substituted C(0)Ci-C8 haloalkyl, optionally substituted C(0)Ci-C8 hydroxyalkyl, optionally substituted C(0)Ci-C8 aminoalkyl, optionally substituted C(0)Cr
CsalkylaminoCi-Csalkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C2-C8 alkenyl, optionally substituted C(0)C -C8 alkynyl, optionally substituted C(0)OCi-C8alkoxyCi-C8alkyl, optionally substituted
C(0)OCi-C8 haloalkyl, optionally substituted C(0)OCi-C8 hydroxyalkyl, optionally substituted C(0)OCr Cs aminoalkyl, optionally substituted C(0)OCi-C8alkylaminoCi-C8alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C2-C8 alkenyl, optionally substituted C(0)0C2-C8 alkynyl, optionally substituted C(0)NCi-C8alkoxyCi-C8alkyl, optionally substituted C(0)NCI-C8 haloalkyl, optionally substituted C(0)NCI-C8 hydroxyalkyl, optionally substituted C(0)NCi-C8 aminoalkyl, optionally substituted C(0)NCi-C8alkylaminoCi-C8alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(0)NC2-C8 alkenyl, optionally substituted C(0)NC -C8 alkynyl, optionally substituted P(0)(OH)2, optionally substituted P(0)(OCi-C8 alkyl) , and optionally substituted P(0)(OCi-C8 aryl) .
In some embodiments, the degradation tag is a moiety of FORMULAE 6B, 6C, and 6D:
Figure imgf000053_0002
FORMULA 6B, FORMULA 6C, FORMULA 6D wherein
R1 and R2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl;
optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 aminoalkyl, optionally substituted Cr C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4- 10 membered heterocyclyl;
R3 is selected from hydrogen, optionally substituted C(0)Ci-C8 alkyl, optionally substituted C(0)Cr C8alkoxyCi-C8alkyl, optionally substituted C(0)Ci-C8 haloalkyl, optionally substituted C(0)Ci-C8 hydroxyalkyl, optionally substituted C(0)Ci-C8 aminoalkyl, optionally substituted C(0)Cr
C8alkylaminoCi-C8alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C2-C8 alkenyl, optionally substituted C(0)C2-C8 alkynyl, optionally substituted C(0)OCi-C8alkoxyCi-C8alkyl, optionally substituted
C(0)0Ci-C8 haloalkyl, optionally substituted C(0)0Ci-C8 hydroxyalkyl, optionally substituted C(0)0Cr C8 aminoalkyl, optionally substituted C(0)OCi-C8alkylaminoCi-C8alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C2-C8 alkenyl, optionally substituted C(0)0C2-C8 alkynyl, optionally substituted C(0)NCi-C8alkoxyCi-C8alkyl, optionally substituted C(0)NCi-C8 haloalkyl, optionally substituted C(0)NCI-C8 hydroxyalkyl, optionally substituted C(0)NCi-C8 aminoalkyl, optionally substituted C(0)NCi-C8alkylaminoCi-C8alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(0)NC2-C8 alkenyl, optionally substituted C(0)NC2-C8 alkynyl, optionally substituted P(0)(0H)2, optionally substituted P(0)(0Ci-C8 alkyl)2, and optionally substituted P(0)(0Ci-C8 aryl)2, and
O
R4 is selected from NR7R8,
Figure imgf000054_0001
, optionally substituted Ci-C8alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteraryl, in which
R7 is selected from hydrogen, optionally substituted Ci-C8alkyl, optionally substituted Ci- C8cycloalkyl, optionally substituted Ci-C8alkyl-CO, optionally substituted Ci-C8cycloalkyl-CO, optionally substituted Ci-C8cycloalkyl-Ci-C8alkyl-CO, optionally substituted 4-10 membered
heterocyclyl-CO, optionally substituted 4-10 membered heterocyclyl-Ci-C8alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-Ci-C8alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-Ci-C8alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;
R8 is selected from hydrogen, optionally substituted Ci-C8alkyl, and optionally substituted Cr C8cycloalkyl;
R9, at each occurance, is independently selected from hydrogen, halogen, cyano, optionally substituted Ci-C8alkyl, optionally substituted Ci-C8cycloalkyl, optionally substituted Ci- C8heterocycloalkyl, optionally substituted Ci-C8alkoxy, optionally substituted Ci-C8cycloalkoxy, halo substituted Ci-C8alkyl, halo substituted Ci-C8cycloalkyl, halo substituted Ci-C8alkoxl, halo substituted Ci- C8cycloalkoxy, and halo substituted Ci-C8heterocycloalkyl;
X is selected from CH and N; and
n is 0, 1, 2, 3, or 4; R6 is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci- Cxalkyl, optionally substituted Ci-Cxcycloalkyl, optionally substituted Ci-Cxalkoxy, and optionally substituted Ci-Cxcycloalkoxy, optionally substituted Ci-Cxheterocycloalkyl, 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 group.
In another embodiment, the degradation tag is a moiety of FORMULA 7A:
Figure imgf000055_0001
wherein
V, W, X, and Z are independently selected from CR4 and N; and
R1, R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C rCx alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; optionally substituted Ci-Csalkoxy, optionally substituted Ci-Csalkylamino, optionally substituted Cr CsalkoxyCi-Csalkyl, optionally substituted C 1 -Cxalkvlam inoC 1 -Cxalkyl. optionally substituted C 1 -Cx haloalkyl, optionally substituted C 1 -Cx hydroxyalkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.
In another embodiment, the degradation tag is a moiety of FORMULA 7B:
Figure imgf000055_0002
wherein
R1, R2, and R3 are independently selected from hydrogen, halogene, optionally substituted C 1 -Cx alkyl, optionally substituted C 1 -CxalkoxyC 1 -Cxalkyl. optionally substituted C 1 -Cx haloalkyl, optionally substituted C 1 -Cx hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl;
R4 and R5 are independently selected from hydrogen, COR6, CO2R6, CONR6R7, SOR6, SO2R6, S02NR6R7, optionally substituted C 1 -Cx alkyl, optionally substituted C 1 -CxalkoxyC 1 -Cxalkyl. optionally substituted C 1 -CxalkylaminoC 1 -Cxalkyl. optionally substituted aryl-Ci-Cxalkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R6 and R7 are independently selected from hydrogen, optionally substituted C' 1 -C'x alkyl, optionally substituted C 1 -CxalkoxyC 1 -Cxalkyl. optionally substituted C 1 -CxalkylaminoC 1 -Cxalkyl. optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R6 and R7 together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring. In another embodiment, the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, and 51.
In another embodiment, the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, and 5F. In another embodiment, the degradation tag is derived from any of the following:
Figure imgf000056_0001
In another embodiment, the degradation tag is derived from any 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.
In another embodiment, the degradation tag is selected from the group consisting of:
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
In another embodiment, the degradation tag is selected from the group consisting of: FORMULA 8 A 8B, 8C, 8D, 8E, 8F, 8G, 8H, 81, 8J, 8K, 8L, 8M, 80, 8P, 8Q, 8R, 8AQ, 8AR, 8AS, 8AT, 8AU, 8AV, 8AW, 8 AX, 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, 8 CL, 8 CM, 8CN, 8CO, 8CP, 8CQ, 8CR, 8CS, 8CT, 8CU, 8CV, 8CW, 8CX, 8CY, 8CZ, 8DA, 8DB, 8DC, 8DD, 8DE, 8DF, 8DG, 8DH, 8DI, 8DJ, 8DK, 8DL, 8DM, 8DN, 8DO, 8DP, 8DQ, 8DR, 8DS, 8DT, 8DU, 8DV, 8DW; 8DX, 8DY, 8DZ, 8EA, 8EB, 8EC, 8ED, 8EE, 8EF, 8EG, 8EH, 8EI, 8EJ, 8EK, 8EL, 8EM, 8EN, 8EO, 8EP, 8EO, 8GU, 8GV, 8GW, 8GX, 8GY, 8GZ, 8HA, 8HB, 8HC, 8HD, 8HE, 8HF, 8HG, 8HH, 8HI, 8HJ 8HK, 8HL, 8HM, 8HN, 8HO, 8HP, 8HQ, 8HR, 8HS, 8HT, 8HU, 8HV, 8HW, 8HX, 8HY, 8HZ, 8IA, 8IB 8IC, 8 ID, 8 IE, 8IF, 8IG, 8IH, 811, 8IJ, 8IK, 8IL, 8IM, 8IN, 810, 8IP, 8IQ, 8IR, 8IS, 8IT, 8IU, 8IV, 8IW,
8 IX, 8IY, 8IZ, 8JA, 8JB, 8JC, 8JD, 8JE, 8JF, 8JG, 8JH, 8JI, 8JJ, 8JK, 8JL, 8JM, 8JN, 8JO, 8JP, 8JQ, 8JR 8JS, and 8JT.
Linker Moiety
As used herein, a“linker” or“linker moiety” is a bond, molecule, or group of molecules that binds two separate entities to one another. Linkers provide for optimal spacing of the two entities. The term “linker” in some aspects 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 the degradation tag, which are not necessary for the function of the PROTACs or SNIPERs of the present disclosure, are ideal sites for attaching a linker, provided that the linker, once attached to the conjugate of the present disclosures, 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 a ubiquitin ligase.
The length of the linker of the bivalent compound can be adjusted to minimize the molecular weight of the bivalent compounds, avoid the clash of the CBP/P300 ligand or targeting moiety with the ubiquitin ligase and/or induce CBP/P300 misfolding by the hydrophobic tag. In certain embodiments, the linker comprises acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic or carbonyl groups. In certain 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.
In some embodiments, the linker moiety
Figure imgf000062_0001
wherein
A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR , R C02R , RCjOjNjR'jR”, R CfSjNjR'jR”, R OR , R SR , R SOR , R S02R ,
R SO N^jR , R N(R')R . R N(R')C0R . RN(R1)CON(R2)R , R N(R' )C(S)R . optionally substituted Cj-C’s alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C i -C8alkoxyC i -C8alkylcnc. optionally substituted Cj-C8 haloalkylene, optionally substituted Cj-C8 hydroxyalkylene, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, 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 null, optionally substituted (Cj-C8 alkylene)-Rr (preferably, CtU-R1). optionally substituted Rr-(Ci-C8 alkylene), optionally substituted (C C8 alkylene)- Rr-(Ci-C8 alkylene), or a moiety comprising of optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted C C8 haloalkyl, optionally substituted C C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted CrC8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R1 and R2 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C C8 alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R1 and R2, R and R1, R and R2, R and R1, R and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
m is 0 to 15.
In another embodiment, W and m are defined as above; and A and B, at each occurrence, are
Figure imgf000063_0002
In another embodiment, W and m are defined as above; and A and B, at each occurrence, are
Figure imgf000063_0003
In another embodiment, Rris selected from FORMULA Cla, C2a, C3a, C4a, C5a, Cl, C2, C3, C4 and C5 as defined hereinafter.
In another embodiment, Rris selected from Group R, and Group R consists of
Figure imgf000063_0001
Figure imgf000064_0001
wherein
R1, R2, R3 and R4, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl amino, cyano, nitro, optionally substituted C|-Cx alkyl optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-Cs alkoxy, optionally substituted Ci-Cs alkoxyalkyl, optionally substituted Ci-Cs haloalkyl, optionally substituted Ci-Cs hydroxyalkyl, optionally substituted Ci-C8 alkylamino, and optionally substituted Ci-C8 alkylaminoCi-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 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R1 and R2, R3 and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR”, R C02R , R C(0)N(R5)R , R C(S)N(R5)R , R OR , R SR , R SOR , R S02R ,
R S02N(R5)R , RN(R5)R , RN(R5)COR , RN(R5)CON(R6)R , RN(R5)C(S)R , optionally substituted Ci-Cg alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1 -CxalkoxyC 1 -Cxalkylcnc. optionally substituted C 1 -Cx haloalkylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, 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 null, optionally substituted (C|-C8 alkyl)-Rr (preferably, CH2-R1), optionally substituted Rr-(Ci-C8 alkylene), optionally substituted (C C8 alkylene)- Rr-(Ci-C8 alkylene), or a moiety comprising of optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R5 and R6 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R5 and R6, R and R5, R and R6, R and R5, R and R6 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
m is 0 to 15;
n, at each occurrence, is 0 to 15; and
o is 0 to 15.
In another embodiment, A, W and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH2)0-8-, -(CH2)o-3-CO-(CH2)o-8-, (CH2)0-8-NH-CO, (CH2)0-8-CO-NH, NH-CO- (CH2) O-8, CO-NH-(CH2) O-8, (CH2) I-3-NH-(CH2) I-3-CO-NH, (CH2) I-3-NH-(CH2) I-3-NH-CO, -CO-NH, CO-NH- (CH2) 1-3-NH-(CH2) 1-3, (CH2) 1-3-NH-(CH2) 1-3, -(CH2)o-3-Rr-(CH2)o-3, -(CH2)o-3-(CO)-(CH2)o-3-Rr- (CH2)O-3-, -(CH2)o-3-(CO-NH)-(CH2)o-3-Rr-(CH2)o-3-, -(CH2)o-3-(NH-CO)-(CH2)o-3-Rr-(CH2)o-3-, and - (CH2)o-3-(NH)-(CH2)o-3-Rr-(CH2)o-3-.
In another embodiment, W and m are defined as above; and A and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH2)o-8-, -(CH2)o-3-CO-(CH2)o-8-, (CH2)I.2- NH-CO, (CH2)I-2-CO-NH, NH-CO-(CH2) I-2, CO-NH-(CH2) I-2, (CH2) I-2-NH-(CH2) 1-2-CO-NH, (CH2) i_2- NH-(CH2) I-2-NH-CO, -CO-NH, CO-NH- (CH2) I-2-NH-(CH2) 1-2, (CH2) I-2-NH-(CH2) i_2,-(CH2)o-2-R (CH2)O-2, -(CH2)o-2-(CO)-(CH2)o-3-Rr-(CH2)o-2-, -(CH2)o-2-(CO-NH)-(CH2)o-3-Rr-(CH2)o-2-, -(CH2)O-2-(NH- CO)-(CH2)o-3-Rr-(CH2)o-2-, -(CH2)o-2-(NH)-(CH2)o-3-Rr-(CH2)o-2-
In another embodiment, Rris selected from FORMULA Cla, C2a, C3a, C4a, C5a, Cl, C2, C3, C4, and C5 as defined hereinafter.
In another embodiment, Rris selected from Group R, and Group R is defined as in FORMULA 9. In one embodiment, the CBP/P300 ligand of the bivalent compound is attached to A in FORMULA
9A.
In another embodiment, A (when A is attached to the CBP/P300 ligand ) is selected from null, CO,
Figure imgf000066_0001
(CH2)o-3-Rr-(CH2)o-3-, wherein
Rris selected from Group R, and Group R is defined as in FORMULA 9; and,
W and B is null.
In one embodiment, the linker moiety is of FORMULA 9A:
wherein
R1, R2, R3 and R4, at each occurrence, are independently selected from hydrogen, optionally substituted Ci-Cg alkyl (preperably, C1-C4 alkyl), or
R1 and R2, R3 and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl (preferably, 3-5 membered cycloalkyl) or 4-20 membered heterocyclyl ring;
A is defined as before; and W and B are null;
m is 0 to 15 (preferably, m is 0, 1, or 2);
n, at each occurrence, is 1 to 15 (preferably, n is 1); and
o is 1 to 15 (preferably, o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13).
In another embodiment, A is independently selected from null, or bivalent moiety selected from R -
Figure imgf000066_0002
above.
In another embodiment, R and R are independently selected from null, optionally substituted (Ci-Cg alkylene)-Rr (preferably, CFL-R1), or optionally substituted Ci-Cg alkyl (preferably, optionally substituted
Ci-C2 alkyl).
In another embodiment, the linker moiety is of FORMULA 9B:
Figure imgf000066_0003
wherein
R1 and R2, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted Ci-Cg alkyl, optionally substituted Ci-Cg alkoxy, optionally substituted Ci-Cg alkoxy Ci-Cg alkyl, optionally substituted Ci-Cg haloalkyl, optionally substituted Ci-Cg hydroxyalkyl, optionally substituted Ci-Cg alkylamino, C 1 -CxalkylaminoC 1 -Cxalkyl. 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
R1 and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or
4-20 membered heterocyclyl ring;
A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from
R -R , R COR , R CO2R , R C(0)N(R )R , R C(S)N(RJ)R , R OR , R SR , R SOR , R S02R , R S02N(R3)R , RN(R3)R , RN(R3)COR , RN(R3)CON(R4)R , RN(R3)C(S)R , optionally substituted C|-C’s alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C i -C8alkoxyC i -C8alkylcnc. optionally substituted C rC8 haloalkylene, optionally substituted C C8 hydroxyalkylene, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, 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 null, optionally substituted (C|-C8 alkylene)-Rr (preferably, CH2-Rr), optionally substituted Rr-(C |-Cx alkylene), optionally substituted (C rCx alkylene)- Rr-(C|-C’x alkylene), or a moiety comprising of optionally substituted C|-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C rC8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is 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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R3 and R4 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R3 and R4, R and R3, R and R4, R and R3, R and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
each m is 0 to 15; and
n is 0 to 15.
In another embodiment, A, W and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH2)0.8-, -(CH2)O-3-CO-(CH2)0-IO-, (CH2)0.8-NH-CO, (CH2)0.8-CO-NH, NH-CO- (CH2) O-8, CO-NH-(CH2) O-8, (CH2) ,_3-NH-(CH2) , 3-CO-NH. (CH2) m3-NH-(0Ή2) 1 3-NH-CO, CO-NH-(CH2) 1_3-NH-(CH2)1_3, (CH2) 1_3-NH-(CH2) !_3, -(CH2)o-3-Rr-(CH2)o-3, -(CH2)o-3-(CO)-(CH2)o-3-Rr-(CH2)o-3-, - (CH2)o-3-(CO-NH)-(CH2)o-3-Rr-(CH2)0-3-, -(CH2)o-3-(NH-CO)-(CH2)0-3-Rr-(CH2)0-3-, -(CH2)0-3-(NH)-(CH2)0- 3-Rr-(CH2)o-3-.
In another embodiment, Rris selected from FORMULA Cla, C2a, C3a, C4a, C5a, Cl, C2, C3, C4, and C5 as defined hereinafter.
In another embodiment, Rris selected from Group R, and Group R is defined as in FORMULA 9.
In another embodiment, the linker moiety is of FORMULA 9C:
Figure imgf000068_0001
wherein
X is selected from O, NH, and NR7;
R1, R2, R3, R4, R5, and R6, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C|-Cx alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C|-Cx alkoxy, optionally substituted C 1 -Cx alkoxy Ci-C8 alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted C 1 -CN alkylamino, optionally substituted C|-Cx alkylaminoC|-Cx alkyl optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
A and B are independently selected from null, or bivalent moiety selected from R -R , R COR ,
R CO2R , R C(0)N(R8)R , R C(S)N(R8)R , R OR , R SR , R SOR , R S02R , R S02N(R8)R , R N(R8)R , RN(R8)COR , RN(R8)CON(R9)R , RN(R8)C(S)R , optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Cr
CxalkoxyCi-Cxalkylene, optionally substituted C' 1 -C'x haloalkylene, optionally substituted C' 1 -C'x hydroxyalkylene, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, 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 null, optionally substituted (Ci-C8 alkylene)-Rr (preferably, CH -Rr), optionally substituted Rr-(Ci-C8 alkylene), optionally substituted (C 1-C3 alkylene)- Rr-(Ci-C8 alkylene), or a moiety comprising of optionally substituted C1-C3 alkyl, optionally substituted C -C8 alkenyl, optionally substituted C -C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted C 1 -C’salkoxyC 1 -C’salkyl. optionally substituted C 1 -C’salkylam inoC 1 -C’salkyl. optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C -C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1-C3 hydroxyalkylene, optionally substituted C i-CsalkoxyC’i-Csalkylcnc. optionally substituted C 1 -C’salkylaminoC 1 -C’salkylcnc. optionally substituted Ci-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R , R and R are independently selected from hydrogen, optionally substituted C|-Cx alkyl optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C|-Cx alkoxyalkyl, optionally substituted C i -Cx haloalkyl, optionally substituted C|-Cx hydroxyalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R8 and R9, R and R8, R and R9, R and R8, R and R9 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
m, at each occurrence, is 0 to 15;
n, at each occurrence, is 0 to 15;
o is 0 to 15; and
p is 0 to 15.
In another embodiment, A and B are independently selected from null, CO, NH, NH-CO, CO-NH, -
Figure imgf000069_0001
In another embodiment, Rris selected from Group R, and Group R is defined as in FORMULA 9.
In another embodiment, A and B, at each occurrence, are independently selected from null, 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
In another embodiment, o is 0 to 5.
In another embodiment, the linker moiety comprises one or more rings selected from the group consisting of 3 to 13 membered rings, 3 to 13 membered fused rings, 3 to 13 membered bridged rings, and 3 to 13 membered spiro rings.
In another embodiment, the linker moiety comprises one or more rings selected from the group consisting o
Figure imgf000069_0002
FORM IJI A C1 a FORM IJI A C?a
Figure imgf000069_0003
Figure imgf000069_0004
FDRM I II A CAP FDRM I I I A CRa
wherein
X’ and Y’ are independently selected from N, CRb;
A1, B1, C1 and D1, at each occurrence, are independently selected from null, O, CO, SO, SO2, NRb, CRbRc;
A2, B2, C2, and D2, at each occurrence, are independently selected from N, CRb ;
A3, B3, C3, D3, and E3, at each occurrence, are independently selected from N, O, S, NRb, CRb;
Rb and Rc, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted CrC8 alkyl. optionally substituted C2-C8 alkenyl, optionally substituted C -C8 alkynyl, optionally substituted C C8 alkoxy, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 alkylamino, and optionally substituted Ci-C8 alkylaminoCi-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 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
m1, n1, o1 and p1 are independently selected from 0, 1, 2, 3, 4 and 5.
In another embodiment, the linker moiety comprises one or more rings selected from the group consisting of formulae Cl, C2, C3, C4 and C5:
Figure imgf000070_0001
In another embodiment, Rris selected from FORMULA Cla, C2a, C3a, C4a, C5a, Cl, C2, C3, C4, and C5 as defined above.
In another embodiment, Rris selected from Group R, and Group R is defined as in FORMULA 9.
In another embodiment, in FORMULA 9A, A and B are independently defined as above, and W is null.
In another embodiment, the length of the linker is 0 to 40 chain atoms.
In another embodiment, the length of the linker is 3 to 20 chain atoms.
In another embodiment, the length of the linker is 5-15 chain atoms.
In another embodiment, when the CBP/P300 ligand of the bivalent compound 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-Rr-(CH2)0-3, - (CH2)o-3-(CO)-(CH2)o-3-Rr-(CH2)o_3, wherein Rr is selected from Group R, and Group R is defined as in FORMULA 9.
In another embodiment, the linker is -(CO)-(CH2)3-7-.
In another embodiment, the linker is -(CH2)I-2(CO)-NH-(CH2)3-7-.
In another embodiment, the linker is -(CH2)0-IO-, and -(CH2)0-3-CO-(CH2)0-IO-,
In another embodiment, the linker is -(CH2)0-3-Rr-(CH2)0-3-, or -(CH2)0-3-(CO)-(CH2)o-3-Rr-(CH2)0-3 , wherein Rr is selected from the group of Group R, and Group R is defined as in FORMULA 9. Without wishing to be bound by any particular theory, it is contemplated herein that, in some embodiments, attaching pomalidomide or VHL-1 to either portion of the molecule can recruit the cereblon E3 ligase or VHL E3 ligase to CBP/P300.
The bivalent compounds disclosed herein can selectively affect CBP/P300-mediated disease cells compared to WT (wild type) cells (i.e., an bivalent compound able to kill or inhibit the growth of an CBP/P300-mediated disease cell while also having a relatively low ability to lyse or inhibit the growth of a WT cell), e.g., possess a GI50 for one or more CBP/P300-mediated disease cells more than 1.5-fold lower, more than 2-fold lower, more than 2.5-fold lower, more than 3-fold lower, more than 4-fold lower, more than 5-fold lower, more than 6-fold lower, more than 7-fold lower, more than 8-fold lower, more than 9-fold lower, more than 10-fold lower, more than 15 -fold lower, or more than 20-fold lower than its GI50 for one or more WT cells, e.g., WT cells of the same species and tissue type as the CBP/P300- mediated disease cells.
In some aspects, provided herein is a method for identifying a bivalent compound which mediates degradation or reduction of CBP/P300, the method comprising: providing a heterobifunctional test compound comprising an CBP/P300 ligand conjugated to a degradation tag through a linker; contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and CBP/P300;
determining whether CBP/P300 level is decreased in the cell; and identifying the heterobifunctional test compound as a bivalent compound which mediates degradation or reduction of CBP/P300. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cancer cell is a CBP/P300-mediated cancer cell.
Synthesis and Testing of Bivalent Compounds
The binding affinity of novel synthesized bivalent compounds can be assessed using standard biophysical assays known in the art (e.g., isothermal titration calorimetry (ITC), surface plasmon resonance (SPR)). Cellular assays can then be used to assess the bivalent compound’s ability to induce CBP/P300 degradation and inhibit cancer cell proliferation. Besides evaluating a bivalent compound’s induced changes in the protein levels of CBP/P300, CBP/P300 mutants, or CBP/P300 fusion proteins, protein-protein interaction or acteryltransferase enzymatic activity can also be assessed. Assays suitable for use in any or all of these steps are known in the art, and include, e.g., western blotting, quantitative mass spectrometry (MS) analysis, flow cytometry, enzymatic activity assay, ITC, SPR, cell growth inhibition, xenograft, orthotopic, and patient-derived xenograft models. Suitable cell lines for use in any or all of these steps are known in the art and include LNCaP, 22RV1, HEL, MV4;11, RS4;11, NCI-H929, MM. IS, Pfeiffer, NCI-H520 and other cell lines. Suitable mouse models for use in 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.
By way of non-limiting example, detailed synthesis protocols are described in the Examples for specific exemplary bivalent compounds.
Pharmaceutically acceptable isotopic variations 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 variations of those reagents). Specifically, an isotopic variation 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 thus include, e.g., 2H, 3H, 13C, 14C, 15N, 170, 180, 32P, 35S, 18F, and 36C1. Isotopic variations (e.g., isotopic variations containing 2H) can provide therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. In addition, certain isotopic variations (particularly those containing a radioactive isotope) can be used in drug or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Pharmaceutically acceptable solvates of the compounds disclosed herein are contemplated. A solvate can be generated, e.g., by substituting a solvent used to crystallize a compound disclosed herein with an isotopic variation (e.g., D 0 in place of H20, ¾-acetone in place of acetone, or ri6-DMSO in place of DMSO).
Pharmaceutically acceptable fluorinated variations 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 fluorinated variations of those reagents). Specifically, a fluorinated variation is a compound in which at least one hydrogen atom is replaced by a fluoro atom. Fluorinated variations can provide therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
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 hydroxyl groups or carboxylic acid groups to ester groups). As used herein, a "prodrug" refers to a compound that can be converted via some chemical or physiological process (e.g., enzymatic processes and metabolic hydrolysis) to a therapeutic agent. Thus, the term "prodrug" also refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, i.e. an ester, but is converted in vivo to an active compound, for example, by hydrolysis to the free carboxylic acid or free hydroxyl. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in an organism.
The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject. Prodrugs of an active compound may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
Characterization of Exemplary Bivalent Compounds
Specific exemplary bivalent compounds were characterized in LNCaP or 22RV1 cells. LNCaP or 22RV1 cells that express CBP/P300 proteins were treated with GNE-781 or the bivalent compounds disclosed herein (P-001 to P-174) for indicated hours. Cells were collected, lysed and subject to immunoblotting using an antibody specific to P300 or CBP proteins. Tubulin or vinculin was included as the loading control. DMSO was used as the negative control. Following treatment of various bivalent compounds, P300 and CBP protein levels in LNCaP or 22RV1 cells were significantly decreased (Figure 1, 2, 5, 6, 10, and 11). Selected bivalent compounds disclosed herein were found to be particularly effective in reducing CBP and P300 protein levels, as the concentrations required to reduce target protein levels by 50% (DC50) for some compounds were less than 1 nM (Figure 6). In addition, LNCaP cells were treated with 20 nM P-004, P-005, P-015, or P-020 for the indicated time. Subsequently, changes in P300 protein levels were measured via immunoblotting. Tubulin was included as the loading control. Significant degradation of P300 was readily detected as early as 2 hours following administration of the compounds (Figure 3).
It has been demonstrated that targeting CBP/P300 using ligands to their bromodomains or lysine acetyltransferase domains compromises 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 mM GNE-781 or selected bivalent compounds, i.e. P-001, P-002, and P-019, following a 12-point 3 -fold serial dilution. Three days after treatment, cell viability was determined using the CellTiter-Glo kit (Promega) following manufacturer’s instructions. Cell viability was normalized to the mean values of 3 replicates of untreated cells. Dose-dependent response was analyzed following the least-squares non linear regression method using the GraphPad Prism 5.0 software. Bivalent compounds dose-dependently suppressed viability of LNCaP cells, as exemplified by P-001, P-002, and P-019 (Figure 4, Table 2-3). These results collectively demonstrated that downregulation of CBP/P300 proteins levels using bivalent compounds described herein induced antineoplastic activities.
The interaction with cereblon is critical to the ability of bivalent compounds to induce degradation of P300/CBP proteins, as a chemical modification that disrupted cereblon binding abolished P300 degradation induced by P-034 in LNCap and 22RV1 cells (Figure 7). The degradation was also dependent on the ubiquitin-proteasome system, because it could be neutralized by co-administration of proteasome inhibitors, MG- 132 and bortezomib, a cullin E3 ligase inhibitor, MLN4924, or high concentration of pomalidomide that compete for cereblon binding, as exemplified by P-007, P-034, and P-100 (Figure 8).
These findings collectively demonstrate that bivalent compounds induce degradation of P300/CBP proteins via a mechanism specifically mediated by cereblon, cullin E3 ligases, and the proteasome. In addition to cultured cells, athymic nude mice bearing 22RV 1 subcutaneous xenograft tumors at the right flank were intrapreitoneally or orally treated with 40 mg/kg bivalent compounds. Six hours after drug administration, animals were sacrificed for immunoblotting of P300 and CBP in homogenized xenograft tumor masses. Bivalent compounds, as exemplified by P-100, P-007 and P-034, exhibited the ability of significantly reducing P300 and CBP protein levels after a single dose of drug administration (Figure 9). Moreoever, ICR mice were orally treated with 40 mg/kg bivalent compounds. Six hours after drug administration, animals were sacrificed for immunoblotting of CBP in homogenized lung tissues. Bivalent compounds, as exemplified in Figure 12, exhibited the ability of significantly reducing CBP protein levels after a single dose of drug administration.
Definition of Terms
As used herein, the terms“comprising” and“including” are used in their open, non-limiting sense.
"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. An alkyl may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain
embodiments, an alkyl comprises one to fifteen carbon atoms ( e.g ., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -Cx alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), «-propyl, 1-methylethyl (Ao-propyl), «-butyl, «-pentyl, 1,1-dimethylethyl (/-butyl), pentyl, 3-methylhexyl, 2-methylhexyl, and the like. "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond. An alkenyl may comprise two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms.
In certain embodiments, an alkenyl comprises two to twelve carbon atoms (e.g., C -Ci alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (e.g., C2-Cx alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (e.g., C2-CV, alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (e.g., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.
The term“allyl,” as used herein, means a -CH2CH=CH2group.
As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond. An alkynyl may comprise two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen carbon atoms. In certain embodiments, an alkynyl comprises two to twelve carbon atoms (e.g., C2-Ci2 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (e.g., C2-C8 alkynyl). In other embodiments, an alkynyl has two to six carbon atoms (e.g., C2-CV, alkynyl). In other embodiments, an alkynyl has two to four carbon atoms (e.g., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond. Examples of such groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.
The term " alkoxy", as used herein, means an alkyl group as defined herein witch is attached to the rest of the molecule via an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
The term“aryl”, as used herein, " refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon atoms.
An aryl may comprise from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. In certain embodiments, an aryl comprises six to fourteen carbon atoms (CVC|4 aryl). In certain embodiments, an aryl comprises six to ten carbon atoms (CVCm aryl). Examples of such groups include, but are not limited to, phenyl, fluorenyl and naphthyl. The terms“Ph” and“phenyl,” as used herein, mean a -C6H5 group.
The term“heteroaryl”, refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. In certain embodiments, a heteroaryl refers to a radical derived from a 3- to 10-membered aromatic ring radical (3-10 membered heteroaryl). In certain embodiments, a heteroaryl refers to a radical derived from 5- to 7-membered aromatic ring (5-7 membered heteroaryl). Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of such groups include, but not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, furopyridinyl, and the like. In certain embodiments, an heteroaryl is attached to the rest of the molecule via a ring carbon atom. In certain embodiments, an heteroaryl is attached to the rest of the molecule via a nitrogen atom (N-attached) or a carbon atom (C-attached). For instance, a group derived from pyrrole may be pyrrol-l-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-l-yl (N-attached) or imidazol-3-yl (C-attached).
The term“heterocyclyl”, as used herein, means a non-aromatic, monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of from 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms in its ring system, and containing from 3 to 12 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms. A heterocyclyl group may include fused, bridged or spirocyclic ring systems. In certain embodiments, a hetercyclyl group comprises 3 to 10 ring atoms (3-10 membered heterocyclyl). In certain embodiments, a hetercyclyl group comprises 3 to 8 ring atoms (3-8 membered heterocyclyl). In certain embodiments, a hetercyclyl group comprises 4 to 10 ring atoms (4-10 membered heterocyclyl). In certain embodiments, a hetercyclyl group comprises 4 to 8 ring atoms (4-8 membered heterocyclyl). A heterocyclyl group may contain an oxo substituent at any available atom that will result in a stable compound. For example, such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible. In addition, it is to be understood that when such a heterocyclyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone. An example of a 4 membered heterocyclyl 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-quinolizinyl. Further examples of such heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,
tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4//-pyranyl. dioxanyl, 1,3- dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3 H- indolyl, quinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, and 1-oxo- 2,8,diazaspiro[4.5]dec-8-yl. A heteroaryl group may be attached to the rest of molecular via a carbon atom (C-attached) or a nitrogen atom (N-attached). For instance, a group derived from piperazine may be piperazin-l-yl (N-attached) or piperazin-2-yl (C-attached).
The term "cycloalkyl" or "carbocyclyl" means a saturated, monocyclic, bicyclic, tricyclic, or tetracyclic radical having a total of from 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms in its ring system.
A cycloalkyl may be fused, bridged or spirocyclic. In certain embodiments, a cycloalkyl comprises 3 to 8 carbon ring atoms (3-8 membered carbocyclyl). In certain embodiments, a cycloalkyl comprises 3 to 10 carbon ring atoms (3-10 membered cycloalkyl). Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, and the like.
The term“cycloalkylene” is a bidentate radical obtained by removing a hydrogen atom from a cycloalkyl ring as defined above. Examples of such groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cycloheptylene, and the like. As used herein, the term "chain atom" refers to atoms that is located on the main chain of the linker moiety.
The term "spirocyclic" as used herein has its conventional meaning, that is, any ring system containing two or more rings wherein two of the rings have one ring carbon in common. Each ring of the spirocyclic ring system, as herein defined, independently comprises 3 to 20 ring atoms. Preferably, they have 3 to 10 ring atoms. Non-limiting examples of a spirocyclic system include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.
The term cyano" refers to a -CºN group.
An "aldehyde" group refers to a -C(0)H group.
An "alkoxy" group refers to both an -O-alkyl, as defined herein.
An "alkoxy carbonyl" refers to a -C(0)-alkoxy, as defined herein.
An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group, as defined herein.
An "alkylsulfonyl" group refer to a -S02alkyl. as defined herein.
An "amino" group refers to an optionally substituted -NEE.
An "aminoalkyl" group refers to an -alky-amino group, as defined herein.
An "aminocarbonyl" refers to a -C(0)-amino, as defined herein.
An "arylalkyl" group refers to -alkylaryl, where alkyl and aryl are defined herein.
An "aryloxy" group refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.
An "aryloxy carbonyl" refers to -C(0)-aryloxy, as defined herein.
An "arylsulfonyl" group refers to a -S02aryl. as defined herein.
A "carbonyl" group refers to a -C(O)- group, as defined herein.
A "carboxylic acid" group refers to a -C(0)OH group.
A“cycloalkoxy” refers to a -O-cycloalkyl group, as defined herein.
A "halo" or "halogen" group refers to fluorine, chlorine, bromine or iodine.
A "haloalkyl" group refers to an alkyl group substituted with one or more halogen atoms.
A "hydroxy" group refers to an -OH group.
A "nitro" group refers to a -N02 group.
An“oxo” group refers to the =0 substituent.
A "trihalomethyl" group refers to a methyl substituted with three halogen atoms.
The term“substituted,” means that the specified group or moiety bears one or more substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C C4 alkyl)(Ci-C4 alkyl), -NH(CI-C4 alkyl), -N(C C4 alkyl)(Ci-C4 alkylphenyl), -NH(CI-C4 alkylphenyl), cyano, nitro, oxo, -C02H, -C(0)OCi-C4 alkyl, -CON(CI-C4 alkyl)(Ci-C4 alkyl), -CONH(CI-C4 alkyl), -CONH2, -NHC(0)(C C4 alkyl), -NHC(0)(phenyl), -N(C C4 alkyl)C(0)(Ci-C4 alkyl), -N(C C4 alkyl)C(0)(phenyl), -C(0)C C4 alkyl, -C(0)C C4 alkylphenyl, -C(0)C C4 haloalkyl, -OC(0)Ci-C4 alkyl, -S02(Ci-C4 alkyl), -S02(phenyl), -S02(Ci-C4 haloalkyl), -S02NH2, -S02NH(Ci-C4 alkyl), -S02NH(phenyl), -NHS02(Ci-C4 alkyl), -NHS02(phenyl), and -NHS02(Ci-C4 haloalkyl).
The term“null” means the absence of an atom or moiety, and there is a bond between adjacent atoms in the structure.
The term“optionally substituted” means that the specified group may be either unsubstituted or substituted by one or more substituents as defined herein. It is to be understood that in the compounds of the present invention when a group is said to be“unsubstituted,” or is“substituted” with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen. For example, if a C( aryl group, also called“phenyl” herein, is substituted with one additional substituent, one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the G, aryl ring (6 initial positions, minus one at which the remainder of the compound of the present invention is attached to and an additional substituent, remaining 4 positions open). In such cases, the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies. Similarly, if a G, aryl group in the present compounds is said to be“disubstituted,” one of ordinary skill in the art would understand it to mean that the G, aryl has 3 carbon atoms remaining that are unsubstituted. Those three unsubstituted carbon atoms are each bound to one hydrogen atom to fill their valencies. Unless otherwise specified, an optionally substituted radical may be a radical unsubstituted or substituted with one or more substituents selected from halogen, CN, NO2, ORm, SRm, NRnR°, CORm, C02Rm, CONRnR°, SORm, S02Rm, S02NRnR°, NRnCOR°, NRmC(0)NRnR°, NRnSOR°, NRnS02R°, C C8 alkyl, C 1 -GalkoxyC 1 -Galkyl. G-G haloalkyl, C 1 -G hydroxyalkyl, C 1 -GalkylaminoC 1 -Galkyl. C3-C7 cycloalkyl, 3-7 membered heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, and heteroaryl, wherein Rm, Rn, and R° are independently selected from null, hydrogen, G-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, 3-7 membered heterocyclyl, aryl, and heteroaryl, or Rn and R° together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.
As used herein, the same symbol in different FORMULA means different definition, for example, the definition of R1 in FORMULA 1 is as defined with respect to FORMULA 1 and the definition of R1 is as defined with respect to FORMULA 6.
As used herein, when m (or n or o or p) is defmited by a range, for example, “m is 0 to 15” or“m = 0-3” mean that m is an integer from 0 to 15 (i.e. m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) or m is an integer from 0 to 3(i.e. m is 0, 1,2, or 3) or is any integer in the defined range.
As used herein, (CH2)a-b (a and b are integer) means a group of (CH2)c , 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 means a group of null, (CH2), (CH2)2, or (CH2)3.
"Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the bivalent compounds described herein is intended to encompass 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.
"Pharmaceutically acceptable acid addition salt" 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 that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, 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. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as alginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of
Pharmaceutical Science, 66: 1-19 (1997), which is hereby incorporated by reference in its entirety). Acid addition salts of basic compounds may be prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
"Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts may 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 salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, /V./V-dibcnzylcthylcncdiaminc. chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, /V-mcthylglucaminc. glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, /V-cthylpipcridinc. polyamine resins and the like. See Berge et ak, supra.
Pharmaceutical Compositions
In some aspects, the compositions and methods described herein include the manufacture and use of pharmaceutical compositions and medicaments that include one or more bivalent compounds as disclosed herein. Also included are the pharmaceutical compositions themselves.
In some aspects, the compositions disclosed herein can include other compounds, drugs, or agents used for the treatment of cancer. For example, in some instances, pharmaceutical compositions disclosed herein can be combined with one or more (e.g., one, two, three, four, five, or less than ten) compounds. Such additional compounds can include, e.g., conventional chemotherapeutic agents or any other cancer treatment known in the art. When co-administered, bivalent compounds disclosed herein can operate in conjunction with conventional chemotherapeutic agents or any other cancer treatment known in the art to produce mechanistically additive or synergistic therapeutic effects.
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 bivalent compound or its delivery form.
Pharmaceutical compositions typically include a pharmaceutically acceptable excipient, adjuvant, or vehicle. As used herein, the phrase“pharmaceutically acceptable” refers to molecular entities and compositions that are generally believed to be physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. A pharmaceutically acceptable excipient, adjuvant, or vehicle is a substance that can be administered to a patient, together with a compound of the invention, and which does not compromise the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Exemplary conventional nontoxic pharmaceutically acceptable excipients, adjuvants, and vehicles include, but not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
In particular, pharmaceutically acceptable excipients, adjuvants, and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric 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, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as a-, b-, and g-cyclodextrin, may also be advantageously used to enhance delivery of compounds of the formulae described herein.
Depending on the dosage form selected to deliver the bivalent compounds disclosed herein, different pharmaceutically acceptable excipients, adjuvants, and vehicles may be used. In the case of tablets for oral use, pharmaceutically acceptable excipients, adjuvants, and vehicles may be used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral
administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
As used herein, the bivalent compounds disclosed herein are defined to include pharmaceutically acceptable derivatives or prodmgs thereof. A“pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, solvate, or prodrug, e.g., carbamate, ester, phosphate ester, salt of an ester, or other derivative of a compound or agent disclosed herein, which upon administration to a recipient is capable of providing (directly or indirectly) a compound described herein, or an active metabolite or residue thereof. Particularly favored derivatives and prodmgs are those that increase the bioavailability of the compounds disclosed herein when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodmgs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the stmcture of formulae described herein. Such derivatives are recognizable to those skilled in the art without undue experimentation.
Nevertheless, reference is made to the teaching of Burger’s Medicinal Chemistry and Dmg Discovery, 5th Edition, Vol. 1: Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.
The bivalent compounds disclosed herein include pure enantiomers, mixtures of enantiomers, pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of
diastereoisomeric racemates and the meso-form and pharmaceutically acceptable salts, solvent complexes, morphological forms, or deuterated derivatives thereof. The single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates.
Resolution of the racemates can be accomplished, for example, by 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- forms) of compounds with carbon-carbon double bonds. Where compounds described herein exist in various tautomeric forms, the term“compound” is intended to include all tautomeric forms of the compound.
The bivalent compounds disclosed herein also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. "Crystalline form," "polymorph," and "novel form" may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Similarly,
“pharmaceutically acceptable salts” of the bivalent compounds also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the pharmaceutically acceptable salts, as well as mixtures thereof.
A“solvate” is formed by the interaction of a solvent and a compound. The term“compound” is intended to include solvates of compounds. Similarly,“pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi -hydrates.
In some aspects, the pharmaceutical compositions disclosed herein can include an effective amount of one or more bivalent compounds. The terms“effective amount” and“effective to treat,” as used herein, refer to an amount or a concentration of one or more compounds or a pharmaceutical composition described herein utilized for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer). In some aspects, pharmaceutical compositions can further include one or more additional compounds, drugs, or agents used for the treatment of cancer (e.g., conventional chemotherapeutic agents) in amounts effective for causing an intended effect or physiological outcome (e.g., treatment or prevention of cell growth, cell proliferation, or cancer).
In some aspects, the pharmaceutical compositions disclosed herein can be formulated for sale in the United States, import into the United States, or export from the United States.
Administration of Pharmaceutical Compositions
The pharmaceutical compositions disclosed herein can be formulated or adapted for administration to a subject via any route, e.g., any route 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, the pharmaceutical compositions can be formulated for and administered via oral, parenteral, or transdermal delivery. The term“parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraperitoneal, intra-articular, intra-arterial, intrasynovial, intrastemal, intrathecal, intralesional, and intracranial injection or infusion techniques.
For example, the pharmaceutical compositions disclosed herein can be administered, e.g., topically, rectally, nasally (e.g., by inhalation spray or nebulizer), buccally, vaginally, subdermally (e.g., by injection or via an implanted reservoir), or ophthalmically.
For example, pharmaceutical compositions of this 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.
For example, the pharmaceutical compositions of this invention can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
For example, the pharmaceutical compositions of this 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 solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, or other solubilizing or dispersing agents known in the art.
For example, the pharmaceutical compositions of this 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 dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, e.g., as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically -acceptable oils, e.g., olive oil or castor oil, especially in their
polyoxyethylated versions. These oil solutions or suspensions can also contain a long -chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens, Spans, or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
In some aspects, an effective dose of a pharmaceutical composition of this invention can include, but is not limited to, e.g., 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 according to the requirements of the particular pharmaceutical composition.
When the pharmaceutical compositions disclosed herein include a combination of the bivalent compounds described herein and one or more additional compounds (e.g., one or more additional compounds, drugs, or agents used for the treatment of cancer or any other condition or disease, including conditions or diseases known to be associated with or caused by cancer), both the bivalent compounds and the additional compounds may be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents can be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents can be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
In some aspects, the pharmaceutical compositions disclosed herein can be included in a container, pack, or dispenser together with instructions for administration.
Methods of Treatment
The methods disclosed herein contemplate administration of an effective amount of a compound or composition to achieve the desired or stated effect. Typically, the compounds or compositions of the invention will be administered from about 1 to about 6 times per day or, alternately or in addition, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations can contain from about 20% to about 80% active compound.
In some aspects, provided herein are a bivalent compound described herein for preventing or treating a disease or condition.
In some aspects, provided herein are a bivalent compound described herein for 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 resulted from CBP/P300 expression, mutation, deletion, or fusion. In certain embodiments, the disease or condition is a cancer. In certain embodiments, the disease or condition comprises acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,
leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T- cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer,
Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor. In certain embodiments, the disease or condition is a relapsed cancer. In certain embodiments, the disease or condition is an inflammatory disorder or the 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 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, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and
Wegener's granulomatosis. In certain embodiments, the disease or condition is refractory to one or more previous treatments.
In some aspects, provided herein are use of a bivalent compound in manufacture of a medicament for preventing or treating one or more diseases or conditions disclosed herein. In some aspects, the methods disclosed include the administration of a therapeutically effective amount of one or more of the compounds or compositions described herein to a subject (e.g., a
mammalian subject, e.g., a human subject) who is in need of, or who has been determined to be in need of, such treatment. In some aspects, the methods disclosed include selecting a subject and administering to the subject an effective amount of one or more of the compounds or compositions described herein, and optionally repeating administration as required for the prevention or treatment of cancer.
In some aspects, subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection. In some aspects, the subject can be confirmed or identified, e.g. by a health care professional, as having had, having an elevated risk to have, or having a condition or disease. In some aspects, suitable subjects include, for example, subjects who have or had a condition or disease but that resolved the disease or an aspect thereof, present reduced symptoms of disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), or that survive for extended periods of time with the condition or disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), e.g., in an asymptomatic state (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease). In some aspects, exhibition of a positive immune response towards a condition or disease can be made from patient records, family history, or detecting an indication of a positive immune response. In some aspects, multiple parties can be included in subject selection. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample. In some aspects, subjects can be selected or referred by a medical practitioner (e.g., a general practitioner). In some aspects, subject selection can include obtaining a sample from a selected subject and storing the sample or using the in the methods disclosed herein. Samples can include, e.g., cells or populations of cells.
In some aspects, methods of treatment can include a single administration, multiple administrations, and repeating administration of one or more compounds disclosed herein as required for the prevention or treatment of the disease or condition disclosed herein (e.g., an CBP/P300-mediated disease). In some aspects, methods of treatment can include assessing a level of disease in the subject prior to treatment, during treatment, or after treatment. In some aspects, treatment can continue until a decrease in the level of disease in the subject is detected.
The term“subject,” as used herein, refers to any animal. In some instances, the subject is a mammal. In some instances, the term“subject,” as used herein, refers to a human (e.g., a man, a woman, or a child).
The terms“administer,”“administering,” or“administration,” as used herein, refer to implanting, ingesting, injecting, inhaling, or otherwise absorbing a compound or composition, regardless of form. For example, the methods disclosed herein include administration of an effective amount of a compound or composition to achieve the desired or stated effect.
The terms“treat”,“treating,” or“treatment,” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating, or relieving the disease or condition from which the subject is suffering. This means any manner in which one or more of the symptoms of a disease or disorder (e.g., cancer) are ameliorated or otherwise beneficially altered. As used herein, amelioration of the symptoms of a particular disorder (e.g., cancer) refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with treatment by the bivalent compounds, compositions and methods of the present 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 prior to treatment; a decrease in the viability (e.g., the average/mean viability) of tumor cells (e.g., in a subject) relative to the viability of tumor cells prior to treatment; a decrease in the rate of growth of tumor cells; a decrease in the rate of local or distant tumor metastasis; or reductions in one or more symptoms associated with one or more tumors in a subject relative to the subject’s symptoms prior to treatment.
The terms“prevent,”“preventing,” and“prevention,” as used herein, shall refer to a decrease in the occurrence of a disease or decrease in the risk of acquiring a disease or its associated symptoms in a subject. The prevention may be complete, e.g., the total absence of disease or pathological cells in a subject. The prevention may also be partial, such that the occurrence of the disease or pathological cells in a subject is less than, occurs later than, or develops more slowly than that which would have occurred without the present invention. In certain embodiments, the subject has an elevated risk of 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 myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T- cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, Wilms' tumor, Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, 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, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.
Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.
An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a therapeutic compound (i.e., an effective dosage) depends on the therapeutic compounds selected. Moreover, treatment of a subject with a therapeutically effective amount of the compounds or compositions described herein can include a single treatment or a series of treatments. For example, effective amounts can be administered at least once. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health or age of the subject, and other diseases present.
Following administration, the subject can be evaluated to detect, assess, or determine their level of disease. In some instances, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected. Upon improvement of a patient’s condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, or composition disclosed herein can be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced, e.g., as a function of the symptoms, to a level at which the improved condition is retained.
Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
The present disclosure is also described and demonstrated by way of 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 invention or of any exemplified term. Likewise, the invention is not limited to any particular preferred embodiment or aspect described herein. Indeed, many
modifications and variations may be apparent to those skilled in the art upon reading this specification, and such variations can be made without departing from the invention in spirit or in scope. The invention is therefore to be limited only by the terms of the appended claims along with the full scope of equivalents to which those claims are entitled.
EXAMPLES
Procedures for the synthesis of linker-attached degradation tags for bivalent compounds.
Example 1: 4-((2-Aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker 1)
Figure imgf000085_0001
A solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (1.66 g, 6.0 mmol), tert- butyl (2-aminoethyl)carbamate (1.25 g, 6.6 mmol) and /V./V-diisopropylethylamine (2.32g, 18 mmmol) in DMF (12 mL) was heated to 85 °C in a microwave reactor for 50 min. 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 hexanes/EtOAc= 1: 1) to give tert- butyl (2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethyl)carbamate (1.3 g, yield: 16%) as a yellow solid. MS (ESI) m/z = 317.1 [M-100+H]+. A solution of tert- butyl (2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl) amino)ethyl)carbamate (2.0 g, 4.5 mmol) in DCM (10 mL) and TFA (5 mL) was stirred at rt for 2 h. The reaction was concentrated and triturated with EtOAc. The solid precipitate was filtered. And the solid was washed with MTBE, and dried to give 4-((2-aminoethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l,3-dione as a yellow solid (Linker 1) (1.3 g, yield: 98%). 'H NMR (400 MHz, DMSO- ) d 11.14 (s, 1 H), 7.85 (s, 3H), 7.45 (t, / = 7.2 Hz, 1H), 7.19 (d, / = 7.2 Hz, 1H), 7.10 (d, / = 7.2 Hz, 1H), 6.84 (t, / = 6.4 Hz, 1H), 5.07 (dd, / = 5.2, 12.8 Hz, 1H), 3.58 (q, / = 6.4 Hz, 2H), 3.00 (s, 2H), 2.94-2.85 (m, 1H), 2.62-2.50 (m, 2H), 2.05-2.00 (m, 1H). MS (ESI) m/z = 317.1 [M+H]+. Example 2: 4-((3-Aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker
Figure imgf000086_0001
Linker 3 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.4 g, yield: 15% over 2 steps). 1H NMR (400 MHz, DMSO-d6) l l . l l(s, 1 H), 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]+
Example 4: 4-((5-Aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker
Figure imgf000086_0002
Linker 5 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.8 g, yield: 20% over 2 steps).‘H NMR (400 MHz, DMSO-d6) 511.10(s, 1 H), 7.76 (s, 3H), 7.58 (t, / = 7.2 Hz, 1H), 7.10 (d, / = 8.4 Hz, 1H), 7.03 (d, / = 7.2 Hz, 1H), 6.54 (t, / = 6.0 Hz, 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]+ Example 6: 4-((7-Aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker
Figure imgf000087_0001
Linker 9 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.1 g, yield: 17% over 2 steps).‘H NMR (400 MHz, DMSO-d6) d 11.1 l(s, 1 H), 7.84 (s, 3H), 7.62-7.58 (m, 1H), 7.15 (d, / = 8.8 Hz, 1H), 7.05 (d, J = 6.8 Hz, 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]+
Example 10: 4-((2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (Linker 10)
Figure imgf000088_0001
Linker 10 was synthesized following th same procedures as Linker 1 as described in Example 1.
(1.3 g, yield: 17% over 2 steps). ¾ NMR (400 MHz, DMSO-d6) d 11.1 l(s, 1 H), 7.83 (s, 3H), 7.61-7.57 (m, 1H), 7.15 (d, / = 8.8 Hz, 1H), 7.05 (d, / = 6.8 Hz, 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]+
Example 11: 4-((14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (Linker 11)
Figure imgf000088_0002
Linker 11 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.2 g, yield: 16% over 2 steps). l NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 7.84 (s, 3H), 7.61-7.57
(m, 1H), 7.15 (d, / = 8.8 Hz, 1H), 7.05 (d, / = 6.8 Hz, 1H), 6.61 (s, 1H), 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]+
Example 12: 4-((17-Amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (Linker 12)
Figure imgf000088_0003
Linker 12 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.2 g, yield: 15% over 2 steps). ¾ NMR (400 MHz, DMSO-d6) d 11.1 l(s, 1 H), 7.82 (s, 3H), 7.61-7.57 (m, 1H), 7.15 (d, / = 8.4 Hz, 1H), 7.05 (d, / = 7.2 Hz, 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]+
Example 13: (2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)glycine (Linker 13)
Figure imgf000089_0002
Linker 13 was synthesized following the same procedures as Linker 1 as described in Example 1. (840 mg, yield: 16% over 2 steps). ¾ NMR (400 MHz, DMSO-d6) d 11.07(s, 1 H), 7.52 (t, / = 7.6 Hz,
1H), 6.99-6.88 (m, 3H), 5.04 (dd, / = 5.2, 12.8 Hz, 1 H), 3.73 (s, 2H), 2.93-2.83 (m, 1H), 2.61-2.50 (m, 2H), 2.02 (t, J = 5.6 Hz, 1H). MS (ESI) m/z = 330.1 [M-H]-
Example 14: 3-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)propanoic acid (
Figure imgf000089_0001
Linker 14 was synthesized following the same procedures as Linker 1 as described in Example 1.
(1.42 g, yield: 24% over 2 steps). ¾ NMR (400 MHz, DMSO- ) d 11.61(br, 1H), 11.08(s, 1H), 7.58 (dd,
/ = 7.2, 8.8 Hz, 1H), 7.15 (d, / = 8.8 Hz, 1H), 7.04 (d, / = 7.2 Hz, 1H), 6.64 (s, 1H), 5.05 (dd, / = 5.2,
12.8 Hz, 1H), 3.53 (t, / = 6.4 Hz, 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]+
Example 15: 4-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino) butanoic acid (Linker 15)
Figure imgf000089_0003
Linker 16 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.4 g, yield: 15% over 2 steps). l NMR (400 MHz, DMSO-ifc) 512.02 (br, 1H), 11.08 (s, 1H), 7.58 (dd
/ = 8.8, 7.2 Hz, 1H), 7.10 (d, / = 8.4 Hz, 1H), 7.02 (d, / = 7.2 Hz, 1H), 6.64 (t, / = 5.6 Hz, 1 H), 5.07-5.03 (m, 1H), 3.32-3.02 (m, 2H), 2.93-2.84 (m, 1H), 2.61-2.54 (m, 2H), 2.28-2.25 (m, 2H), 2.05-2.01 (m, 1H), 1.60-1.51 (m, 4H). MS (ESI) m/z = 374.1 [M+H]+
Example 17: 6-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexanoic acid (Linker 17)
Figure imgf000090_0001
Linker 17 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.43 g, yield: 18% over 2 steps). H NMR (400 MHz, DMSO- ) d 11.97 (s, 1 H), 11.08(s, 1 H), 7.57 (dd / = 7.2, 8.8 Hz, 1H), 7.08 (d, / = 8.8 Hz, 1H), 7.02 (d, / = 7.2 Hz, 1H), 6.52 (t, / = 6.0 Hz, 1H), 5.05 (dd, / = 5.6, 12.8 Hz, 1H), 3.30 (q, / = 6.8 Hz, 2H), 2.93-2.83 (m, 1H), 2.61-2.50 (m, 2H), 2.32 (t, J = 7.2 Hz, 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]+
Example 18: 7-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)heptanoic acid (
Figure imgf000090_0002
Linker 18 was synthesized following the same procedures as Linker 1 as described in Example 1. (2.3 g, yield: 24% over 2 steps). l NMR (400 MHz, DMSO-d6) d 11.92 (br, 1 H), 11 08(s, 1 H), 7.57 (t, / = 8.0 Hz, 1 H), 7.13 (d, / = 8.8 Hz, 1 H), 7.03 (d, / = 6.8 Hz, 1 H), 6.52 (t, / = 5.6 Hz, 1 H), 5.05 (dd, J = 5.6, 12.8 Hz, 1 H), 3.30 (q, J = 6.4 Hz, 2H), 2.93-2.83 (m, 1H), 2.61-2.50 (m, 2H), 2.31 (t, / = 7.2 Hz, 2H), 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]+
Example 19: 8-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)octanoic acid (Linker 19)
Figure imgf000090_0003
Linker 19 was synthesized following the same procedures as Linker 1 as described in Example 1. (1.14 g, yield: 35% over 2 steps). l NMR (400 MHz, DMSO-d6) d 11.94 (s, 1H), 11.08(s, 1H), 7.57 (t, / = 8.0 Hz, 1H), 7.08(d, / = 8.4Hz, 1H), 7.02 (d, / = 6.8 Hz, 1H), 6.52 (t, / = 5.6 Hz, 1H), 5.05 (dd, / = 5.6, 12.8 Hz, 1H), 3.31-3.26 (m, 2H), 2.93-2.83 (m, 1H), 2.61-2.50 (m, 2H), 2.19 (t, J = 7.2 Hz, 2 H), 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]+
Example 20: 3-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy) propanoic acid (Linker 20)
Figure imgf000090_0004
Linker 20 was synthesized following the same procedures as Linker 1 as described in Example 1. (3.5 g, yield: 18% over 2 steps).‘HNMR (400 MHz, DMSO-d6) d 12.18 (s, 1H), 11.08(s, 1 H), 7.58 (dd, / = 7.2 Hz, 8.8 Hz , 1H), 7.13 (d, / = 8.4 Hz, 1H), 7.04 (d, / = 7.2 Hz, 1H), 6.58 (t, / = 5.6 Hz 1H), 5.05 (dd, / = 6.4 Hz, 12.8 Hz, 1H), 3.67-3.58 (m, 4H), 3.47-3.43 (m, 2H), 2.93-2.84 (m, 1H), 2.61-2.45 (m, 4H), 2.07-2.01 (m, 1H). MS (ESI) m/z = 390.1 [M+H]+
Example 21 : 3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoic acid (Linker 21)
Figure imgf000091_0001
Linker 21 was synthesized following the same procedures as Linker 1 as described in Example 1. (2.0 g, yield: 24% over 2 steps).‘HNMR (400 MHz, DMSO-d6) d 12.13 (s, 1H), 11.08 (s, 1 H), 7.58 (dd, / = 7.2 Hz, 8.4 Hz , 1H), 7.14 (d, / = 8.4 Hz, 1H), 7.04 (d, / = 6.8 Hz, 1H), 6.60 (t, / = 6.0 Hz 1H), 5.05 (dd, / = 5.2 Hz, 12.4 Hz, 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]+
Example 22: 3-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (Linker 22)
Figure imgf000091_0002
Linker 22 was synthesized following the same procedures as Linker 1 as described in Example 1. (3.2 g, yield: 42% over 2 steps).‘HNMR (400 MHz, DMSO-d6) d 12.14 (s, 1H), 11.08 (s, 1H), 7.58 (dd, / = 7.2 Hz, 8.4 Hz , 1H), 7.14 (d, / = 8.8 Hz, 1H), 7.04 (d, / = 6.8 Hz, 1H), 6.60 (t, / = 6.0 Hz, 1H), 5.05 (dd, / = 5.2 Hz, 12.8 Hz, 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]+
Example 23: l-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-3,6,9,12- tetraoxapentadecan-15-oic acid (Linker 23)
Figure imgf000091_0003
Linker 23 was synthesized following the same procedures as Linker 1 as described in Example 1.
(2.3 g, yield: 31% over 2 steps). ¾ NMR (400 MHz, DMSO-d6) d 12.14 (s, 1H), 11.08(s, 1H), 7.58 (dd, / = 7.2 Hz, 8.8 Hz , 1H), 7.14 (d, / = 8.4 Hz, 1H), 7.04 (d, / = 7.2 Hz, 1H), 6.60 (t, / = 6.0 Hz, 1H), 5.05 (dd, / = 5.2 Hz, 12.8 Hz, 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]+
Example 24: l-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15- pentaoxaoctadecan-18-oic acid (Linker 24)
Figure imgf000092_0001
Linker 24 was synthesized following the same procedures as Linker 1 as described in Example 1.
(2.4 g, yield: 36% over 2 steps). ¾ NMR (400 MHz, DMSO-d6) d 11.09(s, 1 H), 7.58 (dd, J = 7.2, 8.4 Hz, 1 H), 7.13 (d, / = 8.4 Hz, 1 H), 7.04 (d, / = 7.2 Hz, 1 H), 6.60 (t, / = 5.6 Hz, 1 H), 5.05 (dd, / = 5.6, 12.8 Hz, 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, / = 6.4 Hz, 1H). MS (ESI) m/z = 566.2 [M+H]+
Example 25: (2S,4/?)-l-((S)-2-(2-Aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 25)
Figure imgf000092_0002
Step 1:
To a solution of (2S,4R)-l-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4-(4- methylthiazol- 5- yl)benzyl)pyrrolidine-2 -carboxamide (2.00 g, 4.67 mmol), 2 - ( ( tert-b uto xy carbo n y 1 )am i n o ) 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), 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 chromatography on a silica gel column (DCM/MeOH = 20/1, v/v) to give the desired product terf-butyl (2-(((S)-l-((2S,4R)-4- hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3, 3 -dimethyl- l-oxobutan-2- yl)amino)-2-oxoethyl)carbamate (1.5 g, yield: 55%). MS (ESI) m/z = 588.2 [M+H]+
Step 2:
To a solution of tot-butyl (2-(((S)-l-((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 ethylacetate (EA) (30 mL) was added HCI/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 (2SAR)- 1 -((.S)-2-(2-aminoacctamido)-3.3-dimcthylbutanoyl)- 4-hydroxy-/V-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (Linker 25) (1.07 g, yield: 80%). 'H NMR (400 MHz, DMSO-dg) 9.29 (s, 1H), 8.72 (s, 1H), 8.56 (d, / = 9.2 Hz, 1H), 8.26 (s, 3H), 7.38-7.47 (m, 4H), 4.61 (d, / = 9.2 Hz, 1H), 4.36-4.47 (m, 3H), 4.20-4.25 (m, 1H), 3.60-3.70 (m, 4H), 2.46 (s, 3H), 2.10-2.05 (m, 1H), 1.97-1.89 (m, 1H), 0.95 (s, 9H). MS (ESI) m/z = 488.3 [M+H]+
Example 26: (2S,4/?)-l-((S)-2-(3-Aminopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 26)
Figure imgf000092_0003
Linker 26 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.38 g, yield: 37% over 2 steps).‘H NMR (400 MHz, DMSO-d6) 9.36 (s, 1H), 8.68 (s, 1H), 8.26 (d, / = 9.2 Hz, 1H), 8.16 (s, 3H), 7.49-7.39 (m, 4H), 4.53 (d, J = 9.2 Hz, 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, / = 7.2 Hz, 2H), 2.48 (s, 3H), 2.06-2.01 (m, 1H), 1.92- 1.85 (m, 1H), 0.95 (s, 9H). MS (ESI) m/z = 502.3 [M+H]+
Example 27: (2S,4/?)-l-((S)-2-(4-Aminobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 27)
Figure imgf000093_0001
Linker 27 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.38 g, yield: 46% over 2 steps).‘H NMR (400 MHz, DMSO-d6) 9.66 (s, 1H), 8.74 (t, J = 6.0, 1H), 8.25 (s, 3H), 8.03 (d, / = 9.2 Hz, 1H), 7.49-7.41 (m, 4H), 4.53 (d, / = 9.2 Hz, 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]+.
Example 28: (2S,4/?)-l-((S)-2-(5-Aminopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4-
(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 28)
Figure imgf000093_0002
Linker 28 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.50 g, yield: 57% over 2 steps).‘H NMR (400 MHz, DMSO-d6) 9.52 (s, 1H), 8.73 (t, / = 11.6 Hz, 1H), 8.20 (s, 3H), 7.95 (d, / = 9.6 Hz, 1H), 7.43-7.50 (m, 4H), 4.55 (d, / = 9.2 Hz, 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, / = 4.4 Hz, 4H), 0.96 (s, 9H). MS (ESI) m/z = 530.1 [M+H]+
Example 29: (2S,4/?)-l-((S)-2-(6-Aminohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 29)
Figure imgf000093_0003
Linker 29 was synthesized following the same procedures as Linker 25 as described in Example 25. (2.70 g, yield: 87% over 2 steps).‘H NMR (400 MHz, DMSCM6): 9.36 (s, 1H), 8.69 (t, J = 6.4 Hz, 1H), 8.12 (brs, 3H), 7.92 (d, J = 9.6 Hz, 1H), 7.44 (dd, J = 13.6, 8.4 Hz, 4H), 4.54 (d, / = 9.6 Hz, 1H), 4.48- 4.39 (m, 2H), 4.36 (brs, 1H), 4.28-4.19 (m, 1H), 3.72-3.60 (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]+.
Example 30: (2S,4/?)-l-((S)-2-(7-Aminoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4-
(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 30)
Figure imgf000094_0001
Linker 30 was synthesized following the same procedures as Linker 25 as described in Example 25. (2.13 g, yield: 76% over 2 steps).‘HNMR (400 MHz, DMSCM6): 9.45 (s, 1H), 8.70 (t, J = 6.0 Hz, 1H), 8.14 (brs, 3H), 7.86 (d, J = 9.2 Hz, 1H), 7.44 (dd, J = 12.8, 8.4 Hz, 4H), 4.54 (d, / = 9.2 Hz, 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]+.
Example 31: (2S,4/?)-l-((S)-2-(8-Aminooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 31)
Figure imgf000094_0002
Linker 31 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.81 g, yield: 65% over 2 steps).‘H NMR (400 MHz, DMSCM6): 9.35 (s, 1H), 8.69 (t, J = 6.0 Hz, 1H), 8.11 (brs, 3H), 7.88 (d, J = 9.2 Hz, 1H), 7.44 (dd, J = 14.0, 8.4 Hz, 4H), 4.54 (d, / = 9.6 Hz, 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]+.
Example 32: (2S,4/?)-l-((S)-2-(9-Aminononanamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 32)
Figure imgf000094_0003
Linker 32 was synthesized following the same procedures as Linker 25 as described in Example 25. (2.32 g, yield: 80% over 2 steps).‘HNMR (400 MHz, DMSCM6): 9.30 (s, 1H), 8.67 (t, J = 6.4 Hz, 1H),
8.10 (brs, 3 El), 7.88 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 14.0, 8.8 Hz, 4H), 4.55 (d, / = 9.2 Hz, 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]+.
Example 33: (2S,4/?)-l-((S)-2-(10-Aminodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 33)
Figure imgf000095_0001
Linker 33 was synthesized following the same procedures as Linker 25 as described in Example 25. (2.29 g, yield: 77% over 2 steps).‘HNMR (400 MHz, DMSCM6): 9.41 (s, 1H), 8.67 (t, J = 6.0 Hz, 1H), 8.14 (brs, 3H), 7.85 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 13.6, 8.8 Hz, 4H), 4.54 (d, / = 8.8 Hz, 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]+.
Example 34: (2S,4/?)-l-((S)-2-(ll-Aminoundecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-/V- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 34)
Figure imgf000095_0002
Linker 34 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.10 g, yield: 37% over 2 steps).‘HNMR (400 MHz, DMSCM6): 8.99 (s, 1H), 8.61 (t, J = 6.4 Hz, 1H), 7.87 (d, / = 8.8 Hz, 1H), 7.41 (dd, J = 17.6, 8.0 Hz, 4H), 4.55 (d, J = 9.6 Hz, 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]+.
Example 35: (2S,4/?)-l-((S)-2-(2-(2-Aminoethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy- /V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 35)
Figure imgf000096_0001
Linker 35 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.35 g, yield: 55% over 2 steps).‘HNMR (400 MHz, DMSO-dg) 9.23 (s, 1H), 8.70 (t, J = 6.0 Hz, 1H), 8.35-8.14 (m, 3H), 7.78 (d, J = 9.6 Hz, 1H), 7.47-7.38 (m, 4H), 4.61 (d, / = 9.6 Hz, 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]+
Example 36: (2S,4/?)-l-((S)-2-(3-(2-Aminoethoxy)propanamido)-3,3-dimethylbutanoyl)-4- hydroxy-/V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 36)
Figure imgf000096_0002
Linker 36 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.32 g, yield: 49% over 2 steps).‘HNMR (400 MHz, DMSO-dg) 8.99 (s, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.03 (d, / = 8 Hz, 1H), 7.85 (s, 3H), 7.43-7.37 (m, 4H), 4.57 (d, J = 9.2 Hz, 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]+.
Example 37: (2S,4/?)-l-((S)-2-(2-(2-(2-Aminoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-
4-hydroxy-A (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 37)
Figure imgf000096_0003
Linker 37 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.2 g, yield: 49% over 2 steps).‘HNMR (400 MHz, DMSO-d6) d 9.38 (s, 1H), 8.78 (t, J = 6.0 Hz, 1H), 8.18 (s, 3H), 7.59 - 7.37 (m, 5H), 4.58 (d, J = 9.6 Hz, 1H), 4.49 (t, J = 8.2 Hz, 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] + Example 38: (2S,4/?)-l-((S)-2-(3-(2-(2-Aminoethoxy)ethoxy)propanamido)-3,3- dimethylbutanoyl)-4-hydroxy-/V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker
38)
Figure imgf000097_0001
Linker 38 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.34 g, yield: 49% over 2 steps).1H NMR (400 MHz, DMSO-d6) 9.02 (s, 1H), 8.58 (t, / = 6.0 Hz, 1H), 7.94 (d, / = 8 Hz, 1H), 7.82 (s, 3H), 7.42-7.30 (m, 4H), 4.58 (d, J = 9.2 Hz, 1H), 4.60-4.37 (m, 3H), 4.25- 4.31 (m, 1H), 3.70-3.50 (m, 10H), 3.00-2.96 (m, 2H), 2.57-2.55 (m, 1H), 2.45(s, 3H), 2.41-2.38 (m, 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]+
Example 39: (2 ,47?)-l-(( )-14-Amino-2-(ieri-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4- hydroxy-/V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 39)
Figure imgf000097_0002
Linker 39 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.53 g, yield: 56% over 2 steps).‘HNMR (400 MHz, DMSO-d6) d 9.01 (s, 1H), 8.59 (t, / = 6.0 Hz, 1H), 7.81 (s, 3H), 7.48-7.41 (m, 5H), 4.58 (d, / = 9.6 Hz, 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]+
Example 40: (25,47?)- 1 -( (S)- 1 - Amino- 14-(/er/-butyl)- 12-oxo-3,6,9-trioxa- 13-azapentadecan- 15- oyl)-4-hydroxy-/V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 40)
Figure imgf000097_0003
Linker 40 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.52 g, yield: 51% over 2 steps).‘H NMR (400 MHz, DMSO-d6) d 9.01 (s, 1H), 8.57 (t, / = 6.0 Hz, 1H), 7.91 (d, / = 9.2 Hz, 1H), 7.81 (s, 3H), 7.44-7.38 (m, 4H), 4.58-4.55 (m, 1H), 4.45-4.36 (m, 3H), 4.25-4.21 (m, 1H), 3.70-3.48 (m, 14H), 3.00-2.97 (m, 2H), 2.59-2.52 (m, 1H), 2.46 (s, 3H ), 2.39-2.34 (m, 1H ), 2.08-2.03 (m, 1H), 1.95-1.88 (m, 1H), 0.94 (s, 9H). MS (ESI) m/z = 633.8 [M+H]+
Example 41: (25,47?)-l-((5)-l-Amino-17-(ieri-butyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecan- 18-oyl)-4-hydroxy-/V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Linker 41)
Figure imgf000098_0001
Linker 41 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.12 g, yield: 37% over 2 steps).‘HNMR (400 MHz, DMSO-d6) d 8.98 (s, 1H), 8.58 (t, / = 5.6 Hz, 1H), 7.92 (d, / = 9.2 Hz, 1H), 7.44 - 7.38 (m, 4H), 4.56 (d, J = 9.2 Hz, 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 = 5.6 Hz, 2H), 2.64 (t, / = 5.6 Hz, 2H ), 2.58 - 2.50 (m, 1H), 2.45 (s, 3H), 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]+
Example 42: (25,47?)-l-((5)-l-Amino-20-(ieri-butyl)-18-oxo-3,6,9,12,15-pentaoxa-19- azahenicosan-21-oyl)-4-hydroxy-/V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
(Linke
Figure imgf000098_0002
Linker 42 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.1 g, 1.52 mmol, yield: 32% over 2 steps).‘H NMR (400 MHz, DMSO-*) 9.38 (s, 1H), 8.67 (t, / = 16 Hz, 1H), 8.14 (br, 3H), 7.91 (d, / = 9.2 Hz, 1H), 7.39-7.48 (m, 4H), 4.53 (d, / = 9.2 Hz, 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]+
Example 43: 4-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-4-oxobutanoic acid (Linker 43)
Figure imgf000098_0003
Linker 43
A mixture of (2SAR)- 1 -((.S')-2-amino-3.3-dimethylbutanoyl)-4-hydroxy-/V-(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 rt for overnight. The mixture was concentrated. The residue was purified by flash chromatography (reversed-phase, MeCN/H20) to give the title compound Linker 43 (1.05 g, yield: 86%).‘HNMR (400 MHz, DMSO- ): d 12.02 (s, 1H), 8.99 (s, 1H), 8.58 (t, / = 6.0 Hz, 1H), 7.96 (d, / = 9.2 Hz, 1H), 7.43-7.37 (m, 4H), 5.13 (d, / = 3.6 Hz, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.46-4.40 (m, 2H), 4.34 (s, 1H), 4.21 (dd, J = 16.0, 5.2 Hz, 1H), 3.69-3.60 (m, 2H), 2.45 (s, 3H), 2.44-2.33 (m, 4H), 2.06-2.01 (m, 1H), 1.93-1.87 (m, 1H), 0.93 (s, 9H). 13C NMR (100 MHz, DMSO-d6): 173.83, 171.92, 170.86, 169.56, 151.41, 147.70, 139.48, 131.15, 129.63, 128.62, 127.41, 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]+
Example 44: 5-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-5-oxopentanoic acid (Linker 44)
Figure imgf000099_0001
Linker 44 was synthesized following the same procedures as Linker 43 as described in Example 43. (1.5 g, yield: 79%). l NMR (400 MHz, DMSO- ): d 8.99 ( s, 1H), 8.59 ( t, / = 6.0 Hz, 1H), 7.91 (d, / = 9.2 Hz, 1H), 7.44-7.37 (m, 4H), 5.16 (brs, 1H), 4.54 (d, J = 9.2 Hz, 1H), 4.47-4.42 (m, 2H), 4.36 (s, 1H), 4.21 (dd, / = 16.0, 5.2 Hz, 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). 13C NMR (100 MHz, DMSO-£6): d 174.18, 171.94, 171.63, 169.66, 151.41, 147.70, 139.46, 131.15, 129.61, 128.62, 127.41, 68.86, 58.69, 56.38, 41.65, 37.91, 35.16, 34.03, 33.10, 26.35, 20.89, 15.92. MS (ESI) m/z = 543.2 [M-H]- Example 45: 6-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-6-oxohexanoic acid (Linker
Figure imgf000099_0002
Figure imgf000099_0003
Linker 45 was synthesized following the same procedures as Linker 25 as described in Example 25. (1.2 g, yield: 55% over 2 steps). l NMR (400 MHz, CDC13) 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]+
Example 46: 7-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-7-oxoheptanoic acid (Linker 46)
Figure imgf000100_0001
Linker 46 was synthesized following the same procedures as Linker 45 as described in Example 45. (1.1 g, yield: 33% over 2 steps).‘HNMR (400 MHz, CDC13) 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 = 4.8 Hz, 15.2 Hz, 1H), 4.06-4.03 (m, 1H), 3.70- 3.68 (m, 1H), 2.46 (s, 3H), 2.31-2.11 (m, 6H), 1.55-1.51 (m, 4H), 1.29-1.24 (m, 2H), 0.94 (s, 9H). MS (ESI) m/z = 573.1 [M+H]+
Example 47: 8-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-8-oxooctanoic acid (Linker 47)
Figure imgf000100_0002
Linker 47 was synthesized following the same procedures as Linker 45 as described in Example 45. (1.08 g, yield: 52% over 2 steps).‘HNMR (400 MHz, DMSO-d6) 8.99 (s, 1H), 8.55 (t, / = 2.4 Hz, 1H), 7.83 (d, / = 9.2 Hz, 1H), 7.44-7.38 (m, 4H), 4.55 (d, J = 9.6 Hz, 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]+
Example 48: 9-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-9-oxononanoic acid (Linker
Figure imgf000100_0003
Figure imgf000100_0004
Linker 48 was synthesized following the same procedures as Linker 45 as described in Example 45. (1.16 g, yield: 44% over 2 steps).‘HNMR (400 MHz, CDC13) 8.70 (s, 1H), 7.55 (s, 1H), 7.33-7.27 (m, 4H), 7.08 (d, / = 8.0 Hz, 1H), 4.68-4.52 (m, 4H), 4.31-4.27 (m, 1H), 4.08-4.05 (m, 1H), 3.69-3.67 (m, 1H), 2.48 (s, 3H), 2.33-2.11 (m, 6H), 1.60-1.47 (m, 4H), 1.29-1.20 (m, 6H), 0.96 (s, 9H). MS (ESI) m/z = 601.1 [M+H]+ Example 49: 10-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-10-oxodecanoic acid (
Figure imgf000101_0001
Linker 49
Linker 49 was synthesized following the same procedure as Linker 45 as described in Example 45. (1.1 g, yield: 35%). ¾ NMR (400 MHz, DMSO-dg): 8.99 ( s, 1H), 8.58 ( t, / = 6.0 Hz, 1H), 7.85 (d, / = 9.2 Hz, 1H), 7.43-7.37 (m, 4H), 4.54 (d, / = 9.2 Hz, 1H), 4.47-4.41 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J = 16.0, 5.6 Hz, 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). 13C NMR (100 MHz, DMSO- ): d 172.07, 171.92, 169.69, 151.41, 147.70, 139.48, 131.14, 129.62, 128.61, 127.40, 68.84, 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]+
Example 50: ll-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-ll-oxoundecanoic acid (Linker 50)
Figure imgf000101_0002
Linker 50 was synthesized following the same procedure as Linker 45 as described in Example 45. (1.1 g, yield: 50%). lH NMR (400 MHz, DMSO- ): £ 8.99 (s, 1H), 8.58 ( t, / = 6.0 Hz, 1H), 7.85 (t, / = 9.2 Hz, 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 (100 MHz, DMSO- 6): £174.59, 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]+
Example 51: 3-(3-(((5)-l-((25,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-3- oxopropoxy)propanoic acid (Linker 51)
Figure imgf000101_0003
Linker 51
Linker 51 was synthesized following the same procedure as Linker 45 as described in Example 45. (1.1 g, yield: 42%).‘H NMR (400 MHz, DMSO-d6) 8.98 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.91 (d, / = 9.2 Hz, 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]+
Example 52: 2-(2-(((5)-l-((25,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-2-oxoethoxy)acetic acid
(Linker 52)
Figure imgf000102_0001
Linker 52 was synthesized following the same procedure as Linker 43 as described in Example 43. (1.2 g, yield: 63%). lH NMR (400 MHz, DMSO-d6) 12.81 (br s, 1H), 8.98 (s, 1H), 8.58 (t, / = 6.0 Hz, 1H), 7.60 (d, / = 9.6 Hz, 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]+
Example 53: 3-(2-(3-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-3- oxopropoxy)ethoxy)propanoic acid (Linker 53)
Figure imgf000102_0002
Linker 53 was synthesized following the same procedures as Linker 45 as described in Example 45. (1.4 g, yield 23% over 2 steps).‘HNMR (400 MHz, DMSO- ): 8.98 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H),
7.91 (d, / = 9.2 Hz, 1H), 7.43-7.37 (m, 4H), 4.55 (d, J = 9.6 Hz, 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]+ Example 54: 2-(2-(2-(((S)-l-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-2- oxoethoxy)ethoxy)acetic acid (Linker 54)
Figure imgf000102_0003
Linker 54 was synthesized following the same procedures as Linker 53 as described in Example 53. (1.13 g, yield 20% over 2 steps). ¾ NMR (400 MHz, DMSO- ): 8.98 (s, 1H), 8.60 (t, / = 6.0 Hz, 1H), 7.49 (d, / = 9.2 Hz, 1H), 7.40 (s, 4H), 4.57 (d, J = 9.2 Hz, 1H), 4.47-4.36 (m, 3H), 4.28-4.23 (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]+
Example 55: (S)-15-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14- azaheptadecanoic acid (Linker 55)
Figure imgf000103_0001
Linker 55 was synthesized following the same procedure as Linker 45 as described in Example 45. (1.7 g, yield 37%). ¾ NMR (400 MHz, DMSO- ): 8.99 (s, 1H), 8.56 (t, / = 6.0 Hz, 1H), 7.91 (d, / = 9.6
Hz, 1H), 7.44-7.38 (m, 4H), 4.56 (d, / = 9.2 Hz, 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 [M-H]-
Example 56: (S)-13-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-14,14-dimethyl-ll-oxo-3,6,9-trioxa-12- azapentadecanoic acid (Linker
Figure imgf000103_0003
Figure imgf000103_0002
Figure imgf000103_0004
Linker 56 was synthesized following the same procedures as Linker 45 as described in Example 45. (1.21 g, yield 31% over 2 steps). l NMR (400 MHz, CDC13): d 8.68 (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]+
Example 57: (S)-18-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-19,19-dimethyl-16-oxo-4,7,10,13-tetraoxa-17- azaicos
Figure imgf000103_0005
Linker 57 was synthesized following the same procedure as Linker 45 as described in Example 45. (1.6 g, yield 43%). lH NMR (400 MHz, CDC13): d 8.69 (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]+
Example 58: (S)-21-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-22,22-dimethyl-19-oxo-4,7,10,13,16-pentaoxa-20- azatricosanoic acid (Linker 58)
Figure imgf000104_0001
Linker 58 was synthesized following the same procedure as Linker 45 as described in Example 45. (1.2 g, yield: 23%).‘H NMR (400 MHz, DMSO-d6) 8.98 (s, 1H), 8.57 (t, / = 6.0 Hz, 1H), 7.91 (d, / = 9.6 Hz, 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), 3.69-3.55 (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]+
Example 59: (S)-19-((2S,4/?)-4-Hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-20,20-dimethyl-17-oxo-3,6,9,12,15-pentaoxa-18- azahenicosanoic acid (Linker 59)
Figure imgf000104_0002
Linker 59 was synthesized following the same procedure as Linker 45 as described in Example 45. (1.3 g, yield: 39%).‘H NMR (400 MHz, DMSO-d6) 8.98 (s, 1H), 8.69 (t, / = 6.0 Hz, 1H), 7.45 (d, / = 9.6 Hz, 1H), 7.43-7.37 (m, 4H), 4.57-4.55 (m, 1H), 4.47-4.34 (m, 3H), 4.27-4.22 (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]+
Example 60: 5-((2-(2-Aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione (Linker 60)
Figure imgf000104_0003
A mixture of 5-fluoroisobenzofuran-l,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 down 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 afford a solid which was dried in vacuum to give 2-(2,6- dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (120 g, yield: 83%) as a yellow solid. MS (ESI) m/z = 277.1 [M+H]+
A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,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 microwave reactor for 50 min. After cooling down to room temperature, the mixture was poured into EtOAc (200 mL), washed with water (200 mL x 2) and brine (200 mL). The organic phase was dried over anhydrous NaaSCL, filtered and concentrated to give a crude product which was purified by chromatography on silica gel (petroleum ether / EtOAc = 2 : 1 to 1 : 2 ) to give tert- butyl (2- (2-((2-(2,6-dioxopiperidin-3-yl)-l,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]+
To a solution of tert- butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,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 hrs, and concentrated to dry. The residue was dissolved in water (20 mL), washed with EtOAc (40 mL) and methyl tertiary-butyl ether (MTBE) (40 mL). The aqueous phase was lyophilized to afford TFA salt of 5-((2-(2- aminoethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl) isoindoline-l,3-dione (1.9 g, yield: 77%) as a yellow solid. MS (ESI) m/z = 361.1 [M+H]+. H NMR (400 MHz, DMSO- ) d 11.06 (s, 1H), 8.01 (s, 3H),
7.58 (d, / = 8.4 Hz, 1H), 7.12 (br, s, 1H), 7.02 (d, / = 2.0 Hz, 1H), 6.91 (dd, / = 2.0 Hz, 8.8 Hz, 1H), 5.04 (dd, / = 5.6 Hz, 13.2 Hz, 1H), 3.64 (t, / = 5.6 Hz, 4H), 3.40 (t, / = 5.2 Hz, 2H), 3.01 (br, 2H), 2.89 - 2.83 (m, 1H), 2.60 - 2.50 (m, 2H), 2.03 - 1.97 (m, 1H).
Example 61 : 5-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (Linker 61)
Figure imgf000105_0001
Linker 61 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.4 g, yield: 71%). MS (ESI) m/z = 405.1 [M+H]+. 1H NMR (400 MHz, DMSO- ) d 11.05 (s, 1H), 7.94
(br, 3H), 7.56 (d, / = 8.4 Hz, 1H), 7.01 (s, 1H), 6.90 (d, / = 8.0 Hz, 1H), 5.03 (dd, / = 5.2 Hz, 12.8 Hz, 1H), 3.58 (br, 8H), 3.36 (s, 2H), 2.97 - 2.92 (m, 2H), 2.91 - 2.83 (m, 1H), 2.60 - 2.50 (m, 2H), 2.01 - 1.99 (m, 1H).
Example 62: 5-((2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (Linker 62)
Figure imgf000105_0002
Linker 62 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.19 g, yield: 59%). MS (ESI) m/z = 449.1 [M+H]+. lH NMR (400 MHz, DMSO- ) d 11.05 (s, 1H), 7.79
(br, 3H), 7.57 (d, / = 8.4 Hz, 1H), 7.15 (br, s, 1H), 7.00 (d, / = 2.0 Hz, 1H), 6.90 (dd, / = 2.0 Hz, 8.4 Hz, 1H), 5.03 (dd, / = 5.6 Hz, 12.8 Hz, 1H), 3.61 - 3.55 (m, 12H), 3.36 (t, / = 5.6 Hz, 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).
Example 63: 5-((14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (Linker 63)
Figure imgf000105_0003
Linker 63 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.2 g, yield: 73%). MS (ESI) m/z = 493.1 [M+H]+. 1H NMR (400 MHz, DMSO- ) d 11.05 (s, 1H), 7.79 (br, / = 1.6 Hz, 3H), 7.56 (d, / = 8.4 Hz, 1H), 7.14 (br, s, 1H), 7.01 (d, / = 2.0 Hz, 1H), 6.90 (dd, / = 2.0 Hz, 8.4 Hz, 1H), 5.03 (dd, / = 5.6 Hz, 13.2 Hz, 1H), 3.61 - 3.56 (m, 16H), 3.36 (t, J = 5.2 Hz, 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).
Example 64: 5-((17-Amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (Linker 64)
Figure imgf000106_0001
Linker 64 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.73 g, yield: 88%). MS (ESI) m/z = 537.2 [M+H]+. lH NMR (400 MHz, DMSCMg) d 11.05 (s, 1H), 7.79 (s, 3H), 7.55 (d, / = 8.4 Hz, 1H), 7.18 (br, s, 1H), 7.01 (s, 1H), 6.90 (d, / = 8.4 Hz, 1H), 5.03 (dd, / = 5.2 Hz, 12.8 Hz, 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).
Example 65: (2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)glycine (Linker 65)
Figure imgf000106_0002
Linker 65 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.0 g, yield: 84%). MS (ESI) m/z = 332.0 [M+H]+. lH NMR (400 MHz, DMSO- ) d 12.80 (br, 1H),
11.06 (s, 1H), 7.59 (d, / = 8.4 Hz, 1H), 7.32 (br, s, 1H), 6.98 (d, / = 1.2 Hz, 1H), 6.89 (dd, / = 2.0 Hz, 8.4 Hz, 1H), 5.04 (dd, / = 5.6 Hz, 13.2 Hz, 1H), 4.03 (s, 2H), 2.92 - 2.83 (m, 1H), 2.60 - 2.52 (m, 2H), 2.03 - 1.98 (m, 1H).
Example 66: 3-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)propanoic acid (Linker 66)
Figure imgf000106_0003
Linker 66 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.24 g, yield: 60%). MS (ESI) m/z = 346.0 [M+H]+. lH NMR (400 MHz, DMSCMg) d 11.05 (s, 1H), 7.57
(d, / = 8.4 Hz, 1H), 6.97 (d, / = 2.0 Hz, 1H), 6.87 (dd, / = 2.0 Hz, 8.4 Hz, 1H), 5.02 (dd, / = 5.2 Hz, 12.8 Hz, 1H), 3.41 (t, / = 6.8 Hz, 2H), 2.89 - 2.83 (m, 1H), 2.60 - 2.52 (m, 4H), 2.02 - 1.97 (m, 1H).
Example 67: 4-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino) butanoic acid (Linker 67)
Figure imgf000106_0004
Linker 67 was synthesized following the same procedure as Linker 60 as described in Example 60. (0.52 g, yield: 25%). MS (ESI) m/z = 360.1 [M+H]+. lH NMR (400 MHz, DMSCMg) d 12.12 (s, 1H),
11.05 (s, 1H), 7.55 (d, / = 8.4 Hz, 1H), 7.14 (t, J = 4.8 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 5.02 (dd, / = 5.6 Hz, 12.8 Hz, 1H), 3.21 - 3.16 (m, 2H), 2.91 - 2.83 (m, 1H), 2.60 - 2.51 (m, 2H), 2.34 (t, J = 7.2 Hz, 2H), 2.01 - 1.97 (m, 1H), 1.82 - 1.75 (m, 2H).
Example 68: 5-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)pentanoic acid (Linker 68)
Figure imgf000106_0005
Linker 68 was synthesized following the same procedure as Linker 60 as described in Example 60.
(0.66 g, yield: 51%). MS (ESI) m/z = 374.1 [M+H]+. ¾ NMR (400 MHz, DMSO-ifc) d 12.03 (br, 1H), 11.05 (s, 1H), 7.55 (d, / = 8.4 Hz, 1H), 7.10 (t, / = 5.2 Hz, 1H), 6.94 (s, 1H), 6.83 (dd, / = 1.6 Hz, 8.4 Hz, 1H), 5.02 (dd, / = 5.6 Hz, 12.8 Hz, 1H), 3.17 - 3.16 (m, 2H), 2.92 - 2.83 (m, 1H), 2.60 - 2.53 (m, 2H), 2.26 - 2.25 (m, 2H), 2.01 - 1.98 (m, 1H), 1.60 - 1.59 (m, 4H).
Example 69: 6-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)hexanoic acid (Linker 69)
Figure imgf000107_0001
Linker 69 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.33 g, yield: 66%). MS (ESI) m/z = 388.1 [M+H]+. lH NMR (400 MHz, DMSCM6) d 11.98 (s, 1H),
11.05 (s, 1H), 7.55 (d, / = 8.4 Hz, 1H), 7.08 (t, / = 5.2 Hz, 1H), 6.95 (s, 1H), 6.83 (dd, / = 1.2 Hz, 8.4 Hz, 1H), 5.03 (dd, / = 5.2 Hz, 12.8 Hz, 1H), 3.17 - 3.12 (m, 2H), 2.92 - 2.83 (m, 1H), 2.60 - 2.53 (m, 2H), 2.22 (t, J= 7.2 Hz, 2H), 2.01 - 1.98 (m, 1H), 1.61 - 1.51 (m, 4H), 1.41 - 1.33 (m, 2H).
Example 70: 7-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)heptanoic acid (Linker 70)
Figure imgf000107_0002
Linker 70 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.06 g, yield: 39%). MS (ESI) m/z = 402.1 [M+H]+. lH NMR (400 MHz, DMSO- ) d 11.94 (s, 1H), 11.04 (s, 1H), 7.55 (d, / = 8.4 Hz, 1H), 7.09 (t, / = 5.6 Hz, 1H), 6.94 (d, / = 2.0 Hz, 1H), 6.84 (dd, / = 2.0 Hz, 8.4 Hz, 1H), 5.02 (dd, / = 5.6 Hz, 13.2 Hz, 1H), 3.17 - 3.12 (m, 2H), 2.88 - 2.83 (m, 1H), 2.60 - 2.53 (m, 2H), 2.21 (t, J= 7.2 Hz, 2H), 2.01 - 1.97 (m, 1H), 1.58 - 1.48 (m, 4H), 1.39 - 1.29 (m, 4H).
Example 71: 8-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)octanoic acid
(Linker 71)
Figure imgf000107_0003
Linker 71 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.66 g, yield: 51%). MS (ESI) m/z = 416.1 [M+H]+. 1H NMR (400 MHz, DMSCMg) d 11.95 (s, 1H), 11.05 (s, 1H), 7.55 (d, / = 8.4 Hz, 1H), 7.09 (t, / = 5.6 Hz, 1H), 6.94 (d, / = 2.0 Hz, 1H), 6.84 (dd, / = 2.0 Hz, 8.4 Hz, 1H), 5.02 (dd, / = 5.6 Hz, 13.2 Hz, 1H), 3.17 - 3.12 (m, 2H), 2.88 - 2.83 (m, 1H), 2.60 - 2.53 (m, 2H), 2.19 (t, J= 7.2 Hz, 2H), 2.02 - 1.98 (m, 1H), 1.58 - 1.47 (m, 4H), 1.36 - 1.29 (m, 6H).
Example 72: 5-((2-Aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker 72)
Figure imgf000107_0004
Linker 72 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.74 g, yield: 80%). MS (ESI) m/z = 317.1 [M+H]+. lH NMR (400 MHz, DMSO- ) d 11.08 (s, 1H), 8.10 (s, 3H), 7.62 (d, / = 8.4 Hz, 1H), 7.33 (t, J= 5.2 Hz, 1H), 7.05 (s, 1H), 6.94 (d, / = 8.0 Hz, 1H), 5.07 (dd, / = 5.2 Hz, 12.8 Hz, 1H), 3.50 - 3.49 (m, 2H), 3.03 (t, / = 6.0 Hz, 2H), 2.95 - 2.86 (m, 1H), 2.63 - 2.57 (m, 2H), 2.05 - 2.02 (m, 1H).
Example 73: 5-((3-Aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker 73)
Figure imgf000108_0001
Linker 73 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.3 g, yield: 57%). MS (ESI) m/z = 331.1 [M+H]+. lH NMR (400 MHz, DMSO-ifc) d 11.07 (s, 1H), 7.85 (br, 3H), 7.59 (d, / = 8.4 Hz, 1H), 7.22 (t, / = 5.2 Hz, 1H), 6.98 (d, / = 2.0 Hz, 1H), 6.88 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 5.04 (dd, / = 5.6 Hz, 13.2 Hz, 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).
Example 74: 5-((4-Aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker
74)
Figure imgf000108_0002
Linker 74 was synthesized following the same procedure as Linker 60 as described in Example 60. (2.9 g, yield: 85%). MS (ESI) m/z = 345.1 [M+H]+. lH NMR (400 MHz, DMSO-ifc) d 11.08 (s, 1H), 7.97 (br, 3H), 7.58 (d, / = 8.4 Hz, 1H), 7.22 (br, s, 1H), 6.99 (s, 1H), 6.89 (d, / = 8.0 Hz, 1H), 5.05 (dd, J = 5.2 Hz, 12.8 Hz, 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).
Example 75: 5-((5-Aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker 75)
Figure imgf000108_0003
Linker 75 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.8 g, yield: 78%). MS (ESI) m/z = 359.1 [M+H]+. lH NMR (400 MHz, DMSO-ifc) d 11.09 (s, 1H), 7.89 (br, 3H), 7.57 (d, / = 6.8 Hz, 1H), 7.17 (br, s, 1H), 6.96 (s, 1H), 6.86 (d, / = 6.0 Hz, 1H), 5.05 (d, J = 7.2 Hz, 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).
Example 76: 5-((6-Aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker
76)
Figure imgf000108_0004
Linker 76 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.8 g, yield: 62%). MS (ESI) m/z = 373.1 [M+H]+. lH NMR (400 MHz, DMSO- ) d 11.05 (s, 1H), 7.71 (br, 3H), 7.57 (d, / = 8.4 Hz, 1H), 7.12 (t, / = 5.2 Hz, 1H), 6.94 (d, / = 2.0 Hz, 1H), 6.85 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 5.03 (dd, / = 5.2 Hz, 12.8 Hz, 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).
Example 77 : 5-((7-Aminoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker 77)
Figure imgf000108_0005
Linker 77 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.3 g, yield: 70%). MS (ESI) m/z = 387.1 [M+H]+. lH NMR (400 MHz, DMSO- ) d 11.05 (s, 1H), 7.72 (br, 3H), 7.56 (d, / = 8.4 Hz, 1H), 7.12 (t, / = 5.6 Hz, 1H), 6.94 (d, / = 2.0 Hz, 1H), 6.85 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 5.03 (dd, / = 5.6 Hz, 12.8 Hz, 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).
Example 78: 5-((8-Aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (Linker 78)
Figure imgf000109_0001
Linker 78 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.6 g, yield: 62%). MS (ESI) m/z = 401.1 [M+H]+. 1H NMR (400 MHz, DMSCMg) d 11.05 (s, 1H), 7.73 (br, 3H), 7.56 (d, / = 8.4 Hz, 1H), 7.14 (br, 1H), 6.94 (d, J= 1.6 Hz, 1H), 6.85 (dd, J= 2.0 Hz, 8.8 Hz,
1H), 5.03 (dd, / = 5.6 Hz, 12.8 Hz, 1H), 3.15 (t, / = 7.2 Hz, 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).
Example 79: 3-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)propanoic acid (Linker 79)
Figure imgf000109_0002
Linker 79 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.7 g, yield: 60%). MS (ESI) m/z = 390.1 [M+H]+. lH NMR (400 MHz, DMSO- ) d 12.19 (br, 1H), 11.06 (s, 1H), 7.57 (d, / = 8.4 Hz, 1H), 7.09 (br, 1H), 7.01 (d, / = 2.0 Hz, 1H), 6.90 (dd, / = 2.0 Hz, 8.4 Hz, 1H), 5.04 (dd, / = 5.6 Hz, 13.2 Hz, 1H), 3.66 (t, / = 6.4 Hz, 2H), 3.59 (t, J= 5.6 Hz, 2H), 3.35 (t, J = 5.2 Hz, 2H), 2.93 - 2.84 (m, 1H), 2.62 - 2.56 (m, 2H), 2.52 - 2.47 (m, 2H), 2.03 - 1.99 (m, 1H).
Example 80: 3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)propanoic acid (Linker 80)
Figure imgf000109_0003
Linker 80 was synthesized following the same procedure as Linker 60 as described in Example 60. (2.3 g, yield: 78%). MS (ESI) m/z = 434.1 [M+H]+. lH NMR (400 MHz, DMSO- ) d 11.06 (s, 1H), 7.57 (d, / = 8.4 Hz, 1H), 7.02 (d, / = 2.0 Hz, 1H), 6.90 (dd, / = 2.0 Hz, 8.4 Hz, 1H), 5.04 (dd, / = 5.6 Hz, 13.2 Hz, 1H), 3.63 - 3.59 (m, 4H), 3.57 - 3.51 (m, 4H), 3.36 (t, / = 5.6 Hz, 2H), 2.90 - 2.84 (m, 1H), 2.61 - 2.55 (m, 2H), 2.44 (t, / = 6.4 Hz, 2H), 2.04 - 1.99 (m, 1H).
Example 81: 3-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid (Linker 81)
Figure imgf000109_0004
Linker 81 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.2 g, yield: 52%). MS (ESI) m/z = 478.1 [M+H]+. lH NMR (400 MHz, DMSO-< 6) d 7.59 (d, / = 11.2 Hz, 1H), 7.23 (t, / = 6.8 Hz, 1H), 7.04 (d, / = 1.6 Hz, 1H), 7.04 (dd, / = 2.4 Hz, 11.2 Hz, 1H), 5.06 (dd, / =
7.2 Hz, 16.8 Hz, 1H), 3.64 - 3.57 (m, 8H), 3.54 - 3.48 (m, 4H), 3.40 - 3.38 (m, 2H), 2.92 - 2.89 (m, 1H), 2.64 - 2.54 (m, 2H), 2.42 - 2.38 (m, 2H), 2.05 - 2.01 (m, 1H). Example 82: l-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)-3,6,9,12- tetraoxapentadecan-15-oic acid (Linker 82)
Figure imgf000110_0001
Linker 82 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.3 g, yield: 55%). MS (ESI) m/z = 522.1 [M+H]+. lH NMR (400 MHz, DMSCMg) d 12.17 (br, 1H),
11.07 (s, 1H), 7.56 (d, / = 8.4 Hz, 1H), 7.17 (t, / = 5.6 Hz, 1H), 7.01 (d, / = 1.2 Hz, 1H), 6.90 (dd, / = 1.6 Hz, 8.4 Hz, 1H), 5.03 (dd, / = 5.6 Hz, 12.8 Hz, 1H), 3.61-3.48 (m, 18H), 2.92-2.83 (m, 1H), 2.60- 2.54 (m, 2H), 2.43 (t, J = 6.4 Hz, 2H), 2.03-1.98 (m, 1H).
Example 83: l-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)-3,6,9,12,15- pentaoxaoctadecan-18-oic acid (Linker 83)
Figure imgf000110_0002
Linker 83 was synthesized following the same procedure as Linker 60 as described in Example 60. (1.0 g, yield: 50%). MS (ESI) m/z = 566.1 [M+H]+. lH NMR (400 MHz, DMSO-ifc) d 12.17 (br, s, 1H), 11.07 (s, 1H), 7.56 (d, / = 8.0 Hz, 1H), 7.17 (t, / = 5.6 Hz, 1H), 7.01 (s, 1H), 6.90 (dd, / = 1.6 Hz, 8.4 Hz, 1H), 5.03 (dd, / = 5.6 Hz, 13.2 Hz, 1H), 3.60 - 3.48 (m, 22H), 2.89-2.83 (m, 1H), 2.60-2.54 (m, 2H), 2.43 (t, / = 6.4 Hz, 2H), 2.01-1.98 (m, 1H).
Procedures for the synthesis of P300 binders for P300 PROTACs
Example 84. Synthesis of 3-(7-(difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4- dihydroquinolin-l(2/7)-yl)-/V-methyl-l-(piperidin-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3- c]pyridine-5-carboxamide (P300 binder 1)
Figure imgf000110_0003
Step 1: Synthesis of quinoline-7-carbaldehyde
Figure imgf000111_0001
To a solution of 7-methylquinoline (235.0 g, 1.64 mol) at 160 °C was added SeC>2 (220 g, 1.97 mol) portionwise over 25 min. The mixture was stirred at 160 °C for 8 h. After cooling to room temperature, DCM (2000 mL) was added and the mixture was filtered through a pad of Celite. The organic layer was concentrated in vacuo and the crude residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10: 1) to give quinoline -7-carbaldehyde (100 g, yield: 38%) as a yellow solid.
Step 2: Synthesis of 7-(difluoromethyl)quinoline
Figure imgf000111_0002
To a cooled (0 °C) solution of quinoline-7-carbaldehyde (35.0 g, 223 mmol) in DCM (400 mL) was adde diethylaminosulfurtrifluoride (162.0 g, 1150 mmol) dropwise over 30 min. The mixture was stirred at room temperature for 16 h, before being poured into sat. aq NaHC03(2 L) at 0 °C and extracted with DCM (400 mLx2). The combined organic layers were dried over anhydrous NaaSCL, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5: 1) to give 7-(difluoromethyl)quinolone (26.0 g, yield: 65%) as a yellow oil.
Step 3: Synthesis of 7-(difluoromethyl)-l,2,3,4-tetrahydroquinoline
Figure imgf000111_0003
To a cooled (0 °C) solution of 7-(difluoromethyl)quinolone (26.0 g, 72.6 mmol) and NaBH3CN (46.1 g, 726 mmol) in MeOH (300 mL) was added boron trifluoride diethyl etherate (41.2 g, 290 mmol) dropwise over 20 min. The mixture was heated to 90 °C for 24 h. After cooling to room temperature, the mixture was poured into sat. aq. NaHCCL (2 L) at 0 °C and extracted with DCM (500 mLx2). The combined organic layers were dried overNaaSCL, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20: 1) to give 7-(difluoromethyl)- 1,2,3,4-tetrahydroquinoline (13.0 g, yield: 49%) as a brown oil.
Step 4: Synthesis of 6-bromo-7-(difluoromethyl)-l,2,3,4-tetrahydroquinoline
Figure imgf000111_0004
To a solution of 7-(difluoromethyl)-l,2,3,4-tetrahydroquinoline (29.0 g, 158.5 mmol) in DCM (600 mL) at 0 °C was added /V-b ro m o s iicci n i m i de (6.90 g, 38.3 mmol) portionwise over 20 min. The mixture was stirred at room temperature for 16 h, then poured into water (100 mL) and extracted with DCM (400 mLx2). The combined organic layers were dried over NaaSCL, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether/EtOAc = 300: 1) to give 6- bromo-7-(difhioromethyl)-l,2,3,4-tetrahydroquinoline (22.0 g, yield: 52.8%) as a white solid. 1HNMR (400 MHz, CDCI3) d 7.12 (s, 1H), 6.77 (t, / = 55.2 Hz, 1H), 6.77 (s, 1H), 4.01 (s, 1H), 3.30 (t, / = 6.4 Hz, 2H), 2.74 (t, J= 6.0 Hz, 2H), 1.94-1.88 (m, 2H).
Step 5: Synthesis of 7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-l,2,3,4-tetrahydroquinoline
Figure imgf000111_0005
To a solution of 6-bromo-7-(difluoromethyl)-l,2,3,4-tetrahydroquinoline (2 g, 7.66 mmol) and 1- methyl-4-(4.4.5.5-tetramethyl- 1 3.2-dioxaborolan-2-yl)- 1 //-pyrazole (1.59 g, 7.66 mmol) in 1,4-dixoane (50 mL) were added Pd(dppf)Cl2 (1.6 g, 2.3 mmol), K2C03 (2.11 g, 15.32 mmol). The reaction mixture was heated to 95 °C overnight, then diluted in ethyl acetate, washed with water and brine. The organic layer was concentrated in vacuo and the residue was purified by column (petroleum ether: ethyl acetate = 5: 1) to afforded 7-(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)- 1.2.3.4-tetrahydroquinoline (1.4 g, yield: 69%) as a white solid. MS (ESI) m/z: 264.4 [M+H]+.
Step 6: Synthesis of tert- butyl 4.3 -r |pyridinc-5-carboxylatc
Figure imgf000112_0001
To a solution of tert- butyl l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxylate (10 g, 44.84 mmol) in DMF (100 mL) were added I2 (22.76 g, 89.68 mmol) and KOH (10.04 g, 179.36 mmol). The resulting mixture was stirred at 50 °C overnight. The reaction was quenched with aq. Na2S03 and extracted with EtOAc. The organic layer was dried over Na2S04. filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether : EtOAc =3: 1) to give desired product (8.0 g, yield: 51%) as a colorless oil. MS (ESI) m/z: 350.2 [M+H]+.
Step 7: Synthesis of tert- butyl l-(l-((benzyloxy)carbonyl)piperidin-4-yl)-3-iodo-l,4,6,7-tetrahydro- 5//-pyrazolo [4,3 -c]pyridine-5 -carboxylate
Cbz
Figure imgf000112_0002
To a solution of tert- butyl 3-iodo- 1 4.6.7-tc
Figure imgf000112_0003
-carboxylatc (6 g, 17.19 mmol) in DMF (50 mL) were added benzyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (8.07 g, 25.79 mmol) and K2CO3 (4.74 g, 34.38 mmol). The resulting mixture was stirred at 100°C overnight. After cooling to room temperature, the mixture was diluted with water, extracted with EtOAc. The combined organic phase was washed with brine, dried over Na S04, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether : EtOAc =1: 1) to give desired product (4.0 g, yield: 41%) as a white solid. MS (ESI) m/z: 567.4 [M+H]+.
Step 8: Synthesis of tert- butyl l-(l-((benzyloxy)carbonyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(l- methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2 /)-yl)- 1.4.6.7-tetrahydro-5 /-pyrazolo|4.3-r|pyridine-5- carboxylate
Figure imgf000112_0004
To a solution of tert- butyl l-(l-((benzyloxy)carbonyl)piperidin-4-yl)-3-iodo-l,4,6,7-tetrahydro-5//- pyrazolo[4,3-c]pyridine-5-carboxylate (132 mg, 0.233 mmol) and 7-(difluoromethyl)-6-( 1 -methyl- 1 H- pyrazol-4-yl)-l,2,3,4-tetrahydroquinoline (74 mg, 0.280 mmol) in dioxane (3 mL) were added RuPhos Pd G1 (22.8 mg, 0.028 mmol), RuPhos (13.0 mg, 0.028 mmol) and lBuONa (78.3 mg, 0.816 mmol). The resulting mixture was stirred at reflux overnight. The reaction mixture was purified by reverse phase flash chromatography to give desired product (80 mg, yield: 49%) as a white solid. MS (ESI) m/z :703.1
[M+H]+.
Step 9: Synthesis of benzyl 4-(3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidine- 1 -carboxylate
Figure imgf000113_0001
The mixture of tert- butyl l-(l-((benzyloxy)carbonyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(l- methyl-l//-pyrazol-4-yl)-3,4-dihydroquinolin-l(2//)-yl)-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5- carboxylate (189 mg, 0.27 mmol) in DCM:TFA=1 : 1 (10 ml) was stirred at room temperature for 3 h, before it was concentrated. The residue was used directly in the next step.
Step 10: Synthesis of benzyl 4-(3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-5 -(methylcarbamoyl)-4, 5 ,6,7-tetrahydro- 1 //-pyrazolo [4,3 -c]pyridin- 1 - yl)piperidine- 1 -carboxylate
Figure imgf000113_0002
To the solution of benzyl 4-(3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4, 5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidine- 1 -carboxylate (crude product from above reaction) in DCM (10 ml) were added 2,5-dioxopyrrolidin-l-yl
methylcarbamate (141 mg, 0.81 mmol) and TEA (82 mg, 0.81 mmol). The resulting mixture was stirred at room temperature for 5 h, before the reaction mixture was purified by reverse phase flash chromatography to give desired product (105 mg, yield: 59%) as a white solid. MS (ESI) m/z: 659.9 [M+H]+.
Step 11: Synthesis of 3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-/V-methyl- 1 -(piperidin-4-yl)- 1 ,4,6, 7-tetrahydro-5//-pyrazolo [4,3 -c]pyridine-5 -carboxamide (P300 binder 1)
Figure imgf000113_0003
The mixture of benzyl 4-(3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4-dihydroquinolin- 1 (2//)-yl)-5 -(methylcarbamoyl)-4, 5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidine- 1 - carboxylate (105 mg, 0.16 mmol) and Pd/C (10 %, 100 mg) in MeOH (10 ml) was stirred under H for 8 h. The reaction mixture was filtered through celite and the filtrate was concentrated to give desired product (56 mg, yield: 67%) as a white solid. MS (ESI) m/z: 525.8 [M+H]+.
Example 85. Synthesis of 2-(4-(7-(difluoromethyl)-l-(5-(methylcarbamoyl)-l-(tetrahydro-2/7- pyran-4-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-eJpyridin-3-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-l/7- pyrazol-l-yl)acetic acid (P300 binder 2)
Figure imgf000114_0001
Step 1: Synthesis of tert- butyl 2-(4-(4.4.5.5-tctramcthyl- 1.3.2-dioxaborolan-2-yl)- 1 //-pyrazol- 1 - yl)acetate
Figure imgf000114_0002
The mixture of 4-(4.4.5.5-tetramethyl- 1 3.2-dioxaborolan-2-yl)- 1 //-pyrazole (2.0 g, 10.31 mmol), tert- butyl 2-bromoacetate (2.21 g, 11.34 mmol) and K2CO3 (1.71g, 12.37 mmol) in acetone (20 ml) was stirred at 65 °C overnight. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na S04, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EA=5: 1) to give desired product (1.7 g, yield: 54%) as an oil. MS (ESI) m/z: 309.2 [M+H]+.
Step 2: Synthesis of tert- butyl 2-(4-(7-(difluoromethyl)- 1 2.3.4-tctrahydroquinolin-6-yl)- 1 //-pyrazol- l-yl)acetate
Figure imgf000114_0003
To a solution of 6-bromo-7-(difluoromethyl)-l,2,3,4-tetrahydroquinoline (1.44 g, 5.52 mmol) and tert- butyl 2-(4-(4.4.5.5-tctramcthyl- 1 3.2-dioxaborolan-2-yl)- 1 //-pyrazol- 1 -yl)acctatc (1.7 g, 5.52 mmol) in 1,4-dixoane (50 mL) were added Pd(dppf)Cl2 (1.15 g, 1.66 mmol), K2CO3 (1.52 g, 11.03 mmol). The reaction mixture was heated to 95 °C overnight, then diluted in ethyl acetate, washed with water and brine. The organic layer was concentrated in vacuo and the residue was purified by column (petroleum ether: ethyl acetate = 5: 1) to give desired product (0.9 g, yield: 45%) as an white solid. MS (ESI) m/z: 364.6 [M+H]+.
Step 3: Synthesis of tert- butyl 3-iodo- 1 -(tetrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//- pyrazolo [4,3 -c]pyridine-5 -carboxylate
Figure imgf000114_0004
To a solution of tert- butyl 3-iodo- 1 4.6.7-t
Figure imgf000114_0005
-carboxylatc (6 g, 17.19 mmol) in DMF (50 mL) were added tetrahydro-2H-pyran-4-yl methanesulfonate (4.64 g, 25.79 mmol) and K2CO3 (4.74 g, 34.38 mmol). The resulting mixture was stirred at 100°C overnight. After cooling to room temperature, the mixture was diluted with water, extracted with EA. The combined organic phase was washed with brine, dried over Na2S04. filtered and concentrated. The residue was purified by silica gel chromatography (PE/EA=1: 1) to give desired product (5.0 g, yield: 67%) as a white solid. MS (ESI) m/z: 434.6 [M+H]+.
Step 4: Synthesis of 2-(4-(l-(5-(f<?rf-butoxycarbonyl)-l-(tetrahydro-2//-pyran-4-yl)-4,5,6,7- tetrahydro-l/7-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-l,2,3,4-tetrahydroquinolin-6-yl)-l/7- pyrazol- l-yl)acetic acid
Figure imgf000115_0001
To a solution of tert- butyl 3-iodo- 1 -(tctrahydro-2//-pyran-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3- c]pyridine-5-carboxylate (258 mg, 0.60 mmol) and tert- butyl 2-(4-(7-(difluoromethyl)-l,2,3,4- tctrahydroquinolin-6-yl)- l//-pyrazol- 1 -yl)acctatc (262 mg, 0.72 mmol) in dioxane (10 mL) were added RuPhos Pd G1 (58.6 mg, 0.072 mmol), RuPhos (33.4 mg, 0.072 mmol) and lBuONa (201.3 mg, 2.098 mmol). The resulting mixture was stirred at reflux overnight. The reaction mixture was purified by reverse phase flash chromatography to give desired product (108 mg, yield: 29%) as a white solid. MS (ESI) m/z: 613.7 [M+H]+.
Step 5: Synthesis of 2-(4-(7-(difluoromethyl)-l-(l-(tetrahydro-2//-pyran-4-yl)-4,5,6,7-tetrahydro- 1 //-pyrazolo|4.3-r |pyridin-3-yl)- 1 2.3.4-tctrahydroquinolin-6-yl)- 1 //-pyrazol- 1 -yl)acctic acid
Figure imgf000115_0002
The mixture of 2-(4-( 1 -(5 -(terf-butoxy carbonyl)- 1 -(tetrahydro-2//-pyran-4-yl)-4,5 ,6,7-tetrahydro- 1/7-pyrazolo [4,3 -c]pyridin-3 -yl)-7-(difluoromethyl)- 1 ,2,3 ,4-tetrahydroquinolin-6-yl)- 1/7-pyrazol- 1 - yl)acetic acid (108 mg, 0.176 mmol) in DCM/TFA=1 : 1 (6 ml) was stirred at room temperature for 3 h, then it was concentrated and the residue was used directly in the next step.
Step 6: Synthesis of 2-(4-(7-(difluoromethyl)-l-(5-(methylcarbamoyl)-l-(tetrahydro-2//-pyran-4-yl)- 4,5,6,7-tetrahydro-l//-pyrazolo[4,3-c]pyridin-3-yl)-l,2,3,4-tetrahydroquinolin-6-yl)-l//-pyrazol-l- yl)acetic acid (P300 binder 2)
Figure imgf000115_0003
To the solution of 2-(4-(7-(difluoromethyl)- 1 -( 1 -(tetrahydro-2//-pyran-4-yl)-4.5.6.7-tetrahydro- 1 H- pyrazolo|4.3-c |pyridin-3-yl)- 1 2.3.4-tctrahydroquinolin-6-yl)- 1 //-pyrazol- 1 -yl)acctic acid (crude product from above reaction) in DCM (10 ml) were added 2,5-dioxopyrrolidin-l-yl methylcarbamate (91.9 mg, 0.528 mmol) and TEA (53.5 mg, 0.528 mmol). The resulting mixture was stirred at room temperature for 5h, then the reaction mixture was purified by reverse phase flash chromatography to give desired product (81 mg, yield: 81%) as a white solid. MS (ESI) m/z: 570.4 [M+H]+.
Procedures for the synthesis of P300 PROTACs.
Example 86. 3-(7-(Difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-001)
Figure imgf000116_0001
A solution of 3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2H)-y\)-N- methyl-l-(piperidin-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (8 mg, 0.015 mmol), (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)glycine (6.0 mg, 0.018 mmol), EDCI (4.65 mg, 0.024 mmol), HOAt (3.27 mg, 0.024 mmol) and NMM (9.8 mg, 0.094 mmol) in DMSO (2 mL) was stirred at room temperature overnight. The reaction solution was diluted with EA (20 ml), washed with water (20 ml). The aqueous layer was extracted with EtOAc (20 ml). The combined organic layer was washed with brine twice, dried over NaaSCE, fdtered and concentrated. The residue was purified with reverse phase flash chromatography to give 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 ( 2H)-yl )- 1 -( 1 -((2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)glycyl)piperidin-4- yl)-/V-methyl- 1,4, 6, 7-tetrahydro-5//-pyrazolo [4, 3 -c]pyridine-5 -carboxamide (5.5 mg, 44% yield) as a white solid. MS (ESI) m/z: 839.0 [M+H]+.
Example 87. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)propanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-002)
Figure imgf000116_0002
P-002 was synthesized following the standard procedure for preparing P-001 (5.2 mg, yield 41%). MS (ESI) m/z. 853.0 [M+H]+.
Example 88. 3-(7-(Difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)butanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-003)
Figure imgf000116_0003
P-003 was synthesized following the standard procedure for preparing P-001 (4.7 mg, yield 36%). MS (ESI) m/z : 867.0 [M+H]+.
Example 89. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)pentanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-004)
Figure imgf000117_0001
P-004 was synthesized following the standard procedure for preparing P-001 (5.0 mg, yield 38%). MS (ESI) m/z: 881.0 [M+H]+.
Example 90. 3-(7-(Difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)hexanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-005)
Figure imgf000117_0002
P-005 was synthesized following the standard procedure for preparing P-001 (2.6 mg, yield 16%). MS (ESI) m/z: 895.2 [M+H]+.
Example 91. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(7-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)heptanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-006)
Figure imgf000117_0003
P-006 was synthesized following the standard procedure for preparing P-001 (3.7 mg, yield 27%). MS (ESI) m/z: 909.1 [M+H]+.
Example 92. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)octanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-007)
Figure imgf000118_0001
P-007 was synthesized following the standard procedure for preparing P-001 (2.3 mg, yield 17%). MS (ESI) m/z: 923.0 [M+H]+.
Example 93. 3-(7-(Difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)propanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3- c]pyridine-5-carboxamide (P-008)
Figure imgf000118_0002
P-008 was synthesized following the standard procedure for preparing P-001 (2.5 mg, yield 19%). MS (ESI) m/z: 897.0 [M+H]+.
Example 94. 3-(7-(difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3- c]pyridine-5-carboxamide (P-009)
Figure imgf000118_0003
P-009 was synthesized following the standard procedure for preparing P-001 (2.5 mg, yield 18%). MS (ESI) m/z: 941.0 [M+H]+.
Example 95. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7- pyrazolo[4,3-c]pyridine-5-carboxamide (P-010)
Figure imgf000119_0001
P-010 was synthesized following the standard procedure for preparing P-001 (2.5 mg, yield 17%). MS (ESI) m/z: 985.1 [M+H]+.
Example 96. 3-(7-(Difluoromethyl)-6-( l -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)-3,6,9,12- tetraoxapentadecan- 15-oyl)piperidin-4-yl)-V-methyl- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-cJ pyridine- 5-carboxamide (P-011)
Figure imgf000119_0002
P-011 was synthesized following the standard procedure for preparing P-001 (2.6 mg, yield 17%). MS (ESI) m/z: 1027.1 [M+H]+.
Example 97. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)-3,6,9,12,15- pentaoxaoctadecan-18-oyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine- 5-carboxamide (P-012)
Figure imgf000119_0003
P-012 was synthesized following the standard procedure for preparing P-001 (3.5 mg, yield 22%). MS (ESI) m/z: 1073.2 [M+H]+.
Example 98. /V-(4-(3-(2,6-Difluoro-3-(propylsulfonamido)benzoyl)-l/7-pyrrolo[2,3-6]pyridin-5- yl)benzyl)-8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)octanamide (P-013)
Figure imgf000120_0001
P-013 was synthesized following the standard procedure for preparing P-001 (3.2 mg, yield 25%). MS (ESI) m/z: 838.9 [M+H]+.
Example 99. 3-(7-(Difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)propanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-014)
Figure imgf000120_0002
P-014 was synthesized following the standard procedure for preparing P-001 (2.6 mg, yield 20%). MS (ESI) m/z: 853.0 [M+H]+.
Example 100. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)butanoyl)piperidin-4-yl)-/V- methy
Figure imgf000120_0003
P-015 was synthesized following the standard procedure for preparing P-001 (2.5 mg, yield 19%). MS (ESI) m/z: 867.1 [M+H]+.
Example 101. 3-(7-(Difluoromethyl)-6-(l-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)ethyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-cJ pyridine-5- carboxamide (P-016)
Figure imgf000120_0004
P-016 was synthesized following the standard procedure for preparing P-001 (4.8 mg, yield 37%). MS (ESI) m/z: 869.2 [M+H]+.
Example 102. 3-(7-(Difluoromethyl)-6-(l-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)propyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-iV-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6·] pyridine-5- carboxamide (P-017)
Figure imgf000121_0001
P-017 was synthesized following the standard procedure for preparing P-001 (4.7 mg, 35%). MS (ESI) m/z. 883.0 [M+H]+.
Example 103. N1 -(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-l/7-pyrrolo[2,3-6]pyridin- 5-yl)benzyl)-/V5-((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin- l-yl)-3,3-dimethyl-l-oxobutan-2-yl)glutaramide (P-018)
Figure imgf000121_0002
P-018 was synthesized following the standard procedure for preparing P-001 (6.0 mg, yield 45%). MS (ESI) m/z: 897.0 [M+H]+.
Example 104. 3-(7-(Difluoromethyl)-6-(l-(2-((5-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)pentyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6'J pyridine-5- carboxamide (P-019)
Figure imgf000121_0003
P-019 was synthesized following the standard procedure for preparing P-001 (2.6 mg, yield 19%). MS (ESI) m/z: 911.1 [M+H]+.
Example 105. 3-(7-(Difluoromethyl)-6-(l-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)hexyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6'J pyridine-5- carboxamide (P-020)
Figure imgf000121_0004
P-020 was synthesized following the standard procedure for preparing P-001 (5.0 mg, yield 36%). MS (ESI) m/z : 925.1 [M+H]+.
Example 106. (25,4/?)-l-((5)-2-(2-(2-((4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-l/7- pyrrolo[2,3-6]pyridin-5-yl)benzyl)amino)-2-oxoethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-/V-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (P-021)
Figure imgf000121_0005
P-021 was synthesized following the standard procedure for preparing P-001 (5.3 mg, yield 39%). MS (ESI) m/z : 913.0 [M+H]+.
Example 107. 3-(7-(Difluoromethyl)-6-(l-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4- dihydroquinolin-l(2/7)-yl)-/V-methyl-l-(tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7- pyrazolo[4,3-c]pyridine-5-carboxamide (P-022)
Figure imgf000122_0001
P-022 was synthesized following the standard procedure for preparing P-001 (5.3 mg, yield 37%). MS (ESI) m/z: 957.0 [M+H]+.
Example 108. 3-(7-(Difluoromethyl)-6-(l-(14-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 4-yl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V- methyl-l-(tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide
Figure imgf000122_0002
P-023 was synthesized following the standard procedure for preparing P-001 (5.5 mg, yield 37%). MS (ESI) m/z: 1000.9 [M+H]+.
Example 109. 3-(7-(Difluoromethyl)-6-(l-(17-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 4-yl)amino)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-cJ pyridine-5- carboxamide (P-024)
Figure imgf000122_0003
P-024 was synthesized following the standard procedure for preparing P-001 (5.4 mg, yield 34%). MS (ESI) m/z: 1045.0 [M+H]+.
Example 110. 3-(7-(Difluoromethyl)-6-(l-(20-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 4-yl)amino)-2-oxo-6,9,12,15,18-pentaoxa-3-azaicosyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-/V-methyl-l-(tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5- carboxamide (P-025)
Figure imgf000122_0004
P-025 was synthesized following the standard procedure for preparing P-001 (5.5 mg, yield 34%). MS (ESI) m/z: 1089.2 [M+H]+.
Example 111. 3-(7-(Difluoromethyl)-6-(l-(2-((7-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)heptyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-cJ pyridine-5- carboxamide (P-026)
Figure imgf000122_0005
P-026 was synthesized following the standard procedure for preparing P-001 (3.5 mg, yield 25%). MS (ESI) m/z: 938.9 [M+H]+. Example 112. 3-(7-(Difluoromethyl)-6-(l-(2-((8-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)octyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-/V-methyl-l-(tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5- carboxamide (P-027)
Figure imgf000123_0001
P-027 was synthesized following the standard procedure for preparing P-001 (4.7 mg, yield 33%). MS (ESI) m/z: 953.0 [M+H]+.
Example 113. 3-(7-(Difluoromethyl)-6-(l-(2-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)ethoxy)ethyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin- l(2/7)-yl)-/V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6·] pyridine-5- carboxamide (P-028)
Figure imgf000123_0002
P-028 was synthesized following the standard procedure for preparing P-001 (4.3 mg, yield 31%). MS (ESI) m/z: 912.9 [M+H]+.
Example 114. 3-(7-(Difluoromethyl)-6-(l-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4- dihydroquinolin-l(2/7)-yl)-/V-methyl-l-(tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7- pyrazolo[4,3-c]pyridine-5-carboxamide (P-029)
Figure imgf000123_0003
P-029 was synthesized following the standard procedure for preparing P-001 (4.6 mg, yield 32%). MS (ESI) m/z: 956.9 [M+H]+.
Example 115. 3-(7-(Difluoromethyl)-6-(l-(14-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 5-yl)amino)-2-oxo-6,9,12-trioxa-3-azatetradecyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V- methyl- l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide
Figure imgf000123_0004
P-030 was synthesized following the standard procedure for preparing P-001 (6.4 mg, yield 43%). MS (ESI) m/z: 1001.1 [M+H]+.
Example 116. 3-(7-(Difluoromethyl)-6-(l-(17-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 5-yl)amino)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6'J pyridine-5- carboxamide (P-031)
Figure imgf000123_0005
P-031 was synthesized following the standard procedure for preparing P-001 (5.3 mg, yield 34%). MS (ESI) m/z: 1045.1 [M+H]+.
Example 117. 3-(7-(Difluoromethyl)-6-(l-(20-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 5-yl)amino)-2-oxo-6,9,12,15,18-pentaoxa-3-azaicosyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-iV-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6·] pyridine-5- carboxamide (P-032)
Figure imgf000124_0001
P-032 was synthesized following the standard procedure for preparing P-001 (6.7 mg, yield 41%). MS (ESI) m/z: 1089.2 [M+H]+.
Example 118. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-033)
Figure imgf000124_0002
P-033 was synthesized following the standard procedure for preparing P-001 (1.4 mg, yield 11%). MS (ESI) m/z: 881.0 [M+H]+.
Example 119. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-034)
Figure imgf000124_0003
P-034 was synthesized following the standard procedure for preparing P-001 (1.3 mg, yield 10%). MS (ESI) m/z: 894.9 [M+H]+.
Example 120. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(7-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-035)
Figure imgf000124_0004
P-035 was synthesized following the standard procedure for preparing P-001 (1.55 mg, yield 11%). MS (ESI) m/z: 908.8 [M+H]+.
Example 121. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)octanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-036)
Figure imgf000125_0001
P-036 was synthesized following the standard procedure for preparing P-001 (2.31 mg, yield 17%). MS (ESI) m/z: 922.8 [M+H]+.
Example 122. 3-(7-(Difluoromethyl)-6-(l-(2-((2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)ethyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-cJ pyridine-5- carboxamide (P-037)
Figure imgf000125_0002
P-037 was synthesized following the standard procedure for preparing P-001 (3 mg, yield 23%). MS (ESI) m/z: 868.8 [M+H]+.
Example 123. 3-(7-(Difluoromethyl)-6-(l-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)propyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-cJ pyridine-5- carboxamide (P-038)
Figure imgf000125_0003
P-038 was synthesized following the standard procedure for preparing P-001 (4.5 mg, yield 34%). MS (ESI) m/z: 882.8 [M+H]+.
Example 124. 3-(7-(Difluoromethyl)-6-(l-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)butyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-/V-methyl-l-(tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5- carboxamide (P-039)
Figure imgf000125_0004
P-039 was synthesized following the standard procedure for preparing P-001 (5.6 mg, yield 42%). MS (ESI) m/z: 896.9 [M+H]+.
Example 125. 3-(7-(Difluoromethyl)-6-(l-(2-((5-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)pentyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6'J pyridine-5- carboxamide (P-040)
Figure imgf000126_0001
P-040 was synthesized following the standard procedure for preparing P-001 (5.0 mg, yield 37%). MS (ESI) m/z: 910.8 [M+H]+.
Example 126. 3-(7-(Difluoromethyl)-6-(l-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)hexyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-cJ pyridine-5- carboxamide (P-041)
Figure imgf000126_0002
P-041 was synthesized following the standard procedure for preparing P-026 (1.8 mg, yield 13%). MS (ESI) m/z: 924.7 [M+H]+.
Example 127. 3-(7-(Difluoromethyl)-6-(l-(2-((7-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)heptyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-cJ pyridine-5- carboxamide (P-042)
Figure imgf000126_0003
P-042 was synthesized following the standard procedure for preparing P-001 (2.8 mg, yield 20%). MS (ESI) m/z: 938.9 [M+H]+.
Example 128. 3-(7-(Difluoromethyl)-6-(l-(2-((8-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)octyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-V-methyl-l-(tetrahydro-2/7-pyran-4-yl)- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6'J pyridine-5- carboxamide (P-043)
Figure imgf000126_0004
P-043 was synthesized following the standard procedure for preparing P-001 (3.7 mg, yield 26%). MS (ESI) m/z: 953.0 [M+H]+.
Example 129. 3-(7-(Difluoromethyl)-6-(l-(2-((2-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-2- oxoethyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l- (tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-044)
Figure imgf000126_0005
P-044 was synthesized following the standard procedure for preparing P-001 (4.4 mg, yield 28%). MS (ESI) m/z: 1040.0 [M+H]+.
Example 130. 3-(7-(Difluoromethyl)-6-(l-(2-((3-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-3- oxopropyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-V-methyl-l- (tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide (P-045)
Figure imgf000127_0001
P-045 was synthesized following the standard procedure for preparing P-001 (3.7 mg, yield 23%). MS (ESI) m/z: 1054.1 [M+H]+.
Example 131. 3-(7-(Difluoromethyl)-6-(l-(2-((5-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-5- oxopentyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l- (tetrahydro-2//-pyran-4-yl)-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-6'Jpyridine-5-carboxamide (P-046)
Figure imgf000127_0002
P-046 was synthesized following the standard procedure for preparing P-001 (2.2 mg, yield 14%). MS (ESI) m/z : 1082.1 [M+H]+.
Example 132. 3-(7-(Difluoromethyl)-6-(l-(2-((6-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-6- oxohexyl)amino) -2-oxoethyl) - l/7-pyrazol-4-yl) -3,4-dihydroquinolin- 1 (2/7)-yl)-V-methyl- 1 - (tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide (P-047)
Figure imgf000127_0003
P-047 was synthesized following the standard procedure for preparing P-001 (2.0 mg, yield 12%). MS (ESI) m/z: 1096.1 [M+H]+.
Example 133. 3-(7-(Difluoromethyl)-6-(l-(2-((8-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-8- oxooctyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-V-methyl-l- (tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide (P-048)
Figure imgf000127_0004
P-048 was synthesized following the standard procedure for preparing P-001 (1.05 mg, yield 6%). MS (ESI) m/z : 1124.1 [M+H]+.
Example 134. 3-(7-(Difluoromethyl)-6-(l-(2-((10-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-10- oxodecyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-V-methyl-l- (tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide (P-049)
Figure imgf000127_0005
P-049 was synthesized following the standard procedure for preparing P-001 (0.52 mg, yield 3%). MS (ESI) m/z: 1152.2 [M+H]+.
Example 135. 3-(7-(Difluoromethyl)-6-(l-(2-((ll-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-ll- oxoundecyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l- (tetrahydro-2H-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-050)
Figure imgf000128_0001
P-050 was synthesized following the standard procedure for preparing P-001 (0.74 mg, yield 4%). MS (ESI) m/z : 1166.3 [M+H]+.
Example 136. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(2-(2-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-2-oxoethoxy)acetyl)piperidin-4-yl)-/V-methyl-l,4,6,7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-051/P-064)
Figure imgf000128_0002
P-064 was synthesized following the standard procedure for preparing P-001 (3.7 mg, yield 26%). MS (ESI) m/z : 1053.9 [M+H]+.
Example 137. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(3-(3-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3, 3-dimethyl- l-oxobutan-2-yl)amino)-3-oxopropoxy)propanoyl)piperidin-4-yl)-V-methyl- 1,4, 6, 7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (
Figure imgf000128_0003
Figure imgf000128_0004
P-065 was synthesized following the standard procedure for preparing P-001 (4.2 mg, yield 29%). MS (ESI) m/z: 1082.0 [M+H]+.
Example 138. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(2-(2-(2-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-2- oxoethoxy)ethoxy)acetyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5- carboxamide (CPD-053/P-066)
Figure imgf000128_0005
P-066 was synthesized following the standard procedure for preparing P-001 (4.3 mg, yield 29%). MS (ESI) m/z: 1097.9 [M+H]+.
Example 139. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(3-(2-(3-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-3- oxopropoxy)ethoxy)propanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3- c]pyridine-5-carboxamide (CPD-054/P-067)
Figure imgf000129_0001
P-067 was synthesized following the standard procedure for preparing P-001 (5.2 mg, yield 35%). MS (ESI) m/z: 1126.0 [M+H]+.
Example 140. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-((5)-13-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-l- carbonyl)- 14,14-dimethyl- 11 -oxo-3, 6, 9-trioxa-12-azapentadecanoyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-055/P-068)
Figure imgf000129_0002
P-068 was synthesized following the standard procedure for preparing P-001 (5.6 mg, yield 37%). MS (ESI) m/z: 1142.0 [M+H]+.
Example 141. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-((5)-15-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-l- carbonyl)- 16, 16-dimethyl- 13-0X0-4, 7, 10-trioxa-14-azaheptadecanoyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-056/P-069)
Figure imgf000130_0001
P-069 was synthesized following the standard procedure for preparing P-001 (6.2 mg, yield 40%). MS (ESI) m/z: 1170.1 [M+H]+.
Example 142. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-((S)-18-((2S,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-l- carbonyl)- 19, 19-dimethyl- 16-0X0-4, 7, 10,13-tetraoxa-17-azaicosanoyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-057/P-070)
Figure imgf000130_0002
P-070 was synthesized following the standard procedure for preparing P-001 (4.2 mg, yield 26%). MS (ESI) m/z: 1214.1 [M+H]+.
Example 143. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-((5)-19-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-l- carbonyl)-20,20-dimethyl- 17-oxo-3,6,9,l 2, 15-pentaoxa-18-azahenicosanoyl)piperidin-4-yl)-V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-058/P-071)
Figure imgf000130_0003
P-071 was synthesized following the standard procedure for preparing P-001 (5.4 mg, yield 33%). MS (ESI) m/z: 1230.0 [M+H]+. Example 144. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-((5)-21-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-l- carbonyl)-22,22-dimethyl-l 9-oxo-4,7,10,l 3, 16-pentaoxa-20-azatricosanoyl)piperidin-4-yl)-V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-059/P-072)
Figure imgf000131_0001
P-072 was synthesized following the standard procedure for preparing P-001 (5.1 mg, yield 30%). MS (ESI) m/z: 1258.2 [M+H]+.
Example 145. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(4-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-4-oxobutanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-060/P-056)
Figure imgf000131_0002
P-056 was synthesized following the standard procedure for preparing P-001 (4.5 mg, yield 33%). MS (ESI) m/z: 1038.0 [M+H]+.
Example 146. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(5-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-5-oxopentanoyl)piperidin-4-yl)-/V-methyl-l, 4,6,7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-061/P-057)
Figure imgf000131_0003
P-057 was synthesized following the standard procedure for preparing P-001 (5.0 mg, yield 36%). MS (ESI) m/z: 1052.1 [M+H]+.
Example 147. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(6-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3, 3-dimethyl- l-oxobutan-2-yl)amino)-6-oxohexanoyl)piperidin-4-yl)-/V-methyl- 1,4, 6, 7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (
Figure imgf000132_0002
Figure imgf000132_0001
P-058 was synthesized following the standard procedure for preparing P-001 (3.7 mg, yield 26%). MS (ESI) m/z: 1066.0 [M+H]+.
Example 148. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(7-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-7-oxoheptanoyl)piperidin-4-yl)-/V-methyl-l, 4,6,7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide
Figure imgf000132_0004
Figure imgf000132_0003
P-059 was synthesized following the standard procedure for preparing P-001 (2.3 mg, yield 16%). MS (ESI) m/z: 1080.0 [M+H]+.
Example 149. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(8-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-8-oxooctanoyl)piperidin-4-yl)-/V-methyl-l, 4,6,7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-064/P-060)
Figure imgf000132_0005
P-060 was synthesized following the standard procedure for preparing P-001 (5.6 mg, yield 38%). MS (ESI) m/z: 1094.0 [M+H]+.
Example 150. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(9-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3, 3-dimethyl- l-oxobutan-2-yl)amino)-9-oxononanoyl)piperidin-4-yl)-/V-methyl- 1,4, 6, 7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-065/P-061)
Figure imgf000133_0001
P-061 was synthesized following the standard procedure for preparing P-001 (4.5 mg, yield 30%). MS (ESI) m/z: 1108.1 [M+H]+.
Example 151. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(10-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-10-oxodecanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide
Figure imgf000133_0003
Figure imgf000133_0002
P-062 was synthesized following the standard procedure for preparing P-001 (3.5 mg, yield 23%). MS (ESI) m/z: 1122.2 [M+H]+.
Example 152. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(ll-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l- yl)-3, 3-dimethyl- 1 -oxobutan-2-yl)amino)- 1 l-oxoundecanoyl)piperidin-4-yl)-/V-methyl- 1,4, 6, 7- tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide
Figure imgf000133_0005
Figure imgf000133_0004
P-063 was synthesized following the standard procedure for preparing P-001 (3.4 mg, yield 22%). MS (ESI) m/z: 1136.1 [M+H]+.
Example 153. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3- c]pyridine-5-carboxamide (CPD-068/P-051)
Figure imgf000134_0001
P-051 was synthesized following the standard procedure for preparing P-001 (3.9 mg, yield 33%). MS (ESI) m/z: 896.9 [M+H]+.
Example 154. 3-(7-(Difluoromethyl)-6-( 1 -methyl- 1 /7-pyrazol-4-yl)-3, 4-dihydroquinolin- 1(2/7)- yl)-l-(l-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3- c]pyridine-5-carboxamide (CPD-069/P-052)
Figure imgf000134_0002
P-052 was synthesized following the standard procedure for preparing P-001 (4.6 mg, yield 37%). MS (ESI) m/z: 940.9 [M+H]+.
Example 155. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7- pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-070/P-053)
Figure imgf000134_0003
P-053 was synthesized following the standard procedure for preparing P-001 (5.4 mg, yield 41%). MS (ESI) m/z: 985.0 [M+H]+.
Example 156. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-3,6,9,12- tetraoxapentadecan- 15-oyl)piperidin-4-yl)-V-methyl- 1,4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-6'J pyridine- 5-carboxamide (CPD-071/P-054)
Figure imgf000135_0001
P-054 was synthesized following the standard procedure for preparing P-001 (5.7 mg, yield 42%). MS (ESI) m/z: 1029.0 [M+H]+.
Example 157. 3-(7-(Dilluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15- pentaoxaoctadecan-18-oyl)piperidin-4-yl)-V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine- 5-carboxamide (CPD-072/P-055)
Figure imgf000135_0002
P-055 was synthesized following the standard procedure for preparing P-001 (5.3 mg, yield 37%). MS (ESI) m/z: 1073.1 [M+H]+.
Example 158. 3-(7-(Difluoromethyl)-6-(l-(2-((2-(2-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-2- oxoethoxy)ethyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l- (tetrahydro-2//-pyran-4-yl)-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-6'Jpyridine-5-carboxamide (P-073)
Figure imgf000135_0003
P-073 was synthesized following the standard procedure for preparing P-001 (3.8 mg, yield 40%). MS (ESI) m/z: 1084.0 [M+H]+.
Example 159. 3-(7-(Difluoromethyl)-6-(l-(2-((2-(3-(((5)-l-((25,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-3- oxopropoxy)ethyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l- (tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-074)
Figure imgf000136_0001
P-074 was synthesized following the standard procedure for preparing P-001 (3.1 mg, yield 32%). MS (ESI) m/z: 1098.0 [M+H]+.
Example 160. 3-(7-(Difluoromethyl)-6-(l-((S)-13-((2S,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-14,14-dimethyl-2,ll-dioxo-6,9-dioxa-3,12- diazapentadecyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l-(tetrahydro-2/7- pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-075/P-083)
Figure imgf000136_0002
P-083 was synthesized following the standard procedure for preparing P-001 (1.37 mg, yield 14%). MS (ESI) m/z: 1128.1 [M+H]+.
Example 161. 3-(7-(Difluoromethyl)-6-(l-((S)-14-((2S,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-15,15-dimethyl-2,12-dioxo-6,9-dioxa-3,13- diazahexadecyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l-(tetrahydro-2/7-pyran- 4-yl)-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-6'Jpyridine-5-carboxamide (CPD-076/P-075)
Figure imgf000136_0003
P-075 was synthesized following the standard procedure for preparing P-001 (3.4 mg, yield 34%). MS (ESI) m/z: 1142.1 [M+H]+.
Example 162. 3-(7-(Difluoromethyl)-6-(l-((5)-16-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-17,17-dimethyl-2,14-dioxo-6,9,12-trioxa-3,15- diazaoctadecyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2H)-yl)-/V-methyl-l-(tetrahydro-2/7-pyran- 4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide (CPD-077/P-076)
Figure imgf000136_0004
P-076 was synthesized following the standard procedure for preparing P-001 (3.6 mg, yield 35%). MS (ESI) m/z: 1172.1 [M+H]+.
Example 163. 3-(7-(Difluoromethyl)-6-(l-((S)-17-((2S,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-18,18-dimethyl-2,15-dioxo-6,9,12-trioxa-3,16- diazanonadecyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l-(tetrahydro-2/7- pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (CPD-078/P-077)
Figure imgf000136_0005
P-077 was synthesized following the standard procedure for preparing P-001 (3.0 mg, yield 29%). MS (ESI) m/z: 1186.3 [M+H]+.
Example 164. 3-(7-(Difluoromethyl)-6-(l-((5)-20-((25,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-21,21-dimethyl-2,18-dioxo-6,9,12,15-tetraoxa-3,19- diazadocosyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l-(tetrahydro-2/7-pyran-4- yl)-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-6'Jpyridine-5-carboxamide (CPD-079/P-078)
Figure imgf000137_0001
P-078 was synthesized following the standard procedure for preparing P-001 (2.8 mg, yield 26%).
MS (ESI) m/z: 1230.3 [M+H]+.
Example 165. 3-(7-(Difluoromethyl)-6-(l-((S)-23-((2S,4/?)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-24,24-dimethyl-2,21-dioxo-6,9,12,15,18-pentaoxa-3,22- diazapentacosyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l-(tetrahydro-2/7- pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide (CPD-080/P-082)
Figure imgf000137_0002
P-082 was synthesized following the standard procedure for preparing P-001 (1.9 mg, yield 17%). MS (ESI) m/z: 1274.3 [M+H]+.
Example 166. 3-(7-(Difluoromethyl)-6-(l-(2-((4-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-4- oxobutyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l- (tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide (CPD-
Figure imgf000137_0003
P-079 was synthesized following the standard procedure for preparing P-001 (2.1 mg, yield 22%). MS (ESI) m/z: 1068.1 [M+H]+.
Example 167. 3-(7-(Difluoromethyl)-6-(l-(2-((7-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-7- oxoheptyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-/V-methyl-l- (tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide (CPD-
Figure imgf000137_0004
P-080 was synthesized following the standard procedure for preparing P-001 (0.84 mg, yield 9%). MS (ESI) m/z: 1110.1 [M+H]+.
Example 168. 3-(7-(Difluoromethyl)-6-(l-(2-((9-(((S)-l-((2S,4/?)-4-hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-9- oxononyl)amino)-2-oxoethyl)-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)-yl)-V-methyl-l- (tetrahydro-2/7-pyran-4-yl)-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5-carboxamide (CPD-
Figure imgf000137_0005
P-081 was synthesized following the standard procedure for preparing P-001 (1.6 mg, yield 16%). MS (ESI) m/z: 1138.2 [M+H]+.
Example 169. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)hexanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-084).
Figure imgf000138_0001
Step 1: Synthesis of tert- butyl 6-(tosyloxy)hexanoate
Figure imgf000138_0002
To a solution of tert- butyl 6-hydroxyhexanoate (500 mg, 2.66 mmol), DMAP (16 mg, 0.13 mmol) and TEA (806 mg, 7.97 mmol) in DCM (45 mL) was added TsCI (608 mg, 3.19 mmol) at 0 °C. After the reaction was stirred at room temperature for 2 h, the reaction mixture was washed with water, dried over Na S04, filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product (700 mg, yield 77%) as a colorless oil.
Step 2: Synthesis of tert- butyl 6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)hexanoate
Figure imgf000138_0003
To a solution of tert- butyl 6-(tosyloxy)hexanoate (600 mg, 1.75 mmol) and 2-(2,6-dioxopiperidin-3- yl)-4-hydroxyisoindoline-l,3-dione (480 mg, 1.75 mmol) in DMSO (6 mL) were added K2CO3 (484 mg, 3.5 mmol) and Nal (394 mg, 2.63 mmol). The resulting mixture was stirred at 80 °C for 3 h, before the reaction mixture was filtered. The filtrate was directly purified by reverse phase chromatography to give the desired product (440 mg, yield 57%) as a white solid. (ESI) mh: 388.4 [M-iBh+H]+.
Step 3: Synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)hexanoic acid
Figure imgf000138_0004
A mixture of terf-butyl 6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)hexanoate (440 mg, 0.99 mmol) in DCM (8 mL) and TFA (1 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product (496 mg, yield 99%) as a white solid which was used directly in the next step.
Step 4: Synthesis of 3-(7-(difhioromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3,4-dihydroquinolin- 1 (2H)-y\)-\ -( 1 -(6-((2-(2,6-dioxopiperidin-3 -yl)-l ,3-dioxoisoindolin-4-yl)oxy)hexanoyl)piperidin-4-yl)-/V- methyl-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-084)
Figure imgf000139_0001
P-084 was synthesized following the standard procedure for preparing P-001 (6.8 mg, yield 51%). MS (ESI) m/z: 895.7 [M+H]+.
Example 170. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)heptanoyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-085)
Figure imgf000139_0002
Step 1: Synthesis of 7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hept-6-ynoic acid
Figure imgf000139_0003
To a solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (250 mg, 0.74 mmol) in DMF (5 mL) were added Pd(dppf)Cl2 (27.1 mg, 0.037 mmol), Cul (14.1 mg, 0.074 mmol), TEA (75 mg, 0.074 mmol) and hept-6-ynoic acid (103 mg, 0.082 mmol). The resulting mixture was stirred at 85 °C for 2.5 h under N2. The reaction mixture was purified by reverse phase chromatography to give the desried product (200 mg, yield 71%) as a white solid. MS (ESI) m/z: 383.3 [M+H]+.
Step 2: Synthesis of 7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)heptanoic acid
Figure imgf000139_0004
A mixture of 7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hept-6-ynoic acid (200 mg,
0.52 mmol) and Pd/C (30 mg) in THF (10 mL) was stirred at room temperature for 2 h under H2. After the reaction mixture was filtered through Celite, the filtrate was concentrated to give the desired product (202 mg, yield 99%) as a white solid. MS (ESI) m/z: 387.5 [M+H]+.
Step 3: Synthesis of 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3,4-dihydroquinolin- 1 (2H)-y\)-\ -( 1 -(7-(2-(2,6-dioxopiperidin-3 -yl)- 1 3-dioxoisoindolin-4-yl)hcptanoyl)pipcridin-4-yl)-/V- methyl- 1.4.6.7-tctrahydro-5//-pyrazolo|4.3-r|pyridinc-5-carboxamidc (P-085)
Figure imgf000139_0005
P-085 was synthesized following the standard procedure for preparing P-001 (6 mg, yield 45%). MS (ESI) m/z: 893.8 [M+H]+.
Example 171. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(7-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)heptanoyl)piperidin-4-yl)-/V-methyl- l,4,6
Figure imgf000140_0001
P-086 was synthesized following the similar procedure for preparing P-085 (6 mg, yield 46%). MS (ESI) m/z: 879.8 [M+H]+.
Example 172. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(7-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)heptanoyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-087)
Figure imgf000140_0002
P-087 was synthesized following the similar procedure for preparing P-085 (6.8 mg, yield 52%). MS (ESI) m/z: 879.8 [M+H]+.
Example 173. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(6-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)hexanoyl)piperidin-4-yl)-/V-methyl-
Figure imgf000140_0003
P-088 was synthesized following the similar procedure for preparing P-084 (3 mg, yield 26%). MS (ESI) m/z: 881.9 [M+H]+.
Example 174. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(6-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)oxy)hexanoyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-089)
Figure imgf000141_0001
P-089 was synthesized following the similar procedure for preparing P-084 (5.1 mg, yield 57%). MS (ESI) m/z: 881.8 [M+H]+.
Example 175. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-090)
Figure imgf000141_0002
Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)amino)isoindoline-l,3-dione
Figure imgf000141_0003
To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (500 mg, 1.81 mmol) and 6-aminohexan-l-ol (212 mg, 1.81 mmol) in DMSO (10 mL) was added DIEA (702 mg, 5.43 mmol). The resulting mixture was stirred at 120 °C for 2 h. After cooling to room temperature, the reaction mixture was purified by prep-HPLC to give the desired product (300 mg, yield 44%) as a yellow solid. MS (ESI) m/z: 374.5 [M+H]+.
Step 2: Synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexyl 4- methylbenzenesulfonate
Figure imgf000141_0004
To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)amino)isoindoline-l,3-dione (250 mg, 0.67 mmol) in DCM (15 mL) were added DMAP (4 mg, 0.03 mmol), TEA (202 mg, 2.0 mmol) and TsCI (191 mg, 1.0 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, before the reaction mixture was concentrated. The residue was purified by silica gel column chromatography to give the desired product (270 mg, yield 77%) as a white solid. MS (ESI) m/z: 528.5 [M+H]+.
Step 3: Synthesis of 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3,4-dihydroquinolin- 1 (2H)-y\)-\ -( 1 -(6-((2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxoisoindolin-4-yl)amino)hexyl)piperidin-4-yl)-/V- methyl-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-090)
Figure imgf000142_0001
A mixture of 6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexyl 4- methylbenzene sulfonate (4 mg, 0.00758 mmol), 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-/V-methyl- 1 -(pipcridin-4-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r|pyridinc-5- carboxamide (3.98 mg, 0.00758 mmol) and DIEA (4.85 mg, 0.038 mmol) in DMA (0.5 mL) was stirred at 60 °C for 4 h. The reaction mixture was purified by reverse phase chromatography to give desired product (2 mg, yield 30%) as a white solid. MS (ESI) mlz. 880.9 [M+H]+.
Example 176. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)hexyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-091)
Figure imgf000142_0002
P-091 was synthesized following the similar procedure for preparing P-090 (3 mg, yield 45%). MS (ESI) mlz· 881.8 [M+H]+.
Example 177. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hept-6-ynoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide
Figure imgf000142_0004
Figure imgf000142_0003
P-092 was synthesized following the standard procedure for preparing P-001 (5.3 mg, yield 62%). MS (ESI) ml 889.8 [M+H]+.
Example 178. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(7-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)hept-6-ynoyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-093)
Figure imgf000143_0001
P-093 was synthesized following the standard procedure for preparing P-001 (5.0 mg, yield 55%). MS (ESI) m/z: 875.8 [M+H]+.
Example 179. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(7-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)hept-6-ynoyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-094)
Figure imgf000143_0002
P-094 was synthesized following the standard procedure for preparing P-001 (4.6 mg, yield 51%). MS (ESI) m/z: 875.8 [M+H]+.
Example 180. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(6-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-095)
Figure imgf000143_0003
Step 1: Synthesis of 6-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)hexanoic acid
Figure imgf000143_0004
To a solution of 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (30 mg, 0.12 mmol) and 6- oxohexanoic acid (45 mg, 0.35 mmol) in DMF (4 mL) were added NaBH4 (8.8 mg, 0.23 mmol) and TMSC1 (37.5 mg, 0.35 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h, and stirred at room temperature for 48 h. The reaction mixture was purified by prep-HPLC to give the desired product (16 mg, yield 37%) as a white solid. MS (ESI) m/z: 374.6 [M+H]+.
Step 2: Synthesis of 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3,4-dihydroquinolin- 1 (2H)-y\)-\ -( 1 -(6-((2-(2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)-/V- methyl-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-095)
Figure imgf000144_0001
P-095 was synthesized following the standard procedure for preparing P-001 (3 mg, yield 26%). MS (ESI) m/z: 880.8 [M+H]+.
Example 181. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(6-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)amino)hexanoyl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-096)
Figure imgf000144_0002
P-096 was synthesized following the similar procedure for preparing P-095 (2 mg, yield 24%). MS (ESI) m/z: 881.0 [M+H]+.
Example 182. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)heptyl)piperidin-4-yl)-/V-methyl- l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-097)
Figure imgf000144_0003
P-097 was synthesized following the similar procedure for preparing P-085 (1.08 mg, yield 11%). MS (ESI) m/z: 879.9 [M+H]+.
Example 183. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-(l-(7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hept-6-yn-l-yl)piperidin-4-yl)-/V- methyl-1, 4, 6, 7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-098)
Figure imgf000144_0004
P-098 was synthesized following the similar procedure for preparing P-097 (1.01 mg, yield 12%). MS (ESI) m/z: 875.8 [M+H]+. Example 185. 4-((6-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-6- oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-100)
Figure imgf000145_0001
Step 1: Synthesis of benzyl 4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidine- 1 -carboxylate
Figure imgf000145_0002
To a mixture of benzyl 4-(3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//s)-yl)-4.5.6.7-tetrahydro- 1 //-pyrazolo|4.3-r|pyridin- 1 -yl)piperidine- 1 -carboxylate (77 mg, 0.13 mmol) and TEA (39 mg, 0.38 mmol) in DCM (3 mL) was added a solution of acetyl chloride (15 mg, 0.19 mmol) in DCM (1 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h, then it was concentrated. The residue was dissolved in MeOH and purified by prep-HPLC to give the desired product (51 mg, yield 62%). MS (ESI) m/z : 645.2 [M+H]+.
Step 2: Synthesis of 1 -(3 -(7-(difluoromethyl)-6-(l -methyl- l//-pyrazol-4-yl)-3,4-dihydroquinolin-
1 (2H)-y\)- 1 -(piperidin-4-yl)- 1.4.6.7-tctrahydro-5//-pyrazolo|4.3-r|pyridin-5-yl)cthan- 1 -one
Figure imgf000145_0003
A mixture of benzyl 4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidine- 1 -carboxylate (2.5 g, 3.88 mmol), Pd/C (231 mg) and TFA (one drop) in MeOH (24 mL) was stirred at 30 °C for 4 h, before the reaction mixture was filtered. After the filtrate was concentrated, the resulting residue was diluted with aq. NaHCCh and extracted with EtOAc. The combined organic layers were dried over Na SC> , filtered and concentrated to give the desired product (1.8 g, yield 91%). MS (ESI) rn/z 511.0 [M+H]+.
Step 3: Synthesis of 4-((6-(4-(5-acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4, 5 ,6,7-tetrahydro- l//-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)
Figure imgf000145_0004
P-100 was synthesized following the standard procedure for preparing P-001 (8.7 mg, yield 63%). MS (ESI) m/z: 880.0 [M+H]+. Example 186. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)piperidin-l- yl)acetyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-101)
Figure imgf000146_0001
Step 1: Synthesis oftert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)piperidine- 1 -carboxylate
Figure imgf000146_0002
To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (2 g, 7.2 mmol) in DMSO (30 mL) were added KF (1.26 g, 21.7 mmol) and terf-butyl 4-aminopiperidine-l -carboxylate (4.34 g, 21.7 mmol). The resulting mixture was stirred at 130 °C for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaaSCE, filtered and concentrated. The residue was purified with scilica gel column chromatography to give the desried product (1.2 g, yield 37%). MS (ESI) rn/z 457.4 [M+H]+.
Step 2 to Step 5:
P-101 was synthesized Following the similar procedure for preparing P-103 (6.2 mg, yield 71%). MS (ESI) m/z : 922.1 [M+H]+.
Example 187. 3-(7-(Difluoromethyl)-6-(l-methyl-17 -pyrazol-4-yl)-3,4-dihydroquinolin-l(27 )- yl)-l-(l-(2-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)methyl)piperidin-l- yl)acetyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-102)
Figure imgf000146_0003
P-102 was synthesized following the similar procedure for preparing P-101 (6.8 mg, yield 76%). MS (ESI) m/z: 936.1 [M+H]+.
Example 188. 3-(7-(Difluoromethyl)-6-(l-methyl-17 -pyrazol-4-yl)-3,4-dihydroquinolin-l(27 )- yl)-l-(l-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)ethynyl)piperidin-l- yl)acetyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-57 -pyrazolo[4,3-c]pyridine-5-carboxamide (P-103)
Figure imgf000146_0004
Step 1: Synthesis of tert- butyl 4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)ethynyl)piperidine- 1 -carboxylate
Figure imgf000147_0001
To a solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (300 mg, 0.89 mmol) in DMF (5 mL) were added terf-butyl 4-ethynylpiperidine-l-carboxylate (205 mg, 0.98 mmol), Pd(dppf)Cl2 (32.5 mg, 0.044 mmol), Cul (17 mg, 0.089 mmol) and TEA (899 mg, 8.9 mmol). The resulting mixture was stirred at 80 °C for 16 h under N . The reaction mixture was purified by reverse phase
chromatography to give the desired product (260 mg, yield 63%). MS (ESI) m/z. 410.5 [M-lBu+H]+.
Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-ylethynyl)isoindoline-l,3-dione
Figure imgf000147_0002
A mixture of terf-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)ethynyl)piperidine- 1-carboxylate (260 mg, 0.56 mmol) in DCM (10 mL) and TFA (1 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to give the crude product, which was used directly in the next step without further purification.
Step 3: Synthesis of tert- butyl 2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)ethynyl)piperidin- 1 -yl)acetate
Figure imgf000147_0003
A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-ylethynyl)isoindoline-l,3-dione (181 mg, 0.5 mmol), tert- butyl 2-bromoacetate (145 mg, 0.74 mmol) and DIEA (319 mg, 2.48 mmol) in DMF (5 mL) was stirred at 30 °C for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na2S0 . filtered and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 1: 1) to give the desired product (237 mg, yield 99%). MS (ESI) m/z: 480.9 [M+H]+.
Step 4: Synthesis of 2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)ethynyl)piperidin-l- yl)acetic acid
Figure imgf000147_0004
A mixture of terf-butyl 2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)ethynyl)piperidin-l-yl)acetate (237 mg, 0.49 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to give the desired product, which was used directly in the next step without further purification.
Step 4: Synthesis of 3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3,4-dihydroquinolin- 1 {2H)-y\)-\ -( 1 -(2-(4-((2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxoisoindolin-4-yl)ethynyl)piperidin- 1 - yl)acetyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-103)
Figure imgf000148_0001
P-103 was synthesized following the standard procedure for preparing P-001 (9.3 mg, yield 75%). MS (ESI) m/z: 931.0 [M+H]+.
Example 189. 3-(7-(Difluoromethyl)-6-( 1 -methyl- 1 /7-pyrazol-4-yl)-3, 4-dihydroquinolin- 1(2/7)- yl)-l-(l-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)ethyl)piperidin-l- yl)acetyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide (P-104)
Figure imgf000148_0002
P-104 was synthesized following the similar procedure for preparing P-085 (7.0 mg, yield 32%). MS (ESI) m/z: 935.0 [M+H]+.
Example 190. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-( l-(6-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2, 3-dihydro- l/7-benzo[r/]imidazol-l- yl)hexanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5-carboxamide
Figure imgf000148_0003
Step 1: Synthesis of tert- butyl 6-((2-nitrophenyl)amino)hexanoate
Figure imgf000148_0004
A mixture of l-fluoro-2 -nitrobenzene (528 mg, 3.74 mmol), tert- butyl 6-aminohexanoate (841 mg, 4.49 mmol) and TEA (1.14 g, 11.23 mmol) in EtOH (10 mL) was stirred at 85 °C overnight. The reaction mixture was concentrated to afford the crude product, which was used directly in the next step without further purification.
Step 2: Synthesis of tert- butyl 6-((2-aminophenyl)amino)hexanoate Pd/C,
EtOH
•
A mixture of terf-butyl 6-((2-nitrophenyl)amino)hexanoate (1.2 g, 3.89 mmol), Pd/C (100 mg) in EtOH (30 mL) was stirred under H2 at room temperature for 1.5 h. After the reaction mixture was filtered through a Celite cup, the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 8: 1 to 5: 1) to give the desired product (690 mg, yield 64%). (ESI) m/z. 279.7 [M+H]+.
Step 3: Synthesis of tert- butyl 6-(2-oxo-2.3-dihydro- 1 //-benzo|c/|imidazol- 1 -yl)hexanoate
Figure imgf000149_0001
To a solution of terf-butyl 6-((2-aminophenyl)amino)hexanoate (592 mg, 2.13 mmol) in THF (40 mL) was added CDI (517 mg, 3.19 mmol). The resulting mixture was stirred at room temperature for 16 h, before the reaction mixture was concentrated and diluted with EtOAc, and washed with water. The organic layer was dried over Na2SOzi, filtered and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 3: 1 to 2: 1) to give the desired product (579 mg, yield 89%). (ESI) m/z : 305.5 [M+H]+.
Step 4: Synthesis of tert- butyl 6-(3-(2.6-dioxopiperidin-3-yl)-2-oxo-2.3-dihydro- 1 H- benzo |c/|imidazol- 1 -yl)hexanoate
To a solution of tert- butyl 6-(2-ox
Figure imgf000149_0002
yl)hexanoate (550 mg, 1.81 mmol) in anhydrous DMF (2.2 ml) was added NaH (56 mg, 2.35 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 15 min, before a solution of 3-bromopiperidine-2,6-dione (173 mg, 0.90 mmol) in anhydrous DMF (2.2 mL) was added dropwise over 10 min. After the reaction mixture was stirred at room temperature overnight, it was quenched with water and extracted with EtOAc. The aqueous phase was adjusted to pH= 5~6 with citric acid and extracted with EtOAc. The combined organic layers were dried over Na2SOzi, filtered and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 2: 1 to 1: 1) to give desired product (170 mg, yield 23%). (ESI) m/z: 416.6 [M+H]+.
Step 5: Synthesis of 6-(3-(2.6-dioxopiperidin-3-yl)-2-oxo-2.3-dihydro- 1 //-benzo|c/|imidazol- 1 - yl)hexanoic acid
Figure imgf000149_0003
A mixtrue of terf-butyl 6-(3-(2.6-dioxopiperidin-3-yl)-2-oxo-2.3-dihydro- 1 //-benzo|c/|imidazol- 1 - yl)hexanoate (170 mg, 0.41 mmol) in DCM (3 mL) and TFA (3 mL) was stirred at room temperature for 0.5 h. The solvent was removed to afford the desired product (147 mg, yield 99%). (ESI) m/z. 360.6
[M+H]+. Step 6: Synthesis of 3-(7-(difluoromethyl)-6-(l-methyl-lH-pyrazol-4-yl)-3,4-dihydroquinolin- 1 (2H)-yl)- 1 -( 1 -(6-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2, 3-dihydro- lH-benzo[d]imidazol- 1 - yl)hexanoyl)piperidin-4-yl)-N-methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P- 105)
Figure imgf000150_0001
P-105 was synthesized following the standard procedure for preparing P-001 (10.8 mg, yield 65%). MS (ESI) m/z: 867.1 [M+H]+.
Example 191. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-( l-(7-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2, 3-dihydro- l/7-benzo[r/]imidazol-l- yl)heptanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-c]pyridine-5- carboxamide (P-106)
Figure imgf000150_0002
P-106 was synthesized following the similar procedure for preparing P-105 (13.4 mg, yield 80%). MS (ESI) m/z: 881.2 [M+H]+.
Example 192. 3-(3-(6-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-6- oxohexyl)-2-oxo-2, 3-dihydro- l/7-benzo[i/]imidazol-l-yl)piperidine-2,6-dione (P-107)
Figure imgf000150_0003
P-107 was synthesized following the standard procedure for preparing P-001 (8.4 mg, yield 50%). MS (ESI) m/z: 852.1 [M+H]+. Example 193. 3-(3-(7-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-7- oxoheptyl)-2-oxo-2, 3-dihydro- l/7-benzo[i/]imidazol-l-yl)piperidine-2,6-dione (P-108)
Figure imgf000151_0001
P-108 was synthesized following the standard procedure for preparing P-001 (9.7 mg, yield 57%). MS (ESI) m/z: 866.2 [M+H]+.
Example 194. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-(l-(6-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro- l/7-benzo[r/]imidazol-4- yl)amino)hexanoyl)piperidin-4-yl)-V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'J pyridine-5- carboxamide (P-109)
Figure imgf000151_0002
Step 1: Synthesis of 2-(methylamino)-3-nitrobenzoic acid
Figure imgf000151_0003
A mixture of 2-fluoro-3-nitrobenzoic acid (20 g, 108 mmol), methylamine hydrochloride (36.47 g, 540 mmol) and DIEA (167.25 g, 1.30 mol) in EtOH (300 mL) was stirred at 80 °C for 2 h. The reaction was concentrated and the residue was poured into ice water. The pH was adjusted to ~3 with aq. HC1. The aquoes phase was extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over NaaSOzi, fdtered and concentrated to give the desired product (24 g, yield 99%) as a yellow solid which was used directly in the next step.
Step 2: Synthesis of 1 -methyl-7-nitro- 1.3-dihydro-2//-benzo|c/|imidazol-2-one
Figure imgf000151_0004
A solution of 2-(methylamino)-3-nitrobenzoic acid (24 g, 122.35 mmol), DPPA (35.71 g, 146.82 mmol) and DIEA (31.63 g, 244.70 mmol) in lBuOH (250 mL) was stirred at 90 °C overnight. After the reaction mixture was concentrated, the residue was poured into ice water. The precipitate was collected by fdtration. The collected solid material was washed with water followed by EtOAc, dried in vacuum to give the desired product (22 g, yield 93%) as a yellow solid. (ESI) m!z. 194.1 [M+H]+. Step 3: Synthesis of 3-(3-methyl-4-nitro-2-oxo-2,3-dihydro-l//-benzo[i]imidazol-l-yl)piperidine- 2,6-dione
Figure imgf000152_0001
To a suspension ofNaH (48 mg, 1.20 mmol) in DMF (5 mL) was added 3-methyl-5-nitro- 1 H- benzimidazol-2-one (193 mg, 999.18 umol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, before a slolution of 3-bromopiperidine-2,6-dione (383.70 mg, 2.00 mmol) in DMF (5 mL) was added dropwise. After the completion of addition, the reaction mixture was stirred at 80 °C for 2 h. After concentration, the reaction was purified by prep-HPLC to give the desired product (80 mg, yield 26%) as a black solid. MS (ESI) m/z : 305.3 [M+H]+.
Step 4: Synthesis of 3-(4-amino-3-methyl-2-oxo-2,3-dihydro-l//-benzo[i]imidazol-l-yl)piperidine- 2,6-dione
Figure imgf000152_0002
To a solution of 3-(3-methyl-4-nitro-2-oxo-benzimidazol-l-yl)piperidine-2,6-dione (80 mg, 262.93 umol) in MeOH (10 mL) and THF (10 mL) was added Pd/C (20 mg) at room temperature. After the reaction mixture was stirred at room temperature for 1 h under hydrogen atmosphere, the reaction was filtered and concentrated to give the desired product (70 mg, yield 97%) as a brown solid, which was used in the next step directly without further purification. MS (ESI) m/z. 275.3 [M+H]+.
Step 5: Synthesis of 6-(( 1 -(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro- 1 H- benzo |c/|imidazol-4-yl)amino)hexanoic acid
Figure imgf000152_0003
A mixture of 3-(4-amino-3-mcthyl-2-oxo-2.3-dihydro- 1
Figure imgf000152_0004
yl)pipcridinc-2.6- dione (5 mg, 0.018 mmol) and 6-oxohexanoic acid (4.74 mg, 0.036 mmol) in 'PrOH (2 mL) and AcOH (2 mL) was stirred at 90 °C for 4 h. After the reaction was cooled to room temperature, NaBH3CN (2.3 mg, 0.036 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, before it was concentrated. The residue was purified by prep-TLC (DCM/MeOH = 10: 1) to give desired product (3 mg, yield 42%) as a white solid. MS (ESI) m/z 389.7 [M+H]+.
Step 6: Synthesis of 3-(7-(difluoromethyl)-6-(l-methyl-l//-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- l//-benzo[d]imidazol-4- yl)amino)hexanoyl)piperidin-4-yl)-A-methyl- 1,4,6, 7-tetrahydro-5//-pyrazolo [4,3 -c]pyridine-5- carboxamide (P-109)
Figure imgf000152_0005
P-109 was synthesized following the standard procedure for preparing P-001 (1.5 mg, yield 16%).
MS (ESI) m/z: 896.2 [M+H]+.
Example 195. 3-(4-((6-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-6- oxohexyl)amino)-3-methyl-2-oxo-2,3-dihydro-l/7-benzo[r/]imidazol-l-yl)piperidine-2,6-dione (P-110)
Figure imgf000153_0001
P-110 was synthesized following the standard procedure for preparing P-001 (2.0 mg, yield 22%). MS (ESI) m/z: 881.2 [M+H]+.
Example 196. 3-(4-((7-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-6jpyridin-l-yl)piperidin-l-yl)-7- oxoheptyl)amino)-3-methyl-2-oxo-2, 3-dihydro- l/7-benzo[r/Jimidazol-l-yl)piperidine-2,6-dione (P- 111)
Figure imgf000153_0002
P-111 was synthesized following the similar procedure for preparing P-109 (2.5 mg, yield 11%). MS (ESI) m/z: 895.2 [M+H]+.
Example 197. 4-((6-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-6'Jpyridin-l-yl)piperidin-l- yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-112)
Figure imgf000153_0003
P-112 was synthesized following the similar procedure for preparing P-090 (45 mg, yield 55%). MS (ESI) m/z: 866.0 [M+H]+.
Example 198. 4-((6-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-6'Jpyridin-l-yl)piperidin-l- yl)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-113)
Figure imgf000154_0001
P-113 was synthesized following the similar procedure for preparing P-090 (55 mg, yield 67%). MS (ESI) m/z: 867.0 [M+H]+.
Example 199. 3-(7-(Difluoromethyl)-6-( 1 -methyl- l/7-pyrazol-4-yl)-3,4-dihydroquinolin- 1(2/7)- yl)-l-( l-(7-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro- l/7-benzo[r/]imidazol-4- yl)amino)heptanoyl)piperidin-4-yl)-V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'Jpyridine-5- carboxamide (P-114)
Figure imgf000154_0002
P-114 was synthesized following the standard procedure for preparing P-001 (1.4 mg, yield 6%). MS (ESI) m/z: 910.2 [M+H]+.
Example 200. 3-(7-(Difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4-dihydroquinolin-l(2/7)- yl)-l-( l-(6-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro- l/7-benzo[r/]imidazol-5- yl)amino)hexanoyl)piperidin-4-yl)-V-methyl-l,4,6,7-tetrahydro-5/7-pyrazolo[4,3-6'J pyridine-5- carboxamide (P-115)
Figure imgf000154_0003
P-115 was synthesized following the standard procedure for preparing P-001 (4.4 mg, yield 21%).
MS (ESI) m/z: 896.0 [M+H]+.
Example 201. 3-(5-((6-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l-methyl-l/7-pyrazol-4-yl)-3,4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-6- oxohexyl)amino)-3-methyl-2-oxo-2,3-dihydro-l/7-benzo[r/Jimidazol-l-yl)piperidine-2,6-dione (P-116)
Figure imgf000154_0004
P-116 was synthesized following the standard procedure for preparing P-001 (3.8 mg, yield 19%). MS (ESI) m/z: 881.0 [M+H]+. Example 202. 4-((6-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-6- oxohexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-117)
Figure imgf000155_0001
P-117 was synthesized following the standard procedure for preparing P-001 (37.1 mg, yield 72%). MS (ESI) m/z: 880.9 [M+H]+.
Example 203. 4-(7-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-7- oxoheptyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-118)
Figure imgf000155_0002
P-118 was synthesized following the standard procedure for preparing P-001 (37.0 mg, yield 72%). MS (ESI) m/z: 879.0 [M+H]+.
Example 204. 5-((8-(4-(5-Acetyl-3-(7-(diiluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-6jpyridin-l-yl)piperidin-l-yl)-8- oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P
Figure imgf000155_0004
Figure imgf000155_0003
P-119 was synthesized following the standard procedure for preparing P-001 (28.5 mg, yield 80%). MS (ESI) m/z: 908.0 [M+H]+.
Example 205. 5-((6-(4-(5-Acetyl-3-(7-(diiluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-6jpyridin-l-yl)piperidin-l-yl)-6- oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (
Figure imgf000155_0006
Figure imgf000155_0005
P-120 was synthesized following the standard procedure for preparing P-001 (36.8 mg, yield 71%). MS (ESI) m/z: 879.9 [M+H]+.
Example 206. 3-(4-((6-(4-(5-Acetyl-3-(7-(diiluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-6jpyridin-l-yl)piperidin-l-yl)-6- oxohexyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (P-121)
Figure imgf000156_0001
P-121 was synthesized following the standard procedure for preparing P-001 (42 mg, yield 76%). MS (ESI) m/z: 867.0 [M+H]+.
Example 207. 3-(4-(7-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-7- oxohept-l-yn-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (P-122)
Figure imgf000156_0002
P-122 was synthesized following the standard procedure for preparing P-001 (38.8 mg, yield 77%). MS (ESI) m/z: 860.9 [M+H]+.
Example 208. 4-((( l-(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( l -methyl- l/7-pyrazol-4-yl)-3, 4- dihydroquinolin-l(2/7)-yl)-4,5,6,7-tetrahydro-l/7-pyrazolo[4,3-6jpyridin-l-yl)piperidin-l-yl)-2- oxoethyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-123)
Figure imgf000156_0003
P-123 was synthesized following the standard procedure for preparing P-001 (36.9 mg, yield 68%). MS (ESI) m/z: 921.0 [M+H]+.
Example 209. /V-(3-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 -yl)propyl)-2- ((2-(2,6-dioxopiperidin-3 -yl)-l ,3 -dioxoisoindolin-4-yl)amino)acetamide (P- 124)
Figure imgf000156_0004
Step 1: Synthesis of tert- butyl (3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)- 3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 - yl)propyl)carbamate
Figure imgf000156_0005
A mixture of 1 -(3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2H)-\\)- 1 -(pipcridin-4-yl)- 1.4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridin-5-yl)cthan- 1 -one (5 mg, 0.0098 mmol), tert- butyl (3-bromopropyl)carbamate (3.04 mg, 0.0128 mmol), Nal (1.47 mg, 0.0098 mmol), and DIEA (3.80 mg, 0.029 mmol) in DMF (2 mL) was stirred at 60 °C for 16 h. After the reaction mixture was concentrated, the resulting residue was purified by prep-TLC to give the desired product (6 mg, 92% yield). MS (ESI) m/z: 668.1 [M+H]+.
Step 2: Synthesis of 1 -( 1 -( l -(3-aminopropyl)piperidm-4-yl)-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 H- pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridin-5-yl)cthan- 1 - one
Figure imgf000157_0001
To a solution of terf-butyl (3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 - yl)propyl)carbamate (13 mg, 0.0195 mmol) in DCM (4 mL) was added HCl/dioxane (4 mL). The resulting mixture was stirred at room temperature for 2 h. After the reaction mixture was concentrated, the resulting residue was washed with EtOAc to give the desired product (10 mg, 91% yield). MS (ESI) m/z 567.8 [M+H]+.
Step 3: Synthesis of /V-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 /-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 -yl)propyl)-2- ((2-(2,6-dioxopiperidin-3 -yl)-l ,3 -dioxoisoindolin-4-yl)amino)acetamide (P-124)
Figure imgf000157_0002
P-124 was synthesized following the standard procedure for preparing P-001 (16 mg, yield 99%). MS (ESI) m/z·. 881.0 [M+H]+.
Example 210. 3-(7-(Difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3,4-dihydroquinolin-l(2//)-yl)- 1 -( 1 -(5 -(( 1 -(2,6-dioxopiperidin-3 -yl)-3 -methyl-2-oxo-2.3-dihydro- 1 //-benzo |c/|imidazol-5- yl)amino)pcntanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5- carboxamide (P-125)
Figure imgf000157_0003
P-125 was synthesized following the standard procedure for preparing P-001 (1.46 mg, yield 9%). MS (ESI) m/z·. 882.0 [M+H]+.
Example 211. 3 -(5 -((5 -(4-(5 -Acetyl-3 -(7-(difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 -yl)-5- oxopcntyl)amino)-3-mcthyl-2-oxo-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)pipcridinc-2.6-dionc (P-126)
Figure imgf000158_0001
P-126 was synthesized following the standard procedure for preparing P-001 (1.75 mg, yield 10%). MS (ESI) m/z: 866.9 [M+H]+.
Example 212. 3-(7-(Difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3,4-dihydroquinolin-l(2//)-yl)- 1 -( 1 -(5 -(( 1 -(2,6-dioxopiperidin-3 -yl)-3 -mcthyl-2-oxo-2.3-dihydro- 1 //-bcnzo |c/|imidazol-4- yl)amino)pcntanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5- carboxamide (P-127)
Figure imgf000158_0002
P-127 was synthesized following the standard procedure for preparing P-001 (2.1 mg, yield 13%). MS (ESI) m/z: 882.0 [M+H]+.
Example 213. 3-(4-((5-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 -yl)-5- oxopcntyl)amino)-3-mcthyl-2-oxo-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)pipcridinc-2.6-dionc (P-128)
Figure imgf000158_0003
P-128 was synthesized following the standard procedure for preparing P-001 (3.2 mg, yield 19%). MS (ESI) m/z: 867.0 [M+H]+.
Example 214. 3-(7-(Difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)- 1 -( 1 -(7 -(( 1 -(2,6-dioxopiperidin-3 -yl)-3 -mcthyl-2-oxo-2.3-dihydro- 1 //-bcnzo |c/|imidazol-5- yl)amino)hcptanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridinc-5- carboxamide (P-129)
Figure imgf000158_0004
P-129 was synthesized following the standard procedure for preparing P-001 (4.2 mg, yield 48%). MS (ESI) m/z: 910.1 [M+H]+.
Example 215. 3-(5-((7-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-7- oxohcptyl)amino)-3-mcthyl-2-oxo-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)pipcridinc-2.6-dionc (P-130)
Figure imgf000159_0001
P-130 was synthesized following the standard procedure for preparing P-001 (3.6 mg, yield 41%). MS (ESI) m/z: 895.1 [M+H]+.
Example 216. 4-(2-( 1 -(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-131)
Figure imgf000159_0002
P-131 was synthesized following the standard procedure for preparing P-104 (107 mg, yield 25%). MS (ESI) m/z: 920.1 [M+H]+.
Example 217. 4-(7-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 -yl)hcptyl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-132)
Figure imgf000159_0003
P-132 was synthesized following the standard procedure for preparing P-097 (22 mg, yield 38%). MS (ESI) m/z: 865.1 [M+H]+.
Example 218. 2-(4-( 1 -(5-Acetyl- 1 -(tetrahydro-2H-pyran-4-yl)-4.5.6.7-tetrahydro- 17/-pyrazolo|4.3- r |pyridin-3-yl)-7-(difluoromcthyl)- 1 2.3.4-tctrahydroquinolin-6-yl)- 1 //-pyrazol- 1 -yl)-/V-(7-((2-(2.6- dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)amino)heptyl)acetamide (P-133)
Figure imgf000160_0001
P-133 was synthesized following the standard procedure for preparing P-026 (10.5 mg, yield 23%). MS (ESI) m/z: 924.0 [M+H]+.
Example 219. 4-(2-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)-| 1 4'-bipipcridin |- G- yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-134)
Figure imgf000160_0002
Step 1: Synthesis of tert- butyl 4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)-[ 1 ,4'-bipiperidine]- 1 '- carboxylate
Figure imgf000160_0003
A mixture of 1 -(3 -( 7-(difl uo romethy l )-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2H)-\\)- 1 -(pipcridin-4-yl)- 1.4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridin-5-yl)cthan- 1 -one (150 mg, 0.295 mmol), tert- butyl 4-oxopiperidine-l -carboxylate (88 mg, 0.442 mmol), and Ti(iPrO)4 (168 mg, 0.59 mmol) in anhydrous THF (5 mL) was refluxed for 2.5 h under N . After the reaction was cooled to room
temperature, NaBH3CN (74 mg, 1.18 mmol) was added. After the resulting mixture was stirred at room temperature overnight, the reaction mixture was purified by reverse phase chromatography to give the desired product (88 mg, 43% yield) as a white solid. MS (ESI) mlz· 694.1 [M+H]+.
Step 2: Synthesis of 1 -( 1 -(| 1.4'-bi pipe ridi n |-4-yl)-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4- yl)-3.4-dihydroquinolin- 1 (2 /)-yl )- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridin-5-yl)ethan- 1 -one
Figure imgf000160_0004
A mixture of terf-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)-[ 1 ,4'-bipiperidine]- 1 '- carboxylate (88 mg, 0.127 mmol) in TFA/DCM (2 mL, 1 : 1) was stirred at room temperature for 1 h. The reaction was purified by reverse phase chromatography to give the desire product (78 mg, 99% yield) as a white solid. MS (ESI) m/z: 593.8 [M+H]+.
Step 3: Synthesis of 1 -( 1 -(| 1.4'-bi pipe ridi n |-4-yl)-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 /-pyrazol-4- yl)-3.4-dihydroquinolin- 1 (2H)-y\)- 1 4.6.7-tctrahydro-5//-pyrazolo|4.3-r |pyridin-5-yl)ethan- 1 -one (P-134)
Figure imgf000161_0001
P-134 was synthesized following the standard procedure for preparing P-090 (13.2 mg, yield 38%). MS (ESI) m/z : 894.0 [M+H]+.
Example 220. 3-(3-(8-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-8-oxooctyl)- 2 2 3-dihydro- 1 //-benzo|c/|imidazol- 1 -yl)pipcridinc-2.6-dionc (P-135)
Figure imgf000161_0002
P-135 was synthesized following the standard procedure for preparing P-105 (25 mg, yield 37%). MS (ESI) m/z : 880.1 [M+H]+.
Example 221. 6-(4-(5 -Acetyl-3 -(7-(difluoromethyl)-6-(l -methyl- l//-pyrazol-4-yl)-3 ,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-/V-(2-(2.6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hexanamide (P-136)
Figure imgf000161_0003
P-136 was synthesized following the standard procedure for preparing P-124 (28 mg, yield 99%). MS (ESI) m/z : 880.0 [M+H]+.
Example 222. 3-(7-(Difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(2-(4-((2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-4-yl)methyl)piperazin- 1 -yl)acetyl)piperidin- 4-yl)-/V-methyl-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-137)
Figure imgf000162_0001
P-137 was synthesized following the standard procedure for preparing P-101 (40 mg, yield 99%). MS (ESI) m/z. 922.0 [M+H]+.
Example 223. 4-((4-(2-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl
Figure imgf000162_0002
P-138 was synthesized following the standard procedure for preparing P-001 (34 mg, yield 86%). MS (ESI) m/z: 907.0 [M+H]+.
Example 224. 4-(3-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)-| 1 4'-bipipcridin |- G- yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-139)
Figure imgf000162_0003
P-139 was synthesized following the standard procedure for preparing P-134 (39.8 mg, yield: 50%). MS (ESI) m/z : 908.0 [M+H]+.
Example 225. 4-(3 -(3 -(4-(5 -Acetyl-3 -(7-(difluoromethyl)-6-(l -methyl- l//-pyrazol-4-yl)-3, 4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)azetidin- 1 - yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-140)
Figure imgf000163_0001
P-140 was synthesized following the standard procedure for preparing P-134 (17.7 mg, yield: 23%). MS (ESI) m/z: 880.0 [M+H]+.
Example 226. 4-(((4-(2-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl)morpholin-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-141)
Figure imgf000163_0002
P-141 was synthesized following the standard procedure for preparing P-001 (50 mg, yield: 92%). MS (ESI) m/z: 923.0 [M+H]+.
Example 227. 4-(((4-(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl)morpholin-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-142)
Figure imgf000163_0003
P-142 was synthesized following the standard procedure for preparing P-124 (24.9 mg, yield: 29%). MS (ESI) m/z: 909.0 [M+H]+.
Example 228. 4-((( 1 -(2-(4-(5 -Acetyl-3 -(7 -(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 - yl)ethyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-143)
Figure imgf000164_0001
P-143 was synthesized following the standard procedure for preparing P-142 (2 mg, yield: 19%). MS (ESI) m/z: 906.9 [M+H]+.
Example 229. 3-(7-(Difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2 /)-yl)- 1 -( 1 -(2-(4-((2-(2,6-dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-4-yl)methyl)piperazin- 1 -yl)ethyl)piperidin-4- yl)-/V-methyl- 1,4, 6, 7-tetrahydro-5//-pyrazolo [4, 3 -c]pyridine-5 -carboxamide (P-144)
Figure imgf000164_0002
P-144 was synthesized following the standard procedure for preparing P-156 (7.3 mg, yield: 49%). MS (ESI) m/z: 908.0 [M+H]+.
Example 230. 4-((4-(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 - yl)ethyl)piperazin-l-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-145)
Figure imgf000164_0003
P-145 was synthesized following the standard procedure for preparing P-156 (7.5 mg, yield: 40%). MS (ESI) m/z: 892.9 [M+H]+.
Example 231. 4-(3-(4-(4-(5 -Acetyl-3 -(7-(difluoromethyl)-6-(l -methyl- l//-pyrazol-4-yl)-3, 4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-4- oxobutyl)azetidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-146)
Figure imgf000164_0004
P-146 was synthesized following the standard procedure for preparing P-001 (105 mg, yield: 78%). MS (ESI) m/z: 891.9 [M+H]+. Example 232. 4-(3 -( 1 -(2-(4-(5 -Acetyl-3 -(7 -(difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3 ,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl)piperidin-4-yl)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-147)
Figure imgf000165_0001
P-147 was synthesized following the standard procedure for preparing P-001 (5 mg, yield: 6%). MS (ESI) m/z: 934.0 [M+H]+.
Example 233. 4-(2-( 1 -(3 -(4-(5 -Acetyl-3 -(7 -(difluoromethyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-3- oxopropyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P-148)
Figure imgf000165_0002
P-148 was synthesized following the standard procedure for preparing P-001 (39 mg, yield: 62%). MS (ESI) m/z: 934.0 [M+H]+.
Example 234. 4-(3-(4-((4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 - yl)methyl)piperidin-l-yl)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-149)
Figure imgf000165_0003
P-149 was synthesized following the standard procedure for preparing P-142 (16 mg, yield: 17%). MS (ESI) m/z: 906.0 [M+H]+.
Example 235. 4-(3-(4-((4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 - yl)methyl)piperidin- 1 -yl)prop- 1 -yn- 1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1 ,3-dione (P-150)
Figure imgf000166_0001
P-150 was synthesized following the standard procedure for preparing P-142 (12 mg, yield: 26%). MS (ESI) m/z: 901.9 [M+H]+.
Example 236. 3-(5-((6-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-6- oxohcxyl)amino)-4-oxobcnzo|c/|| 1.2.3 |triazin-3(4//)-yl)pipcridinc-2.6-dionc (P-151)
Figure imgf000166_0002
P-151 was synthesized following the standard procedure for preparing P-001 (8.8 mg, yield: 40%). MS (ESI) m/z: 880.0 [M+H]+.
Example 237. 3 -(5 -((7 -(4-(5 -Acetyl-3 -(7-(difluoromethyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-7- oxoheptyl )am i no)-2-methyl -4-oxoquinazol in-3(4//)-yl )piperidi ne-2.6-dione (P-152)
Figure imgf000166_0003
P-152 was synthesized following the standard procedure for preparing P-151 (13 mg, yield: 59%). MS (ESI) m/z: 907.0 [M+H]+.
Example 238. 3 -(5 -((7 -(4-(5 -Acetyl-3 -(7-(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-7- oxoheptyl)amino)-4-oxobenzo[i][l, 2, 3]triazin-3(4//)-yl)piperidine-2, 6-dione (P-153)
Figure imgf000167_0001
P-153 was synthesized following the standard procedure for preparing P-151 (9 mg, yield: 40%). MS (ESI) m/z: 894.0 [M+H]+.
Example 239. 3 -(5 -((5 -(4-(5 -Acetyl-3 -(7-(difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 -yl)-5- oxopcntyl)amino)-2-mcthyl-4-oxoquinazolin-3(4//)-yl)pipcridinc-2.6-dionc (P-154)
0
Figure imgf000167_0002
P-154 was synthesized following the standard procedure for preparing P-151 (11 mg, yield: 40%). MS (ESI) m/z: 879.0 [M+H]+.
Example 240. 3 -(5 -((5 -(4-(5 -Acetyl-3 -(7-(difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-5- oxopcntyl)amino)-4-oxobcnzo|c/|| 1.2.3 |triazin-3(4//)-yl)piperidine-2.6-dione (P-155)
o
Figure imgf000167_0003
P-155 was synthesized following the standard procedure for preparing P-151 (13 mg, yield: 43%). MS (ESI) m/z: 865.9 [M+H]+.
Example 241. 4-((3-(3-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 -yl)-3- oxopropyl)azetidin-l-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-156)
Figure imgf000168_0001
Step 1. Synthesis of 1 -(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-3-(azctidin- 3 -yl)propan- 1 -one
Figure imgf000168_0002
A mixture of 1 -(3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4-dihydroquinolin- 1 (2H)-\\)- 1 -(piperidin-4-yl)- 1.4.6.7-tetrahydro-5 //-pyrazolo|4.3-r |pyridin-5-yl )ethan- 1 -one (180 mg, 0.354 mmol), 3-(l-(terf-butoxycarbonyl)azetidin-3-yl)propanoic acid (81 mg, 0.354 mmol), EDCI (102 mg, 0.531 mmol), HO At (72 mg, 0.531 mmol) and NMM (107 mg, 1.062 mmol) in DMSO (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with water, dried over Na2SOzi, fdtered and concentrated. The residue was purified by silica gel column chromatography to give a crude product (110 mg), which was dissolved in DCM (5 mL) followed by addition of TFA (1 mL). The resulting mixture was stirred at room temperature for 3 h, before it was concentrated. The resulting residue was purified by Prep-TLC to give desired product (23 mg, 10% for 2 steps) which was used directly in the next step.
Step 2. Synthesis of 4-((3-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 -yl)-3- oxopropyl)azetidin- 1 -yl)methyl)-2-(2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione
Figure imgf000168_0003
P-156 was synthesized following the standard procedure for preparing P-142 (20 mg, yield: 61%). MS (ESI) m/z: 891.9 [M+H]+.
Example 242. 4-(2-( 1 -(2-(4-(5 -Acetyl-3 -(7 -(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 - yl)ethyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-157)
Figure imgf000168_0004
P-157 was synthesized following the standard procedure for preparing P-142 (13 mg, yield: 16%). MS (ESI) m/z: 905.9 [M+H]+. Example 243. 4-((( 1 -(2-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2 /)-yl)-4.5.6.7-tetrahydro- 1 /-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl)azetidin-3 -yl)methyl)amino)-2-(2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P-158)
Figure imgf000169_0001
P-158 was synthesized following the standard procedure for preparing P-001 (77 mg, yield: 88%). MS (ESI) m/z: 892.9 [M+H]+.
Example 244. 3-(4-((8-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-8- oxooctyl)amino)-3 dionc (P-159)
Figure imgf000169_0002
P-159 was synthesized following the standard procedure for preparing P-109 (4.4 mg, yield: 40%). MS (ESI) m/z: 909.1 [M+H]+.
Example 245. 3-(4-((9-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-9- oxononyl)amin onc (P-160)
Figure imgf000169_0003
P-160 was synthesized following the standard procedure for preparing P-109 (5.4 mg, yield: 36%). MS (ESI) m/z: 923.1 [M+H]+.
Example 246. 3-(5-((8-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-8- oxooctyl)amino)-3-mcthyl-2-oxo-2.3-dihydro- 1 //-benzo|c/|imidazol- l -yl)piperidine-2.6-dione (P-161)
Figure imgf000170_0001
P-161 was synthesized following the standard procedure for preparing P-109 (3.5 mg, yield: 32%). MS (ESI) m/z: 909.0 [M+H]+.
Example 247. 3-(5-((9-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 /-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-9- oxononyl)amino)- 6-dionc (P-162)
Figure imgf000170_0002
CO¾
P-162 was synthesized following the standard procedure for preparing P-109 (4.3 mg, yield: 40%). MS (ESI) m/z: 923.0 [M+H]+.
Example 248. 3 -(3 -(9-(4-(5 -Acetyl-3 -(7-(difluoromethyl)-6-(l -methyl- l//-pyrazol-4-yl)-3, 4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-9- oxononyl)-2-ox
Figure imgf000170_0003
P-163 was synthesized following the standard procedure for preparing P-105 (48 mg, yield: 72%). MS (ESI) m/z: 894.0 [M+H]+.
Example 249. 3 -(3 -( 10-(4-(5 -Acetyl-3 -(7 -(difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3 ,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-l 0- oxodecyl)-2-oxo-2.3-dihydro- 1 //-benzo|c/|imidazol- 1 -yl)pipcridinc-2.6-dionc (P-164)
Figure imgf000171_0001
P-164 was synthesized following the standard procedure for preparing P-105 (37 mg, yield: 56%). MS (ESI) m/z: 908.0 [M+H]+.
Example 250. 3-(5-((6-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-6- oxohcxyl)amino)-2-mcthyl-4-oxoqiiinazolin-3(4//)-yl)pipcridinc-2.6-dionc (P-165)
Figure imgf000171_0002
P-165 was synthesized following the standard procedure for preparing P-151 (6.2 mg, yield: 35%). MS (ESI) m/z: 892.9 [M+H]+.
Example 251. 3-(4-((4-((4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 - yl)methyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (P-166)
Figure imgf000171_0003
Step 1. Synthesis of (4-(((f<?rf-butyldimethylsilyl)oxy)methyl)phenyl)methanol
Figure imgf000171_0004
To a solution of 1,4-phenylenedimethanol (13.8 g, 99.88 mmol) in DCM (400 mL) was added imidazole (13.6 g, 199.76 mmol) followed by TBSC1 (15.05 g, 99.88 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h, before it was concentrated. The resulting residue was purified by silica gel chromatography (petroleum ether : EtOAc = 10: 1 to 5: 1) to give the desired product (15 g, yield: 59%) as colorless oil. Step 2. Synthesis of ((4-(bromomethyl)benzyl)oxy)(f<?rf-butyl)dimethylsilane
Figure imgf000172_0001
To a solution of (4-(((terf-butyldimethylsilyl)oxy)methyl)phenyl)methanol (252 mg, 1 mmol) in DCM (10 mL) were added CBr4 (496 mg, 1.5 mmol) and PPh3 (392 mg, 1.5 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 4 h, before it was concentrated. The resulting residue was purified by prep-TLC to give the desired product (240 mg, yield: 76%) as white solid.
Step 3. Synthesis of 3-(4-((4-(hydroxymethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000172_0002
To a solution of ((4-(bromomethyl)benzyl)oxy)(f<?rf-butyl)dimethylsilane (770 mg, 2.44 mmol) and 3 -(4-hydroxy- l-oxoisoindolin-2-yl)piperidine-2,6-dione (635 mg, 2.44 mmol) in DMF (10 mL) was added K2C03 (674 mg, 4.88 mmol). The resulting mixture was stirred at 40 °C for 16 h, before TBAF (2.55 g, 9.77 mmol) was added. The reaction mixture was purified by prep-HPLC to give the desired product (450 mg, yield: 48%) as white solid. MS (ESI) m/z: 381.3 [M+H]+.
Step 4. Synthesis of 3-(4-((4-(bromomethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000172_0003
To a solution of 3-(4-((4-(hydroxymethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.26 mmol) in DCM (10 mL) were added CBr4 (105 mg, 0.32 mmol) and PPh3 (103 mg, 0.39 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, before it was concentrated. The resulting residue was purified by silica gel chromatography (DCM/MeOH = 30: 1 to 15: 1) to give the desired product (90 mg, yield: 77%) as white solid. MS (ESI) m/z: 443.1 [M+H]+.
Step 5. Synthesis of 3-(4-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 - yl)methyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure imgf000172_0004
P-166 was synthesized following the standard procedure for preparing P-143 (50 mg, yield: 63%). MS (ESI) m/z: 873.1 [M+H]+.
Example 252. 4-(( 1 -(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 - yl)ethyl)piperidin-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-167)
Figure imgf000173_0001
P-167 was synthesized following the standard procedure for preparing P-157 (4 mg, yield: 9%). MS (ESI) m/z: 907.0 [M+H]+.
Example 253. 4-(( 1 -(2-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl)piperidin-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-168)
Figure imgf000173_0002
P-168 was synthesized following the standard procedure for preparing P-001 (16.5 mg, yield: 77%). MS (ESI) m/z: 921.9 [M+H]+.
Example 254. 4-(2-(4-(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl)piperazin- 1 -yl)ethyl)-2-(2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P-169)
Figure imgf000173_0003
P-169 was synthesized following the standard procedure for preparing P-001 (32 mg, yield: 75%). MS (ESI) m/z: 921.0 [M+H]+.
Example 255. 4-((2-( 1 -(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl)azetidin-3-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-170)
Figure imgf000174_0001
P-170 was synthesized following the standard procedure for preparing P-001 (2.1 mg, yield: 19%). MS (ESI) m/z: 906.8 [M+H]+.
Example 256. 4-((6-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-6-oxohex-3- yn- 1 -yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1 ,3-dione (P-171)
Figure imgf000174_0002
P-171 was synthesized following the standard procedure for preparing P-001 (6.4 mg, yield: 56%). MS (ESI) m/z: 875.9 [M+H]+.
Example 257. 4-((2-(4-(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- l//-pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-2- oxoethyl)morpholin-2-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-172)
Figure imgf000174_0003
P-172 was synthesized following the standard procedure for preparing P-001 (16 mg, yield: 76%). MS (ESI) m/z: 936.9 [M+H]+.
Example 258. 3-(4-((4-(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 - yl)ethyl)benzyl)oxy)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dione (P-173)
Figure imgf000174_0004
P-173 was synthesized following the standard procedure for preparing P-166 (41 mg, yield: 42%). MS (ESI) m/z : 886.8 [M+H]+.
Example 259. 3-(4-(4-((4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4- dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 //-pyrazolo|4.3-r |pyridin- 1 -yl)piperidin- 1 - yl)methyl)phenethoxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (P-174)
Figure imgf000175_0001
P-174 was synthesized following the standard procedure for preparing P-166 (4.2 mg, yield: 37%). MS
(ESI) m/z: 887.1 [M+H]+.
Certain compounds disclosed herein have the structures shown in Table 1.
Table 1
Figure imgf000175_0002
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
As used herein, in case of discrepancy between the structure and chemical name provided for a particular compound, the structure shall control.
Example 260. Bivalent compounds reduced P300 protein levels (Fig. 1).
LNCaP cells were treated with DMSO or indicated bivalent compounds at 5 nM for 6 hours. P300 protein levels were markedly reduced following treatment of some compounds as shown by
immunoblotting assays.
Example 261. Bivalent compounds concentration dependently reduced P300 protein levels (Fig.
2).
LNCaP cells were treated with bivalent compounds at indicated concentrations for 16 hours. Data showed that P300 proteins levels were reduced in a concentration-dependent manner. The concentrations required to reduce P300 by 50% (DC50) were below 5 nM for the selected compounds.
Example 262. Bivalent compounds rapidly reduced P300 protein levels (Fig. 3).
LNCaP cells were treated with selected bivalent compounds at 20 nM for indicated period of time. Data showed that P300 protein levels were significantly reduced as early as 2 hours following treatment.
Example 263. Bivalent compounds suppressed viability of LNCaP prostate cancer cells (Fig. 4).
LNCaP cells were treated with GNE-781 or selected bivalent compounds for 3 days at indicated concentrations following a 3-fold serial dilution. Data showed that cell viability was significantly reduced in the presence of bivalent compounds in a concentration-dependent manner.
Example 264. Bivalent compounds reduced P300/CBP protein levels (Fig. 5).
LNCaP cells were treated with DMSO or indicated bivalent compounds at 20 nM or 100 nM for 16 hours. P300/CBP protein levels were markedly reduced following treatment of some compounds as shown by immunoblotting assays.
Example 265. Bivalent compounds concentration-dependently reduced P300/CBP protein levels (Fig. 6). LNCaP cells were treated with compounds at indicated concentrations for 6 hours. Data showed that P300/CBP proteins levels were reduced in a concentration-dependent manner. The concentrations required to reduce P300/CBP by 50% (DC50) were below 1 nM for the selected compounds.
Example 266. Bivalent compound-mediated degradation of P300 is dependent on the interaction with cereblon (Fig. 7).
LNCaP or 22RV1 cells were treated with various concentrations of P-100 or P-100-negative. The latter lost binding to cereblon (CRBN) due to a chemical modification. Data showed that P-100 reduced P300 protein levels in a concentration-dependent manner while P-100-neg had no effects on P300 protein levels.
Example 267. Bivalent compound-mediated degradation of P300/CBP is dependent on the ubiqutin-proteasome system (Fig. 8).
LNCaP cells were treated with a single dose of bivalent compounds, P-007, P-034 or P-100, or combination with pomalidomide, MG-132, Bortezomib, MLN4924. Data showed that bivalent compound- mediated degradation of P300/CBP is compromised by excessive CRBN ligand, pomalidomide, proteasome inhibitors, MG-132 or Bortezomib, or cullin E3 ligase inhibitor, MLN4924.
Example 268. Bivalent compounds reduced P300/CBP protien levels in 22RV1 subcutaneous xenograft tumors (Fig. 9).
Athymic nude mice bearing 22RV 1 subcutaneous xenograft tumors at the right flank were intraperitoneally or orally treated with selected bivalent compounds at 40 mg/kg. Six hours after drug administrateion, animals were sacrificed, and xenograft tumors were collected for immunoblotting of P300 and CBP.
Example 269. Bivalent compounds concentration-dependently reduced P300/CBP protein levels (Fig. 10).
LNCaP (Fig. 10A-B) or 22RV1 (Fig. 10C-E) cells were treated with bivalent compounds at indicated concentrations for 6 hours. Data showed that P300/CBP proteins levels were reduced in a concentration- dependent manner. The concentrations required to reduce P300/CBP by 50% (DC50) were below 1 nM for the selected compounds.
Example 270. Bivalent compounds concentration-dependently reduced P300/CBP protein levels (Fig. 11).
FNCaP (Fig. 11B-E) or 22RV1 (Fig. 11A) cells were treated with bivalent compounds at indicated concentrations for 6 hours. Data showed that P300/CBP proteins levels were reduced in a concentration- dependent manner. The concentrations required to reduce P300/CBP by 50% (DC50) were below 1 nM for the selected compounds.
Example 271. Bivalent compounds reduced CBP protien levels in the lung tissues of ICR mice (Fig. 12).
ICR mice were orally treated with 40 mg/kg bivalent compounds. Six hours after drug administration, animals were sacrificed, and the ling tissues were collected for immunoblotting of mouse CBP.
Materials and Methods:
General Chemistry Methods:
All chemicals and reagents were purchased from commercial suppliers and used without further purification. FCMS spectra for all compounds were acquired using a Shimadzu FC-MS 2020 system or a Waters UPFC-MS H class system. The Shimadzu FC-MS 2020 system comprising a pump (FC-20AD) with degasser (DGU-20A3), an autosampler (SIF-20AHT), a column oven (CTO-20A) (set at 40 °C, unless otherwise indicated), a photo-diode array (PDA) (SPD-M20A) detector, an evaporative light- scattering (EFSD) (Alltech 3300EFSD) detector. Chromatography was performed on a Shimadzu SunFire C 18 (5 mhi 50 * 4.6mm) with water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B at a flow rate of 2.0 ml/min. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Labsolution data system. The Waters UPLC- MS H class system comprising a pump (Quaternary Solvent Manager) with degasser, an autosampler (FTN), a column oven (set at 40 °C, unless otherwise indicated), a photo-diode array PDA detector.
Chromatography was performed on a AcQuity UPLC BEH C18 ( 1.7 pm 50 * 2.1mm) with water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B at a flow rate of 0.6 mL/min. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a MassLynx data system. Proton Nuclear Magnetic Resonance ('H-NMR) spectra were recorded on a Bruker Avance III400 spectrometer. Chemical shifts are expressed in parts per million (ppm) and reported as d value (chemical shift d). Coupling constants are reported in units of hertz (/value, Hz; Integration and splitting patterns: where s = singlet, d = double, t = triplet, q = quartet, brs = broad singlet, m = multiple). Preparative HPLC was performed on Agilent Prep 1260 series with UV detector set to 254 nm or 220 nm. Samples were injected onto a Phenomenex Luna 75 x 30 mm, 5 pm,
C18 column at room temperature. The flow rate was 40 mL/min. A linear gradient was used with 10% (or 50%) of MeOH (A) in H20 (with 0.1 % TFA) (B) to 100% of MeOH (A). All compounds showed > 90% purity using the LCMS methods described above.
Cell Culture
LNCaP (clone FGC), 22RV1 and other cells were cultured at 37°C with 5% C02 in RPMI 1640 Medium supplemented with 10% fetal bovine serum. Cells were authenticated using the short tandem repeat (STR) assays. Mycoplasma test results were negative.
Antibodies and reagents
Rabbit anti-P300 antibody (86377S), anti-CBP antibody (7389S) and anti-vinculin antibody (18799S) were purchased from Cell Signaling Technology. HRP-conjugated anti-tubulin antibody was produced in house. Media and other cell culture reagents were purchased from Thermo Fisher Scientific. The
CellTiter-Glo Luminescent Assay kit was purchased from Promega.
Immunoblotting
Cultured cells or tissue chunks were washed with cold PBS once and lysed in cold RIPA buffer supplemented with protease inhibitors and phosphatase inhibitors (Beyotime Biotechnology). The solutions were then incubated at 4 °C for 30 minutes with gentle agitation to fully lyse cells. Cell lysates were centrifuged at 13,000 rpm for 10 minutes at 4 °C and pellets were discarded. Total protein concentrations in the lysates were determined by BCA assays (Beyotime Biotechnology). Cell lysates were mixed with Laemmli loading buffer to 1 X and heated at 99 °C for 5 min. Proteins were resolved on SDS-PAGE and visualized by chemiluminescence. Images were taken by a ChemiDoc MP Imaging system (Bio-Rad). Protein bands were quantitated using the accompanied software provided by Bio-Rad.
Cell viability assays
Cells were seeded at a density of 5000 cells per well in 96-well assay plates and treated with test compounds following a 12-point 3-fold serial dilution. Three days later, cell viability was determined using the CellTiter-Glo assay kit according to the manufacturer’s instructions. The dose-response curves were determined and IC50 values were calculated using the GraphPad Prism software following a nonlinear regression (least squares fit) method.
The LNCaP prostate cancer cell viability inhibition results and the percentage of inhibition of p300 of selected bivalent compound compounds are set forth in Tables 2 and 3 below. Table 2.
Figure imgf000242_0001
A: Degradation ³ 80%; B: 50% < Degradation < 80%; C: 20% < Degradation <50%; D: Degradation <
20%; ND: not determined.
Table 3.
Figure imgf000242_0002
Figure imgf000243_0001
A: Degradation ³ 80%; B: 50% < Degradation < 80%; C: 20% < Degradation <50%; D: Degradation <
20%; ND: not determined.
P-007 and P-034 potently inhibited cell viability of multiple cancel cell lines shown in Table 4 below.
Table 4.
Figure imgf000243_0002
Figure imgf000244_0001
The IC50 value of each compound was determined as described in Figure 4 and calculated using the GraphPad Prism 5.0 software.
Pharmacodynamic (PD) studies
All animal experiments were performed under protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Cullgen. Athymic nude mice (male, 5-weeks old) received 5 million 22RV1 cells subcutaneously inoculated at the right flank site. Twenty days following inoculation, tumors were approximately 500 mm3 in size. Tumor-bearing mice were treated intraperitoneally or via oral gavage with vehicle or bivalent compounds at indicated doses. 6 hours after drug administration, animals were sacrificed, tumors were resected. Small chunks of tumors were homogenized for immunoblotting of P300/CBP and other proteins as indicated. Alternatively, ICR mice (male, 5-weeks old) were treated via oral gavage with vehicle or bivalent compounds at indicated doses. 6 hours after drug administration, animals were sacrificed, lung tissues were resected. Small chunks of lung tissues were homogenized for immunoblotting of CBP and other proteins as indicated.
OTHER EMBODIMENTS
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
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Claims

CLAIMS WHAT IS CLAIMED IS:
1. A bivalent compound comprising a cyclic -AMP response element binding protein (CBP) and/or adenoviral E1A binding protein of 300 kDa (P300) ligand (CBP/P300 ligand) conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof.
2. The bivalent compound of claim 1, wherein the CBP/P300 ligand is capable of binding to a CBP/P300 protein comprising CBP/P300, a CBP/P300 mutant, CBP/P300 deletion, or a CBP/P300 fusion protein.
3. The bivalent compound of any one of claims 1 to 2, wherein the CBP/P300 ligand is a CBP/P300 inhibitor or a portion of CBP/P300 inhibitor.
4. The bivalent compound of any one of claims 1 to 3, wherein 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.
5. The bivalent compound of any one of claims 1 to 3, wherein 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, HBS1, OHM1, KCN1, ICG-001, YH249, YH250, and analogs thereof.
6. The bivalent compound of any one of claims 1 to 5, wherein the degradation tag binds to an ubiquitin ligase, or is a hydrophobic group or a tag that leads to misfolding of the CBP/P300 protein.
7. The bivalent compound of claim 6, wherein the ubiquitin ligase is an E3 ligase.
8. The bivalent compound of claim 7, wherein the E3 ligase is selected from the group consisting of a cereblon E3 ligase, a VHL E3 ligase, an IAP ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, DCAF16 ligase, RNF4 ligase, RNF114 ligase, and AhR ligase.
9. The bivalent compound of claim 7, wherein the E3 ligase is selected from the group consisting of a cereblon E3 ligase, a VHL E3 ligase, an IAP ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, and a REAP 1 ligase .
10. The bivalent compound of any one of claims 6 to 9, wherein the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, 1 -((4, 4, 5, 5, 5- pentafluoropentyl)sulfmyl)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.
11. The bivalent compound of any one of claims 6 to 9, wherein the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, 1 -((4, 4, 5, 5, 5- pentafluoropentyl)sulfmyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, and analogs thereof.
12. The bivalent compound of any one of claims 1 to 11, wherein the CBP/P300 ligand is conjugated to the degradation tag via a linker moiety.
13. The bivalent compound of claim 12, wherein the CBP/P300 ligand comprises a moiety of FORMULA 1:
Figure imgf000251_0001
FORMULA 1,
wherein
the linker moiety of the bivalent compound is attached to R2;
X1 and X3 are independently selected from C and N, with the proviso that at least one of X1 and X3 is C and at most only one of X1 and X3 is N;
X2 is selected from CR’, O, and NR’, wherein
R’ is selected from H, optionally substituted Ci-Cs alkyl, and optionally substituted 3-10 membered carbocyclyl;
A is selected from null, CR4R5, CO, O, S, SO, SO2, and NR4, wherein
R4 and R5 are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, optionally substituted CrCx alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C' 1 -C'x alkoxy, optionally substituted C 1 -CxalkoxyC 1 -C’xalkyl. optionally substituted Ci-Cs alkylamino, optionally substituted Ci-CsalkylaminoCi-Csalkyl, 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;
Ar and R4, Ar and R5, and/or R4 and R5 together with the atom to which they are connected form an optionally substituted 3-20 membered cycloalkyl or heterocyclyl ring;
Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO2, OR6, SR6, NR6R7, OCOR6,
OCO2R6, OCONR6R7, COR6, CO2R6, CONR6R7, SOR6, SO2R6, SO2NR6R7, NR8CO2R6, NR8COR6,
NR8C(0)NR6R7,NR8S0R6, NR8S02R6, NR8S02NR6R7, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C' 1 -CN alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-Csalkylamino, optionally substituted C 1 -Chalky lam inoC 1 -Cxalkyl. 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
R6, R7, and R8 are independently selected from hydrogen, optionally substituted C' 1 -CN alkyl, optionally substituted C -C8 alkenyl, optionally substituted C -C8 alkynyl, optionally substituted Ci- CsalkoxyCi-Csalkyl, optionally substituted C 1 - C x al k y 1 am i n o C 1 - C xal k y 1. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R6 and R7, R6 and R8 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;
R1 is selected from hydrogen, halogen, CN, N02, OR9, SR9, NR9R10, OCOR9, 0C02R9, OCONR9R10, COR9, CO2R9, C0NR9R10, SOR9, SO2R9, S02NR9R10, NRUC02R9, NRUCOR9, NRUC(0)NR9R10, NRuSOR9, NRUS0 R9, NRUS02NR9R10, optionally substituted Ci-C8 alkyl, optionally substituted C -C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1 -Cx alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted C C8alkylaminoCi-C8alkyl, 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
R9, R10, and R11 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R9 and R10, R9 and R11 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
R2 is connected to the“linker” moiety of the bivalent compound, and is selected from null, R O, R S, R NR12, R OC(O), R 0C(0)0, R OCON(R12, R C(O), R C(0)0, R CON(R12, R S(O), R S(0)2,
R S02NR12, R NR13C(0)0, R NR13C(0), R NR13C(0)NR12, R NR13S(0), R NR13S(0)2,
R NR13S(0) NR12, optionally substituted C C8 alkylene, optionally substituted C -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 heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R is is null, or a bivalent moiety selected from optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Cr
C8alkoxyCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted Ci-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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R12 and R13 are independently selected from optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R12 and R13 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
R3 is selected from hydrogen, COR14, C02R14, CONR14R15, SOR14, S02R14, S02NR14R15, optionally substituted Ci-C6 alkyl, optionally substituted C -C6 alkenyl, optionally substituted C -C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R14 and R15 are independently selected from hydrogen, optionally substituted C 1 -C(, 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 R14 and R15 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring.
14. The bivalent compound of claim 13, wherein
X1 is C; and X2 and X3 are N. The
Figure imgf000253_0001
FORMULA 1A,
wherein
A, Ar, R1, R2 and R3 are the same as in FORMULA 1.
15. The bivalent compound of any one of claims, 13 and 14, wherein
A-Ar-R1 is a moiety of FORMULA Al:
Figure imgf000253_0002
wherein
A and R1 are the same as in FORMULA 1.
X is selected from CR”’ and N, wherein
R and is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Cr C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 alkoxy, optionally substituted C i -C( alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
Ra is optionally formed a ring with A, and is selected from null, hydrogen, halogen, RbNR . RbOR16, RbSR16, RbNR16R17, RbOCOR16, Rb0C02R16, RbOCONR16R17, RbCOR16, RbC02R16, RbCONR16R17, RbSOR16, RbS02R16, RbS02NR16R17, RbNR18C02R16, RbNR18COR16, RbNR18C(0)NR16R17, RbNR18SOR16, RbNR18S02R16, RbNR18S02NR16R17, optionally substituted Ci-C8 alkyl, optionally substituted Ci-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
Rb is is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-Cg alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R16, R17, and R18 are independently selected from null, hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr
C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R16 and R17, R16 and R18 together with the atom to which they are connected form a 3-20 membered cycloalkyl or heterocyclyl ring.
16. The bivalent compound of any one of claims 13 to 15, wherein
A is null.
17. The bivalent compound of claim 16, wherein
Ar-R1 is a moiety
Figure imgf000254_0001
wherein
R1 is the same as in FORMULA 1.
18. The bivalent compound of any one of claims 13 to 15, wherein
A is NR4, wherein
R4 is selected from hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C -C8 alkenyl, optionally substituted CVCx alkynyl, optionally substituted C i -CxalkoxyC i -Cxalkyl. optionally substituted C I -CxalkylaminoC i -Cxalkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
19. The bivalent compound of claim 13 to 15, wherein
A-Ar-R1 is a moiety
Figure imgf000254_0002
wherein
R1 is the same as in FORMULA 1.
20. The bivalent compound of any one of claims 13 to 19, wherein
R1 is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.
21. The bivalent compound of claim 20, wherein
R1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
22. The bivalent compound of claim 21, wherein
R1 is is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
23. The bivalent compound of any one of claims 13 to 22, wherein
R2 is selected from optionally substituted C rCx alkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocycly, optionally substituted aryl, and optionally substituted heteroaryl.
24. The bivalent compound of any one of claims 13 to 23, wherein
R3 is selected from COR14 and CONR14R15.
25. The bivalent compound of claim 24, wherein
R3 is selected from COMe and CONHMe.
26. The bivalent compound of claim 12, wherein the CBP/P300 ligand comprises a moiety of FORMULA 2:
Figure imgf000255_0001
FORMULA 2,
wherein
the linker moiety of the bivalent compound is attached to R1; and
X1 and X3 are independently selected from C and N, with the proviso that at least one of X1 and X3 is C and at most only one of X1 and X3 is N;
X2 is selected from CR’, O, and NR’, wherein
R’ is selected from H, optionally substituted Ci-C8 alkyl, and optionally substituted 3-10 membered carbocyclyl;
A is selected from null, CR4R5, CO, O, S, SO, SO2, and NR4, wherein
R4 and R5 are independently selected from hydrogen, halogen, hydroxyl amino, cyano, nitro, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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;
Ar and R4, Ar and R5, and/or R4 and R5 together with the atom to which they are connected form an optionally substituted 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
Ar is selected from aryl, heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, tricyclic heteroaryl groups, each of which is substituted with R1 and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, N02, OR6, SR6, NR6R7, OCOR6,
OCO2R6, OCONR6R7, COR6, CO2R6, CONR6R7, SOR6, SO2R6, SO2NR6R7, NR8CO2R6, NR8COR6,
NR8C(0)NR6R7, NR8S0R6, NR8S02R6, NR8S02NR6R7, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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
R6, R7, and R8 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R6 and R7, R6 and R8 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring; and
R1 is connected to the“linker” moiety of the bivalent compound, and R1 is selected from null, R O,
R S, R NR9, R OC(O), R 0C(0)0, R OCONR9, R C(O), R C(0)0, R CONR9, R S(O), R S(0)2,
R S02NR9, R NR10C(O)O, R NR10C(O), R NR10C(0)NR9, R NR10S(0), R NR10S(O)2, R NR10S(O)2NR9, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2- C8 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocycly, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R is is null, or a bivalent moiety selected from optionally substituted C|-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C
C8alkoxyCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R9 and R10 are independently selected from optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R9 and R10 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
R2 is selected from hydrogen, halogen, CN, N02, OR11, SR11, NRUR12, OCOR11, OC02Ru, OCONRuR12, COR11, C02Ru, CONRUR12, SOR11, S02Ru, S02NRUR12, NR13C02Ru, NR13CORu, NR13C(0)NRUR12,NR13S0Ru, NR13S02Ru, NR13S02NRUR12, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylamino, optionally substituted Ci-C8alkylaminoCi-C8alkyl, 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
R11, R12, and R13 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Cr C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R and R , R and R together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
R3 is selected from hydrogen, COR14, C02R14, CONR14R15, SOR14, S02R14, S02NR14R15, optionally substituted Ci-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
R14 and R15 are independently selected from hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted CVG, alkenyl, optionally substituted CVG, alkynyl, optionally substituted 3-6 membered cycloalkyl, and optionally substituted 4-6 membered heterocyclyl, or
R14 and R15 together with the atom to which they are connected form a 4-6 membered heterocyclyl ring.
27. The bivalent compound of claim 26, wherein
X1 is C; and X2 and X3 are N, and the FORMULA 2 is FORMULA 2A:
Figure imgf000257_0001
FORMULA 2A,
wherein
A, Ar, R1, R2 and R3 are the same as in FORMULA 2.
28. The bivalent compound of any one of claims 26 and 27, wherein
A-Ar-R1 is a moiety of FORMULA B l :
Figure imgf000257_0002
FORMULA B l,
wherein
* indicates the connection to the linker moiety of the bivalent compound;
A and R1 are the same as in FORMULA 2;
X is selected from CR”’ and N, wherein
R and is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Cr Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C 1 -C( alkylamino, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkoxy, optionally substituted 3-6 membered cycloalkylamino, optionally substituted 4-6 membered heterocyclyl; and
Ra optionally forms a ring with A, and is selected from null, hydrogen, halogen, RbNR16, RbOR16, RbSR16, RbNR16R17, RbOCOR16, Rb0C02R16, RbOCONR16R17, RbCOR16, RbC02R16, RbCONR16R17, RbSOR16, RbS02R16, RbS02NR16R17, RbNR18C02R16, RbNR18COR16, RbNR18C(0)NR16R17, RbNR18SOR16, RbNR18S02R16, RbNR18S02NR16R17, optionally substituted C|-C8 alkyl, optionally substituted C 1 -C8 alkylene, optionally substituted C -C8 alkenyl, optionally substituted C -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
Rb is is null, or a bivalent or trivalent moiety selected from optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R16, R17, and R18 are independently selected from null, a bond, hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C -C8 alkenyl, optionally substituted C -C8 alkynyl, optionally substituted Ci- C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R16 and R17, R16 and R18 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring.
29. The bivalent compound of any one of claims 26 to 28, wherein A is null.
30. The bivalent compound of claim 29, wherein Ar-R1 is a moiety of FORMULAE B2 or B3:
Figure imgf000258_0001
FORMULA B2 FORMULA B3,
wherein
* indicates the connection to the linker moiety of the bivalent compound; and
R1 is the same as in FORMULA 2.
31. The bivalent compound of any one of claims 26 to 28, wherein
A is NR4, wherein
R4 is selected from hydrogen, optionally substituted Ci-Cg alkyl, optionally substituted C -C8 alkenyl, optionally substituted CVCg alkynyl, optionally substituted C i -CxalkoxyC i -Cxalkyl. optionally substituted C I -CxalkylaminoC i -Cxalkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
32. The bivalent compound of claim 31, wherein
A-Ar-R1 is a moiety
Figure imgf000258_0002
FORMULA B4 FORMULA B5 FORMULA B6,
wherein
indicates the connection to the linker moiety of the bivalent compound; and
R1 is the same as in FORMULA 2.
33. The bivalent compound of any one of claims 26 to 32, wherein
R1 is selected from optionally substituted 3-10 membered carbocyclylene, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.
34. The bivalent compound of claim 33, wherein
R1 is selected from optionally substituted aryl and optionally substituted heteroaryl.
35. The bivalent compound of claim 34, wherein
R1 is selected from optionally substituted pyrazole and optionally substituted pyridinyl.
36. The bivalent compound of any one of claims 26 to 335, wherein
R2 is selected from optionally substituted Ci-Cx alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
37. The bivalent compound of any one of claims 26 to 36, wherein
R3 is selected from COR14 and CONR14R15.
38. The bivalent compound of claim 37, wherein
R3 is selected from COMe and CONHMe.
39. The bivalent compound of claim 12, wherein the CBP/P300 ligand is derived from any of the following:
Figure imgf000259_0001
40. The bivalent compound of claim 12, wherein the CBP/P300 ligand is derived from any of the following: CBP/P300 inhibitors: C646, naphthol-AS-E, compound 1-10, MYBMIM, CCS1477, ICG-001, YH249, YH250, HBS1, OHM1, and KCN1.
41. The bivalent compound of claim 12, wherein the CBP/P300 ligand is selected from the group consisting of:
Figure imgf000259_0002
42. The bivalent compound of any one of claims 12 to 41, wherein
(i) the degradation tag is a moiety selected from the group consisting of FORMULAE 5A, 5B, 5C, and 5D:
Figure imgf000260_0001
FORMULA 5A FORMULA 5B FORMULA 5C FORMULA 5D, wherein
V, W, and X are independently selected from CR2 and N;
Y is selected from CO, CR3R4, N=CR3, and N=N;
Z is selected from null, CO, CR5R6, NR5, O, optionally substituted C Cio alkylene, optionally substituted C Cio alkenylene, optionally substituted C Cio alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH , CH=CH, CºC, NH and O;
R1, and R2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R3 and R4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
R5 and R6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C i -C( alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R5 and R6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl;
or, (ii) the degradation tag is a moiety selected from the group consisting of FORMULAE 5E, 5F, 5G, 5H, and 5E
Figure imgf000260_0002
wherein
U, V, W, and X are independently selected from CR2 and N;
Y is selected from CR3R4, NR3 and O; preferably, Y is selected from CH2, NH, NCH3 and O;
Z is selected from null, CO, CR5R6, NR5, O, optionally substituted C Cio alkylene, optionally substituted Ci-Ci0 alkenylene, optionally substituted Ci-Ci0 alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH , CH=CH, CºC, NH and O;
R1, and R2 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted Ci-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R3 and R4 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and
R5 and R6 are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C i -C( alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R5 and R6 together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl;
or, (iii) the degradation tag is a moiety selected from the group consisting of FORMULAE 5J, 5K, 5L, 5M, 5N, 50,
Figure imgf000261_0001
Figure imgf000261_0002
wherein,
X’ are independently selected from CR2 and N;
Y’, Y”, and Y”’ are independently selected from CR3R4;
R’ is selected from hydrogen, optionally substituted C i -C( alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;
U, V, W, X, Z, R1 and R2 are defined as in FORMULAE 5E, 5F, 5G, 5H, or 51.
43. The bivalent compound of any one of claims 12 to 41, wherein the degradation tag is a moiety selected from the group consisting of FORMULAE 5A, 5B, 5C, and 5D:
Figure imgf000262_0001
wherein
V, W, and X are independently selected from CR2 and N;
Y is selected from CO, and N=N;
Z is selected from CH2, NH and O; and
R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, and C1-C5 alkyl.
44. The bivalent compound of any one of claims 12 to 41, wherein
(i) the degradation tag is a moiety of FORMULA 6A:
Figure imgf000262_0002
wherein
R1 and R2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl;
optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 aminoalkyl, optionally substituted Cr C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4- 10 membered heterocyclyl; and
R3 is selected from hydrogen, optionally substituted C(0)Ci-C8 alkyl, optionally substituted C(0)Cr C8alkoxyCi-C8alkyl, optionally substituted C(0)Ci-C8 haloalkyl, optionally substituted C(0)Ci-C8 hydroxyalkyl, optionally substituted C(0)Ci-C8 aminoalkyl, optionally substituted C(0)Cr
C8alkylaminoCi-C8alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C2-C8 alkenyl, optionally substituted C(0)C2-C8 alkynyl, optionally substituted C(0)OCi-C8alkoxyCi-C8alkyl, optionally substituted
C(0)OCi-C8 haloalkyl, optionally substituted C(0)OCi-C8 hydroxyalkyl, optionally substituted C(0)OCr C8 aminoalkyl, optionally substituted C(0)OCi-C8alkylaminoCi-C8alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C2-C8 alkenyl, optionally substituted C(0)0C2-C8 alkynyl, optionally substituted C(0)NCi-C8alkoxyCi-C8alkyl, optionally substituted C(0)NCi-C8 haloalkyl, optionally substituted C(0)NCI-C8 hydroxyalkyl, optionally substituted C(0)NCi-C8 aminoalkyl, optionally substituted C(0)NCi-C8alkylaminoCi-C8alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(0)NC2-C8 alkenyl, optionally substituted C(0)NC2-C8 alkynyl, optionally substituted P(0)(OH)2, optionally substituted P(0)(OCi-C8 alkyl)2, and optionally substituted P(0)(OCi-C8 aryl)2;
or, (ii) the degradation tag is a moiety of FORMULAE 6B, 6C, and 6D:
Figure imgf000263_0001
wherein
R1 and R2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C rC8 alkyl, optionally substituted C -C8 alkenyl, optionally substituted C2-C8 alkynyl;
optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 aminoalkyl, optionally substituted Cr C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4- 10 membered heterocyclyl;
R3 is selected from hydrogen, optionally substituted C(0)Ci-C8 alkyl, optionally substituted C(0)Ci- C8alkoxyCi-C8alkyl, optionally substituted C(0)Ci-C8 haloalkyl, optionally substituted C(0)Ci-C8 hydroxyalkyl, optionally substituted C(0)Ci-C8 aminoalkyl, optionally substituted C(0)Cr
C8alkylaminoCi-C8alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(0)C2-C8 alkenyl, optionally substituted C(0)C2-C8 alkynyl, optionally substituted C(0)OCi-C8alkoxyCi-C8alkyl, optionally substituted
C(0)OCi-C8 haloalkyl, optionally substituted C(0)OCi-C8 hydroxyalkyl, optionally substituted C(0)OCr C8 aminoalkyl, optionally substituted C(0)OCi-C8alkylaminoCi-C8alkyl, optionally substituted C(0)0(3- 10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(0)0C2-C8 alkenyl, optionally substituted C(0)0C2-C8 alkynyl, optionally substituted C(0)NCi-C8alkoxyCi-C8alkyl, optionally substituted C(0)NCi-C8 haloalkyl, optionally substituted C(0)NCI-C8 hydroxyalkyl, optionally substituted C(0)NCi-C8 aminoalkyl, optionally substituted C(0)NCi-C8alkylaminoCi-C8alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(0)NC2-C8 alkenyl, optionally substituted C(0)NC2-C8 alkynyl, optionally substituted P(0)(OH)2, optionally substituted P(0)(OCi-C8 alkyl)2, and optionally substituted P(0)(OCi-C8 aryl)2, and
R4 is selected from NR7R8,
Figure imgf000263_0002
, optionally substituted Ci-C8alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteraryl, in which
R7 is selected from hydrogen, optionally substituted Ci-C8alkyl, optionally substituted C r
C8cycloalkyl, optionally substituted Ci-C8alkyl-CO, optionally substituted Ci-C8cycloalkyl-CO, optionally substituted Ci-C8cycloalkyl-Ci-C8alkyl-CO, optionally substituted 4-10 membered heterocyclyl-CO, optionally substituted 4-10 membered heterocyclyl-Ci-C8alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-Ci-C8alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-Ci-C8alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;
R8 is selected from hydrogen, optionally substituted Ci-C8alkyl, and optionally substituted Cr C8cycloalkyl;
R9, at each occurance, is independently selected from hydrogen, halogen, cyano, optionally substituted Ci-C8alkyl, optionally substituted Ci-C8cycloalkyl, optionally substituted Ci- C8heterocycloalkyl, optionally substituted Ci-C8alkoxy, optionally substituted Ci-C8cycloalkoxy, halo substituted Ci-C8alkyl, halo substituted Ci-C8cycloalkyl, halo substituted Ci-C8alkoxl, halo substituted Ci- C8cycloalkoxy, and halo substituted Ci-C8heterocycloalkyl;
X is selected from CH and N; and
n is 0, 1, 2, 3, or 4;
R6 is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Cr C8alkyl, optionally substituted Ci-C8cycloalkyl, optionally substituted Ci-C8alkoxy, and optionally substituted Ci-C8cycloalkoxy, optionally substituted Ci-C8heterocycloalkyl, 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 group.
45. The bivalent compound of any one of claims 12 to 41, wherein
(i) the degradation tag is a moiety of FORMULA 7A:
Figure imgf000264_0001
wherein
V, W, X, and Z are independently selected from CR4 and N; and
R1, R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C rC8 alkyl, optionally substituted C -C8 alkenyl, and optionally substituted C2-C8 alkynyl; optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxy, optionally substituted Cr
C8alkylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;
or, (ii) the degradation tag is a moiety of FORMULAE 7B:
Figure imgf000264_0002
wherein
R1, R2, and R3 are independently selected from hydrogen, halogene, optionally substituted C rC8 alkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl;
R4 and R5 are independently selected from hydrogen, COR6, C02R6, CONR6R7, SOR6, S02R6, S02NR6R7, optionally substituted Ci-C8 alkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted aryl-Ci-C8alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein
R6 and R7 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R6 and R7 together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.
46. The bivalent compound of any one of claims 12 to 41, wherein the degradation tag is derived from any of the following:
Figure imgf000265_0001
47. The bivalent compound of any one of claims 12 to 41, wherein the degradation tag is selected from the group consisting of:
Figure imgf000267_0001
Figure imgf000269_0001
Figure imgf000270_0001
of claims 12 to 47, wherein the linker moiety is of
48 The bivalent compound of any one
FORMULA 9: FORMULA 9
wherein
A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR”, R C02R , R C(0)N(R1)R , R C(S)N(R1)R , R OR , R SR , R SOR , R S02R ,
R SO^R^R , R N(R')R . R N(R' )C OR . R N(R')CON(R2)R . RN(R1)C(S)R , optionally substituted C|-C’s alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted C rC8 haloalkylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, 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 null, optionally substituted (Ci-C8 alkylene)-Rr (preferably, CH2-Rr), optionally substituted Rr-(Ci-C8 alkylene), ptionally substituted (Ci-C8 alkylene)- Rr-(Ci-C8 alkylene), or a moiety comprising of optionally substituted C C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is 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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R1 and R2 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R1 and R2, R and R1, R and R2, R and R1, R and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and
m is 0 to 15.
49. The bivalent compound of any one of claim 48, wherein R and R are independently selected from null, , or a moiety comprising of optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C -C8 alkynylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted Ci-CxalkoxyCi-Cxalkylene, optionally substituted C 1 -CxalkylaminoC 1 -Cxalkylene. optionally substituted Ci-Cs haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
50. The bivalent compound of any one of claims 12 to 47, wherein the linker moiety is of
FORMULA 9A:
Figure imgf000272_0001
wherein
R1, R2, R3 and R4, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C|-Cx alkyl optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-Cs alkoxy, optionally substituted Ci-Cs alkoxyalkyl, optionally substituted Ci-Cs haloalkyl, optionally substituted Ci-Cs hydroxyalkyl, optionally substituted Ci-Cs alkylamino, and optionally substituted C 1 -Cx alkylaminoC 1 -Cx alkyl optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R1 and R2, R3 and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected
Figure imgf000272_0002
R S02N(R5)R , RN(R5)R , RN(R5)COR , RN(R5)CON(R6)R , RN(R5)C(S)R , optionally substituted Ci-Cg alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C 1 -C’salkoxyC 1 -C’salkylcnc. optionally substituted C1-C3 haloalkylene, optionally substituted C 1-C3 hydroxyalkylene, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, 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 null, optionally substituted (C1-C3 alkyl)-Rr (preferably, CH -Rr), optionally substituted Rr-(Ci-C8 alkylene), optionally substituted (C1-C3 alkylene)- Rr-(Ci-C8 alkylene), or a moiety comprising of optionally substituted Ci-Cx alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1 -C3 hydroxyalkyl, optionally substituted C 1 -C’salkoxyC 1 -C’salkyl. optionally substituted C 1 -C’salkylam inoC 1 -C’salkyl. optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C -C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C3 hydroxyalkylene, optionally substituted Ci-CsalkoxyC’i-Csalkylcnc. optionally substituted C 1 -C’salkylaminoC 1 -C’salkylcnc. optionally substituted Ci-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R5 and R6 are independently selected from hydrogen, optionally substituted CrCx alkyl optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1 -Cx alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted C I -C’salkylaminoC 1 -Cxalkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R5 and R6, R and R5, R and R6, R and R5, R and R6 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
m is 0 to 15;
n, at each occurrence, is 0 to 15; and
o is 0 to 15..
51. The bivalent compound of any one of claims 50, wherein R and R are independently selected from null, or a moiety comprising of optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-Cs hydroxyalkyl, optionally substituted C 1 -CxalkoxyC 1 -Cxalkyl. optionally substituted C 1 -Cxalkylam inoC 1 -Cxalkyl. optionally substituted Ci-Cs haloalkyl, optionally substituted Ci-Cs alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-Cs hydroxyalkylene, optionally substituted Ci-CsalkoxyCi-Csalkylene, optionally substituted C 1 -CxalkylaminoC 1 -Cxalkylcnc. optionally substituted Ci-Cs haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
52. The bivalent compound of any one of claims 12 to 47, wherein the linker moiety is of
FORMULA 9B:
Figure imgf000273_0001
wherein
R1 and R2, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted Ci-Cs alkyl, optionally substituted C 1 -Cx alkoxy, optionally substituted Ci-Cs alkoxy Ci-Cs alkyl, optionally substituted Ci-Cs haloalkyl, optionally substituted Ci-Cs hydroxyalkyl, optionally substituted Ci-Cs alkylamino, C 1 -CxalkylaminoC 1 -Cxalkyl. 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
R1 and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R -R , R COR , R C02R , R C(0)N(R3)R , R C(S)N(R3)R , R OR , R SR , R SOR , R S02R ,
R S02N(R3)R , RN(R3)R , RN(R3)COR , RN(R3)CON(R4)R , RN(R3)C(S)R , optionally substituted C|-C’s alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C i -C8alkoxyC i -C8alkylcnc. optionally substituted CrC8 haloalkylene, optionally substituted CrC8 hydroxyalkylene, optionally substituted C3-C 13 fused cycloalkyl, optionally substituted C3-C 13 fused heterocyclyl, optionally substituted C3-C 13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C 13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, 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 null, optionally substituted (Ci-C8 alkylene)-Rr (preferably, CH2-Rr), optionally substituted Rr-(C|-Cx alkylene), optionally substituted (C|-C8 alkylene)- Rr-(C|-C8 alkylene), or a moiety comprising of optionally substituted C 1 -C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is 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 heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C 13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R3 and R4 are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted CrC8 haloalkyl, optionally substituted C C8 hydroxyalkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4- 10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R3 and R4, R and R3, R and R4, R and R3, R and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
each m is 0 to 15; and
n is 0 to 15.
53. The bivalent compound of any one of claims 12 to 47, wherein the linker moiety is of
FORMULA 9C:
Figure imgf000275_0001
wherein
X is selected from O, NH, and NR7;
R1, R2, R3, R4, R5, and R6, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxy, optionally substituted Ci-C8 alkoxy Ci-C8 alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 alkylamino, optionally substituted Ci-C8 alkylaminoCi-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
A and B are independently selected from null, or bivalent moiety selected from R -R , R COR ,
R C02R , R C(0)N(R8)R , R C(S)N(R >88\)Rr> , r R> OR , R SR , R SOR , R S02R , R S02N(R 88\)rR> , r R> AN(R8)R
RN(R5)C0R , RN(R5)CON(R9)R , RN(R8)C(S)R , optionally substituted C i -C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Cr
CxalkoxyC|-C8alkylcnc. optionally substituted C|-C8 haloalkylene, optionally substituted C|-C8 hydroxyalkylene, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, 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 null, optionally substituted (CVC8 alkylene)-Rr (preferably, CH2-Rr), optionally substituted Rr-(C|-Cx alkylene), optionally substituted (C|-C8 alkylene)- Rr-(C|-C8 alkylene), or a moiety comprising of optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Ci-C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8 hydroxyalkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Ci-C8alkylaminoCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rr is selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro
heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R7, R8 and R9are independently selected from hydrogen, optionally substituted Ci-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 alkoxyalkyl, optionally substituted C C8 haloalkyl, optionally substituted C C8 hydroxyalkyl, optionally substituted C i -C8alkylam inoC i -C8alkyl. optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R and R , R8 and R9, R and R8, R and R9, R and R8, R and R9 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
m, at each occurrence, is 0 to 15;
n, at each occurrence, is 0 to 15;
o is 0 to 15; and
p is 0 to 15.
54. The bivalent compound of any one of claims 53, wherein
R and R are independently selected from null, or a moiety comprising of optionally substituted Cr Cg alkyl, optionally substituted C -C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8alkoxyCi-C8alkyl, optionally substituted Cr
C8alkylaminoCi-C8alkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted Ci-C8 hydroxy alkylene, optionally substituted Ci-C8alkoxyCi-C8alkylene, optionally substituted Cr C8alkylaminoCi-C8alkylene, optionally substituted Ci-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-Ci3 fused cycloalkyl, optionally substituted C3-Ci3 fused heterocyclyl, optionally substituted C3-Ci3 bridged cycloalkyl, optionally substituted C3-Ci3 bridged heterocyclyl, optionally substituted C3-Ci3 spiro cycloalkyl, optionally substituted C3-Ci3 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
55. The bivalent compound of any one of claims 48 to54, wherein the linker moiety comprises one or more rings selected from the group consisting of 3 to 13 membered rings, 3 to 13 membered fused rings, 3 to 13 membered bridged rings, and 3 to 13 membered spiro rings.
56. The bivalent compound of any one of claims 48 to 54, wherein A, B, and W, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, -(CH2)0.8-, -(CH2)0-3-CO-(CH2)0-8-, (CH2)O-8-NH-CO, (CH2)O-8-CO-NH, NH-CO-(CH2) O-8, CO-NH-(CH2) O-8, (CH2) !-3-NH-(CH2) 1 3-CO-NH, (CH2) !-3-NH-(CH2) 1 3-NH-CO, -CO-NH, CO-NH- (CH2) !-3-NH-(CH2) (CH2) !-3-NH-(CH2) -(CH2)0.
3-Rr-(CH2)0-3, -(CH2)o-3-(CO)-(CH2)o-3-Rr-(CH2)0-3-, -(CH2)0-3-(CO-NH)-(CH2)0-3-Rr-(CH2)0-3-, -(CH2)0.3- (NH-CO)-(CH2)o-3-Rr-(CH2)o-3-, and -(CH2)0-3-(NH)-(CH2)0-3-Rr-(CH2)0-3-.
57. The bivalent compound of any one of claims 48 to 54, wherein A and B, at each occurrence, are independently selected from null, 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.
58. The bivalent compound of any one of claims 48 to 54, wherein the linker moiety comprises one or more rings selected from the group consisting of FORMULA Cla, C2a, C3a, C4a and C5a:
Figure imgf000277_0001
FORM ULA C4a FORM ULA C5a
wherein
X’ and Y’ are independently selected from N, CRb;
A1, B1, C1 and D1, at each occurrence, are independently selected from null, O, CO, SO, SO2, NRb, CRbRc;
A2, B2, C2, and D2, at each occurrence, are independently selected from N, CRb ;
A3, B3, C3, D3, and E3, at each occurrence, are independently selected from N, O, S, NRb, CRb;
Rb and Rc, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted CrCx alkyl optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C 1 -Cx alkoxy, optionally substituted C|-Cx alkoxyalkyl, optionally substituted Ci-C8 haloalkyl, optionally substituted Ci-C8 hydroxyalkyl, optionally substituted Ci-C8 alkylamino, and optionally substituted C 1 -Cx alkylaminoCi-Cx alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
m1, n1, o1 and p1 are independently selected from 0, 1, 2, 3, 4 and 5.
59. The bivalent compound of any one of claims 48 to 54, wherein the linker moiety comprises one or more rings selected from the group consisting of FORMULA Cl, C2, C3, C4 and C5:
Figure imgf000277_0002
A si CH, C/Oi.s alkyl), <srN A* C, CH, 0(C ^ alkyl), N, NH, (C t ¾ alkyl), O, S
B « CH, C{Ct 3 alkyl), H B » C, C H Ci .s alkyl), , NH, NCC^ alkyl), O. S
C ~ CH, C(C,,¾ alkyl), or N C - C, CH, alkyl), N, NH, N{0^ alkyl), O, $
O * CH, 0(OίL alkyl), N
D * C, CH, CiC^ alkyl), N, NH, N{C ¾ alkyl), O, S
and E ~ C, CH, C(C 1 -3 alkyl), N, N
FORMULA C4, FORM
Figure imgf000277_0003
60. The bivalent compound of claim 12, wherein 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.
61. The bivalent compound of claim 12, wherein the linker is selected from -(CH2)o-n-, -(CH2)o-3- CO-(CH2)O-IO-, -(CO)-(CH2)3-IO- (preferably, -(CO)-(CH2)3-7-), -(CH2)0-3(CONH)-(CH2)0-IO- (preferably, - (CH2)O-3-(CONH)-(CH2)3.9, more preferably, -(CH2),.2(CONH)-(CH2)3.7-), -(CH2)0-3-(CO)-(CH2)o-5-Rr- (CH2)O-5- (preferably, -(CH2)0-3-(CO)-(CH2)0-3-Rr-(CH2)0-3-), -(CH2)0-3-(CONH)-(CH2)o_5-Rr-(CH2)o_5- and - (CH2)o-5-Rr-(CH2)o-5. (preferably, -(CH2)0-3-Rr-(CH2)1.2).
62. The bivalent compound of claim 12, wherein the linker is selected from -(CH2)0-n-, -(CH2)0-3-
Figure imgf000278_0001
63. The bivalent compound of claim 12, wherein the linker is selected from -(CO)-(CH2)3-7- and - (CH2)1.2(CONH)-(CH2)3.7.
64. The bivalent compound of claims 48 to 63, wherein Rris selected from FORMULA Cl, C2, C3, C4, and C5 as defined in Claim 59, or selected from FORMULA Cla, C2a, C3a, C4a, and C5a as defined in 58.
65. The bivalent compound of claims 48 to 63, wherein Rrisselected from
Figure imgf000278_0002
66. The bivalent compound of claims 48 to 63, wherein Rrisselected from
Figure imgf000279_0001
67. The bivalent compound of claim 12, wherein the bivalent compound is selected from the group consisting of P-001 to P-174 and CPD-1139 to CPD-1179 or a pharmaceutically acceptable salt or analog thereof, and a pharmaceutically acceptable carrier or diluent.
68. The bivalent compound of claim 12, wherein the bivalent 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 a pharmaceutically acceptable salt or analog thereof.
69. The bivalent compound of claim 12, wherein the bivalent compound is
3-(7-(Difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2H)-y\)- 1 -( l -(5-((2-(2.6- dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)amino)pentanoyl)piperidin-4-yl)-/V-methyl- 1 ,4,6,7- tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-004);
3 -(7 -(Difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(6-((2-(2,6- dioxopiperidin-3 -yl)- 1 ,3 -dioxoisoindolin-5 -yl)amino)hexanoyl)piperidin-4-yl)-/V-methyl- 1 ,4,6,7- tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-005);
3 -(7 -(Difluoromethyl)-6-( 1 -methyl- lH-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2H)-yl)- 1 -( 1 -(7 -((2-(2,6- dioxopiperidin-3-yl)-l, 3-dioxoisoindolin-5-yl)amino)heptanoyl)piperidin-4-yl)-N-methyl-l, 4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (P-006);
3 -(7 -(Difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( l-(8-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)octanoyl)piperidin-4-yl)-/V-methyl-l,4,6,7- tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-007);
3 -(7 -(Difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(4-((2-(2,6- dioxopiperidin-3 -yl)- 1.3-dioxoisoindolin-4-yl)amino)biitanoyl)piperidin-4-yl)-/V-methyl- 1 ,4,6,7- tetrahydro-5//-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)- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-/V-methyl- 1 - (tetrahydro-2//-pyran-4-yl)-l,4,6,7-tetrahydro-5//-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)- l//-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2//)-yl)-N-methyl- 1 - (tetrahydro-2//-pyran-4-yl)-l,4,6,7-tetrahydro-5//-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)- 1 //-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2//)-yl)-/V-methyl- 1 - (tetrahydro-2//-pyran-4-yl)-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-027);
3-(7-(Difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 {2H)-y\)- 1 -( l -(5-((2-(2.6- dioxopiperidin-3 -yl)- 1 3-dioxoisoindolin-4-yl)amino)pcntanoyl)pipcridin-4-yl)-/V-mcthyl- 1 ,4,6,7- tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-033);
3 -(7 -(Difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(6-((2-(2,6- dioxopiperidin-3 -yl)- 1 3-dioxoisoindolin-4-yl)amino)hcxanoyl)pipcridin-4-yl)-/V-mcthyl- 1 ,4,6,7- tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-034); 3-(7-(Difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2H)-y\)- 1 -( l -(7-((2-(2,6- dioxopiperidin-3 -yl)- 1.3-dioxoisoindolin-4-yl)amino)hcptanoyl)pipcridin-4-yl)-/V-mcthyl- 1 ,4,6,7- tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-035);
3-(7-(Difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(8-((2-(2,6- dioxopiperidin-3 -yl)- 1.3-dioxoisoindolin-4-yl)amino)octanoyl)pipcridin-4-yl)-/V-mcthyl- 1 ,4,6,7- tetrahydro-5//-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)hcxyl)amino)-2-oxocthyl)- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-/V-methyl- 1 - (tctrahydro-2//-pyran-4-yl)- 1 ,4,6,7-tetrahydro-5//-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)- 1 //-pyrazol-4-yl)-3 ,4-dihydroquinobn- 1 (2//)-yl)-/V-methyl- 1 - (tetrahydro-2//-pyran-4-yl)-l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-043);
3 -(7 -(difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2H)-y\)- 1 -( 1 -(7 -(2-(2,6- dioxopipcridin-3-yl)- 1.3-dioxoisoindolin-4-yl)hcptanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//- pyrazolo [4,3 -c]py ridine -5 -carboxamide (P-085 ) ;
3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 {2H)-y\)- 1 -( 1 -(6-((2-(2,6- dioxopipcridin-3-yl)- l -oxoisoindolin-4-yl)oxy)hcxanoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//- pyrazolo [4,3 -c]py ridine -5 -carboxamide (P-088);
3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 {2H)-x\)- 1 -( 1 -(6-((2-(2.6- dioxopipcridin-3-yl)- 1.3-dioxoisoindolin-4-yl)amino)hcxyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro- 5//-pyrazolo [4,3 -c]pyridine-5 -carboxamide (P-090);
3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 {2H)-x\)- 1 -( 1 -(6-((2-(2.6- dioxopipcridin-3-yl)- 1.3-dioxoisoindolin-4-yl)oxy)hexyl)piperidin-4-yl)-/V-methyl- 1 4.6.7-tctrahydro-5//- pyrazolo [4,3 -c]pyridine -5 -carboxamide (P-091);
3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 {2H)-x\)- 1 -( 1 -(7-(2-(2.6- dioxopipcridin-3-yl)- 1 -oxoisoindolin-4-yl)hcpt-6-ynoyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//- pyrazolo[4,3-c]pyridine-5-carboxamide (P-093);
3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 {2H)-x\)- 1 -( 1 -(6-((2-(2.6- dioxopipcridin-3-yl)-3-oxoisoindolin-4-yl)amino)hcxanoyl)pipcridin-4-yl)-/V-mcthyl- 1.4.6.7-tctrahydro- 5//-pyrazolo [4,3 -c]pyridine-5 -carboxamide (P-096);
3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 {2H)-x\)- 1 -( 1 -(7-(2-(2.6- dioxopipcridin-3-yl)- 1 3-dioxoisoindolin-4-yl)hcptyl)pipcridin-4-yl)-/V-mcthyl- 1 4.6.7-tctrahydro-5//- pyrazolo[4,3-c]pyridine-5-carboxamide (P-097);
4-((6-(4-(5-acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- l (2//)- yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-6-oxohexyl)amino)-2-(2.6- dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P- 100);
3-(7 -(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3 ,4-dihydroquinobn- 1 (2H)-y\)- 1 -( 1 -(2-(4-(2-(2- (2.6-dioxopipcridin-3-yl)- 1 3-dioxoisoindolin-4-yl)cthyl)pipcridin- 1 -yl)acctyl)pipcridin-4-yl)-/V-mcthyl- l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-104);
3-(7 -(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3 ,4-dihydroquinobn- 1 (2H)-y\)- 1 -( 1 -(7 -(3 -(2,6- dioxopiperidin-3-yl)-2-oxo-2.3-dihydro- 17/-bcnzo|d |imidazol- 1 -yl)hcptanoyl)pipcridin-4-yl)-/V-mcthyl- l,4,6,7-tetrahydro-5//-pyrazolo[4,3-c]pyridine-5-carboxamide (P-106);
3-(7 -(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3 ,4-dihydroquinobn- 1 (2H)-y\)- l-(l-(6-((l-(2,6- dioxopiperidin-3-yl)-3-methyl-2 -oxo-2, 3-dihydro-l//-benzo[ri]imidazol-4-yl)amino)hexanoyl)piperidin-4- yl)-A/-methyl- 1,4, 6, 7-tetrahydro-5//-pyrazolo [4, 3 -c]pyridine-5 -carboxamide (P-109); 3-(4-((6-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- 1 / -pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-6-oxohexyl)amino)-3 - methyl-2-oxo-2, 3 -dihydro- l//-benzo[i]imidazol- 1 -yl)piperidine-2,6-dione (P- 110);
3-(4-((7-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-7-oxoheptyl)amino)-3- mcthyl-2-oxo-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)pipcridinc-2.6-dionc (P-111);
4-((6-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4-dihydroqiiinohn- 1 (2//)- yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pvridin- 1 -yl)pipcridin- 1 -yl)hexyl)amino)-2-(2.6-dioxopiperidin-
3-yl)isoindoline-l,3-dione (P-112);
4-((6-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4-dihydroqiiinohn- 1 (2//)- yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pvridin- 1 -yl)pipcridin- 1 -yl)hcxyl)oxy)-2-(2.6-dioxopipcridin-3- yl)isoindoline-l,3-dione (P-113);
3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 {2H)-x\)- 1 -( 1 -(6-(( 1 -(2.6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-l//-benzo[/]imidazol-5-yl)amino)hexanoyl)piperidin-4- yl)-/V-methyl- 1,4, 6, 7-tetrahydro-5//-pyrazolo [4, 3 -c]pyridine-5 -carboxamide (P-115);
3-(5-((6-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo| 4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-6-oxohexyl)amino)-3- methyl -2 -oxo-2, 3 -dihydro- l//-benzo |c/|imidazol- 1 -yl)piperidine-2,6-dione (P-116);
5-((8-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4-dihydroqiiinohn- l (2//)- yl)-4,5,6,7-tetrahydro-l//-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-8-oxooctyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l,3-dione (P-119);
5-((6-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4-dihydroqiiinohn- 1 (2//)- yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo|4.3-r |pvridin- 1 -yl)pipcridin- 1 -yl)-6-oxohcxyl)amino)-2-(2.6- dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P- 120);
3 -(7 -(difluoromethyl)-6-( 1 -methyl- l//-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2/ )-yl)- 1 -( 1 -(7-(( 1 -(2,6- dioxopiperidin-3-yl)-3-methyl-2 -oxo-2, 3-dihydro-l//-benzo[i]imidazol-5-yl)amino)heptanoyl)piperidin-
4-yl)-/V-mcthyl- 1.4.6.7-tctrahydro-5//-pyrazolo|4.3-r|pyridinc-5-carboxamidc (P-129);
3-(5-((7-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(l-methyl-l//-pyrazol-4-yl)-3 ,4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo| 4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-7-oxohcptyl)amino)-3- methyl -2 -oxo-2, 3 -dihydro- l//-benzo |c/|imidazol- 1 -yl)piperidine-2,6-dione (P-130);
4-(2-( 1 -(2-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo| 4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-2-oxocthyl)pipcridin-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- l//-pyrazolo [4,3 -c]pyridin-3 -yl)- 7-(difluoromcthyl)- 1.2.3.4-tctrahydroquinolin-6-yl)- 1 //-pyrazol- 1 -yl)-/V-(7-((2-(2.6-dioxopipcridin-3-yl)- 1 ,3 -dioxoisoindolin-5 -yl)amino)heptyl)acetamide (P-133);
3-(3-(8-(4-(5-Acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tetrahydro- 1 / -pyrazolo| 4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-8-oxooctyl)-2-oxo-2.3- dihydro- l//-benzo[i]imidazol- 1 -yl)piperidine-2,6-dione (P-135);
4-(((4-(2-(4-(5 -acetyl-3 -(7 -(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin-
1 (2//)-yl)-4.5.6.7-tetrahydro- 1 / -pyrazolo| 4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-2-oxocthyl)morpholin-2- yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-142);
4-((( 1 -(2-(4-(5 -acetyl-3 -(7 -(difluoromethyl)-6-( 1 -methyl- 17/-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (27/)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo| 4.3-r |pyridin- 1 -yl)piperidin- 1 -y l )cth\ l )pi pcridin-4- yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-143); 4-(3-(4-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- l / -pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2H)- yl)-4,5,6,7-tetrahydro-l//-pyrazolo[4,3-c]pyridin-l-yl)piperidin-l-yl)-4-oxobutyl)azetidin-l-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- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-2-oxoethyl)piperidin-4- yl)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-147);
4-(2-( 1 -(3-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo| 4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-3-oxopropyl)pipcridin-4- yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-148);
4-(3-(4-((4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 //-pyrazolo| 4.3-r |pyridin- 1 -yl)piperidin- 1 -yl)methyl)piperidin- 1 - yl)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (P-149);
3-(5-((6-(4-(5-acetyl-3-(7-(difluoromethyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo| 4.3 -r |pyridin- 1 -yl)pipcridin- 1 -yl)-6-oxohexyl)amino)-4- oxobcnzo|c/|| 1.2.3 |triazin-3(4//)-yl)pipcridinc-2.6-dionc (P-151);
3-(5-((7-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo| 4.3 -r |pyridin- 1 -yl)pipcridin- 1 -yl)-7-oxoheptyl)amino)-4- oxobcnzo|c/|| 1.2.3 |triazin-3(4//)-yl)pipcridinc-2.6-dionc (P-153);
3-(5-((5-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo| 4.3 -r |pyridin- 1 -yl)pipcridin- 1 -yl)-5-oxopentyl)amino)-4- oxobcnzo|c/|| 1.2.3 |triazin-3(4//)-yl)pipcridinc-2.6-dionc (P-155);
4-(2-( 1 -(2-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin-
1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)cthyl)pipcridin-4-yl)cthyl)-2- (2,6-dioxopiperidin-3 -yl)isoindoline- 1 ,3 -dione (P- 157);
3-(4-((8-(4-(5-acctyl-3-(7-(difliioromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 /-pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-8-oxooctyl)amino)-3-methyl- 2-OXO-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)pipcridinc-2.6-dionc (P-159);
3-(4-((9-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- 1 / -pyrazolo [4,3 -c]pyridin- 1 -yl)piperidin- 1 -yl)-9-oxononyl)amino)-3 - methyl -2 -oxo-2, 3 -dihydro- l//-benzo |c/|imidazol- 1 -yl)piperidine-2,6-dione (P-160) ;
3-(5-((8-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-8-oxooctyl)amino)-3-mcthyl- 2-OCO-2.3-dihydro- 1 //-bcnzo|c/|imidazol- 1 -yl)pipcridinc-2.6-dionc (P-161);
3-(5-((9-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo| 4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)-9-oxononyl)amino)-3- methyl -2 -oxo-2, 3 -dihydro- l//-benzo |c/|imidazol- 1 -yl)piperidine-2,6-dione (P-162) ;
3-(3-(9-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- l //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2H)- yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo|4.3-r|pyridin- 1 -yl)pipcridin- 1 -yl)-9-oxononyl)-2-oxo-2.3-dihydro- 1 H- benzo[i]imidazol- 1 -yl)piperidine-2,6-dione (P- 163);
3-(3-( 10-(4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 1 / -pyrazolo| 4.3-r |pyridin- 1 -yl)pipcridin- 1 -yl)- 10-oxodccyl)-2-oxo-2.3- dihydro- l//-benzo[i]imidazol- 1 -yl)piperidine-2,6-dione (P- 164);
3-(4-((4-((4-(5-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3.4-dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- 1 / -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-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4-dihydroquinolin- 1 (2//)-yl)-4.5.6.7-tctrahydro- 17/-pyrazolo| 4.3-r |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-acctyl-3-(7-(difluoromcthyl)-6-( 1 -methyl- 1 //-pyrazol-4-yl)-3,4-dihydroquinolin- 1 (2//)-yl)-4,5 ,6,7-tetrahydro- 1 / -pyrazolo [4,3 -cjpyridin- 1 -yl)piperidin- 1 -yl)methyl)phenethoxy)- 1 - oxoisoindolin-2-yl)piperidine-2,6-dione (P-174).
70. A composition comprising a bivalent compound according to any of claims 1 to 69 or a pharmaceutically acceptable salt or analog thereof, and a pharmaceutically acceptable carrier or diluent.
71. A method of treating a CBP/P300-mediated disease, comprising administering to a subject with a CBP/P300-mediated disease a bivalent compound or a pharmaceutically acceptable salt or analog thereof according to any one of claims 1 to 69, or a composition according to claim 70.
72. The method of claim 71, wherein the CBP/P300-mediated disease results from CBP/P300 expression, mutation, deletion, or fusion.
73. The method of claim 71 or 72, wherein the subject with the CBP/P300-mediated disease has an elevated CBP/P300 function relative to a healthy subject without the CBP/P300-mediated disease.
74. The method of any one of claims 71 to 73, wherein the bivalent compound is selected from the group consisting of P-001 to P-174 and CPD-1139 to CPD-1179 (preferably, 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-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, and P-174), or analogs thereof.
75. The method of any one of claims 70 to 74 wherein the bivalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.
76. The method of any one of claims 70 to 75, further comprising administering to the subject an additional therapeutic regimen for treating cancer, inflammatory disorders, or autoimmune diseases.
77. The method of claim 76, wherein the additional therapeutic regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.
78. The method of any one of claims 70 to 77 wherein the CBP/P300-mediated disease is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen- receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T- cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer,
Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.
79. The method of claim 78 wherein the CBP/P300-mediated disease is selected from the group consisting of prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and melanoma.
80. The method of any one of claims 71 to 77, wherein the CBP/P300-mediated disease is selected from the group consisting of 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 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, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.
81. The method of any one of claims 71 to 80, wherein the CBP/P300-mediated disease is a relapsed cancer.
82. The method of any one of claims 71 to 80, wherein the CBP/P300-mediated disease is refractory to one or more previous treatments.
83. A method for identifying a bivalent compound which mediates degradation or reduction of CBP/P300, the method comprising:
providing a heterobifunctional test compound comprising an CBP/P300 ligand conjugated to a degradation tag through a linker;
contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and CBP/P300;
determining whether CBP/P300 level is decreased in the cell; and
identifying the heterobifunctional test compound as a bivalent compound which mediates degradation or reduction of CBP/P300.
84. The method of claim 83, wherein the cell is a cancer cell.
85. The method of claim 84, wherein the cancer cell is a CBP/P300-mediated cancer cell.
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