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WO2025222132A1 - Compounds and uses thereof - Google Patents

Compounds and uses thereof

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Publication number
WO2025222132A1
WO2025222132A1 PCT/US2025/025388 US2025025388W WO2025222132A1 WO 2025222132 A1 WO2025222132 A1 WO 2025222132A1 US 2025025388 W US2025025388 W US 2025025388W WO 2025222132 A1 WO2025222132 A1 WO 2025222132A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
compound
attorney docket
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/025388
Other languages
French (fr)
Inventor
Shawn E.R. Schiller
Wesley Francis Austin
Md Imran Hossain
Melek Nihan UCISIK
Paige Justine MONSEN
Thomas Michael DIXON
Solymar NEGRETTI EMMANUELLI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Foghorn Therapeutics Inc
Original Assignee
Foghorn Therapeutics Inc
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Filing date
Publication date
Application filed by Foghorn Therapeutics Inc filed Critical Foghorn Therapeutics Inc
Publication of WO2025222132A1 publication Critical patent/WO2025222132A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • EP300 is a histone acetyltransferase that regulates transcription of genes via chromatin 5 remodeling. EP300 is involved in regulating cell growth and division. The present invention is related to useful compositions and methods for the treatment of EP300-related disorders, such as cancer and infection. SUMMARY EP300 is an intracellular protein that regulates cell growth and division. EP300 is overexpressed 10 in multiple cancer cell lines. Accordingly, agents that reduce the levels and/or activity of EP300 may provide new methods for the treatment of disease and disorders, such as cancer and infection.
  • agents that degrade EP300 are useful in the treatment of disorders (e.g., cancers or infections) related to EP300 and/or MYC.
  • disorders e.g., cancers or infections
  • the present disclosure features compounds and methods useful for treating EP300-related disorders (e.g., cancer or infection).
  • the disclosure features A compound having the structure of Formula I: A-L-B Formula I, wherein A is an EP300 binding moiety has the structure of Formula IIIa: 20 Formula IIIa wherein X 1’ is N or CR 6 ; X 2’ is N, or CR 5 ; R 1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(R a )2, S(O)N(R a )2, 25 S(O)2N(R a )2, OR a , SR a , OC(O)R a , OC(O)OR a , C(O)R a , C(O)OR a , S(O)R a , S(O)2R a , OC(O)N(R a )2,
  • each R h is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl 15 that is optionally substituted with one or more groups independently selected from halo;
  • B is a degradation moiety; and L is a linker between the EP300 binding moiety and the degradation moiety.
  • each R e is, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(R f )2, CN, C(O)N(R f )2, S(O)N(R f )2, S(O)2N(R f )2, OR f , SR f , OC(O)R f , OC(O)OR f , C(O)R f , C(O)OR f , S(O)R f , 20 S(O)2R f , OC(O)N(R f )2, N(R f )C(O)OR f , N(R f )C(O)N
  • each R f is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(R g )2, CN, 30 C(O)N(R g )2, S(O)N(R g )2, S(O)2N(R g )2, OR g , SR g , OC(O)R g , C(O)R g , C(O)OR g , S
  • each R g is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups 40 independently selected from oxo and halo; or two R g are taken together with the nitrogen to which they 3 PATENT ATTORNEY DOCKET NO
  • the EP300 binding moiety has the structure of Formula IIIb: 5 Formula IIIb wherein X 3 is O, NR N2’ or CR 7 , wherein R N2’ is C1-C3 alkyl or H, 10 R 1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I,C(O)N(R a )2, S(O)N(R a )2, S(O)2N(R a )2, OR a , SR a , OC(O)R a , OC(O)OR a , C(O)R a , C(O)OR a , S(O)R a , S(O)2R a , OC(O)N(R a )2, N(R a )C(O)OR
  • R 2 has the structure: . 5
  • R 1’ is H, halo, C1-C3 alkoxy, or C1-C4 alkyl optionally substituted with one or more substituent groups independently selected from F.
  • X 3 is CH2, NCH3, or O.
  • the EP300 binding moiety has the structure: 10 .
  • the EP300 binding moiety has the structure of Formula IIIc: 15 Formula IIIc wherein X 1’ is N or CR 6 , wherein R 6 is H, halo, C1-C3 alkyl, or C1-C3 alkoxy; X 2’ is N, or CR 5 , wherein R 5 is H, C1-C3 alkyl, or C1-C3 alkoxy; 5 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 R 1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(R a )2, S(O)N(R a )2, S(O)2N(R a )2, OR a , SR a , OC(O)R a , OC(O)OR a
  • R 2 has the structure: 30 .
  • R 1’ is H, halo, C1-C3 alkoxy, or C1-C4 alkyl optionally substituted with one or more substituent groups independently selected from F.
  • X 1 is CH, C1-C3 alkoxy, or N. 35
  • X 2 is CH or N.
  • R 4 is hydrogen. In some embodiments, R 4 is methyl.
  • the EP300 binding moiety has the structure: 6 PATENT ATTORNEY DOCKET NO.: 51121-103WO2
  • R 3 is optionally substituted C2-C9 heteroaryl, wherein the C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from halo, C1-C4 alkoxy, C1- 5 C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl, that is optionally substituted with one or more groups independently selected from halo, C1-C3 alkyl or C3-C10 carbocyclyl.
  • R 3 is optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, wherein the C1- C4 alkyl C2-C9 heteroaryl is optionally substituted with one or more groups independently selected with one or more groups independently selected from oxo, and C 1 -C 3 alkyl.
  • R 3 is: , , , 8 PATENT ATTORNEY DOCKET NO.: 51121-103WO2
  • the the EP300 binding moiety has the structure:
  • the EP300 binding moiety of Formula IIIa has the structure of Formula IIID: 5 wherein X 1 is NR N , CH2, or O; R N is C1-C3 alkyl or H; R 1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(R a )2, S(O)N(R a )2, 10 S(O)2N(R a )2, OR a , SR a , OC(O)R a , OC(O)OR a , C(O)R a , C(O)OR a
  • R 1’ is C1-C4 alkyl optionally substituted with one or more F groups. 10 In some embodiments, R 1’ is difluroromethyl. In some embodiments, R 2 has the structure: . In some embodiments, X 1 is CH2. In some embodiments, the EP300 binding moiety has the structure: .
  • the EP300 binding moiety has the structure of Formula IV: wherein R 7 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each alkyl, alkenyl, alkynyl, 3-12 membered carbocycle, and 3-12 membered 20 heterocycle of R 3 is optionally substituted with A 1 and/or C1-C6 alkyl; R 8 is C 1- C 12 alkyl, C 2- C 12 alkenyl, C 2- C 12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each alkyl, alkenyl, alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 3 is optionally substituted with A 1 and/or C1-C6 alkyl; R 9 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12
  • each R e is, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 20 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(R f )2, CN, C(O)N(R f )2, S(O)N(R f )2, S(O)2N(R f )2, OR f , SR f , OC(O)R f , OC(O)OR f , C(O)R f , C(O)OR f , S(O)
  • NR 2a R 3a taken together has the structure: 5 . In some embodiments, NR 2a R 3a taken together has the structure: , , 10 In some embodiments, R 3a is methyl.
  • the EP300 binding moiety has the structure: Formula I, wherein A is an EP300 binding moiety has the structure of Formula III: 12 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Formula III wherein R 1 is halo, C1-C4 alkyl, wherein any C1-C4 alkyl is optionally substituted with one or more 5 substituent groups independently selected from F, Cl, Br, I, C(O)N(R a )2, S(O)N(R a )2, S(O)2N(R a )2, OR a , SR a , OC(O)R a , OC(O)OR a , C(O)R a , C(O)OR a , S(O)
  • R 1 is C1-C4 alkyl optionally substituted with one or more F groups. In some embodiments, R 1 is difluroromethyl. In some embodiments, R 2 has the structure: 25 . In some embodiments, X 1 is CH2. In some embodiments, the EP300 binding moiety has the structure: 13 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 . In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety.
  • the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof.
  • the degradation moiety includes the structure of Formula Y: Formula Y, 5 where A 2 is a bond between the degradation moiety and the linker; v1 is 0, 1, 2, 3, 4, or 5; u1 is 1, 2, or 3; 10 R 5A is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each R J1 is, independently, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; J A is absent, O, optionally substituted amino, optionally substituted C1-C6 alkyl, or optionally 15 substituted C1-C6 heteroalkyl; and J is absent, optionally substituted C3-C10 carbocyclylene, optionally substituted C6-C10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene, or a pharmaceutically acceptable salt thereof.
  • T 2 is . In some embodiments, T 2 is or . so e e o e s, s . In some embodiments, T 2 is . In some embodiments, the structure of Formula Y has the structure of Formula Y1: 5 Formula Y1, or a pharmaceutically acceptable salt thereof. In some embodiments, T 1 is a bond. In some embodiments, . In some embodiments, the structure of Formula Y has the structure of Formula Y2: 10 Formula Y2, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula Y has the structure of Formula Z: Formula Z, 15 or a pharmaceutically acceptable salt thereof.
  • u1 is 1. In some embodiments, u1 is 2. In some embodiments u1 is 3. In some embodiments, the structure of Formula Z has the structure of Formula AA0: Formula AA0, 15 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula Z has the structure of Formula AB: Formula AB, 5 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula Z has the structure of Formula AC: Formula AC, or a pharmaceutically acceptable salt thereof. 10 In some embodiments, J A is absent. In some embodiments, J A is optionally substituted C1-C6 alkyl.
  • J A is optionally substituted C1-C6 heteroalkyl. In some embodiments, J A is O or optionally substituted amino. In some embodiments, .
  • the structure of Formula AA0 has the structure of Formula AA0: 15 Formula AA, or a pharmaceutically acceptable salt thereof.
  • v1 is 0, 1, 2, or 3. In some embodiments, v1 is 0. In some embodiments, v1 is 1. In some embodiments, v1 is 2. In some embodiments, v1 is 3. 20 In some embodiments, the structure of Formula AA has the structure of Formula AA1: Formula AA1, or a pharmaceutically acceptable salt thereof.
  • the structure of Formula AB has the structure of Formula AB1: 16 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Formula AB1, or a pharmaceutically acceptable salt thereof.
  • the structure of Formula AC has the structure of Formula AC1: 5 Formula AC1, or a pharmaceutically acceptable salt thereof.
  • J is absent.
  • J is optionally substituted C3-C10 carbocyclylene or optionally substituted C6-C10 arylene.
  • J is optionally substituted 10 C2-C9 heterocyclylene or optionally substituted C2-C9 heteroarylene.
  • J is optionally substituted heterocyclylene.
  • J is optionally substituted C6-C10 arylene.
  • the structure of Formula AA has the structure of Formula AA2: 15 Formula AA2, or a pharmaceutically acceptable salt thereof.
  • the structure of Formula AA has the structure of Formula AA3: Formula AA3, or a pharmaceutically acceptable salt thereof.
  • the structure of Formula AA has the structure of Formula AA4: Formula AA4, or a pharmaceutically acceptable salt thereof.
  • R A5 is H or optionally substituted C1-C6 alkyl. In some embodiments, R A5 is optionally substituted C1-C6 heteroalkyl.
  • R A5 is H or methyl. In some embodiments, R A5 is H. In some embodiments, R A5 is methyl. In some embodiments, R A5 is . In some embodiments, T 1 is a bond. In some embodiments, T 2 is , In some embodiments, R A5 is H. In some embodiments, J A is absent. In some embodiments, J is absent. 5 In some embodiments, the structure of Formula . In some embodiments, J is optionally substituted C2-C9 heteroarylene or optionally substituted C6- C10 arylene. In some embodiments, the structure of Formula , .
  • the structure of Formula Y is in some embodiments, the structure of Formula Y is . 15 18 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, . In some embodiments, J is optionally substituted C6-C10 arylene.
  • the structure of Formula Y is 5
  • the structure of Formula AA has the structure of Formula AY: , 10
  • R A5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl
  • R A6 is H or optionally substituted C1-C6 alkyl
  • R A7 is H or optionally substituted C1-C6 alkyl
  • R A6 and R A7 together with the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl
  • R A6 and R A7 together with the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or 15 optionally substituted C2-C5 heterocyclyl
  • R A8 is H, optionally substituted C1-C6 alkyl, or
  • each of R A1 , R A2 , R A3 , and R A4 is, independently, H, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, 15 or optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , and/or R A3 and R A4 , together with the carbon atoms to which each is attached, combine to form ; a is optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl
  • each of R A1 , R A2 , R A3 , and R A4 is, H, A 2 , halogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted -O-C3-C6 carbocyclyl, hydroxyl, optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , or R A3 and R A4 , together with the carbon atoms to which each is attached, combine to form ; a is optionally substituted C2-C9 heterocyclyl, which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A4 is A 2 , or is substituted 25 with A 2 .
  • each of R A1 , R A2 , R A3 , and R A4 is, independently, H, A 2 , F, , together with the carbon atoms to which each is attached, combine to form is optionally substituted C2- C9 heterocyclyl, which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , 30 is substituted with A 2 .
  • R A1 is A 2 .
  • R A2 is A 2 .
  • R A3 is A 2 .
  • R A4 is A 2 .
  • R A5 is A 2 . In some embodiments, R A5 is H or optionally substituted C1-C6 alkyl. In some embodiments, R A5 is H or . In some embodiments, R A5 is H. In some 5 embodiments, . . In some embodiments, . In some embodiments, each of R A6 and R A7 is, independently, H, F, , , ; or R A6 and R A7 , together with the carbon atom to which each is bound, combine to form 10 s , In some embodiments, the structure of Formula AY has the structure of Formula A1: 15 , Formula AY1 or a pharmaceutically acceptable salt thereof.
  • the structure of Formula AY has the structure of Formula A2: , 20 Formula AY2 or a pharmaceutically acceptable salt thereof. 21 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, the structure of Formula AY has the structure of Formula A3: , Formula AY3 or a pharmaceutically acceptable salt thereof. 5 In some embodiments, the structure of Formula AY has the structure of Formula A4: , Formula AY4 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A5: 10 , or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A6: , 15 Formula AY6 or a pharmaceutically acceptable salt thereof.
  • the structure of Formula AY has the structure of Formula A7: , Formula AY7 20 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A8: 22 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , Formula AY8 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A9: 5 , Formula AY9 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A10: , 10 Formula AY10 or a pharmaceutically acceptable salt thereof.
  • the structure of Formula AY is 24 PATENT ATTORNEY DOCKET NO.: 51121-103WO2
  • the structure of Formula . optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. 5
  • R A9 is H, A 2 , or optionally substituted C1-C6 alkyl.
  • R A9 is H, A 2 , or methyl.
  • R 9A is H.
  • R 9A is methyl. In some embodiments, R A9 is A 2 . 25 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, the structure of Formula . In some embodiments, the structure of Formula .
  • the structure of Formula AA has the structure of Formula BY: , 5 Formula BY where R A5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each of R A1 , R A2 , R A3 , and R A4 is, independently, H, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted 10 C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 15 R A3 , and R A4 is A 2 , or is substituted with A 2 , or a pharmaceutically acceptable salt thereof.
  • each of R A1 , R A2 , R A3 , and R A4 is, H, A 2 , halogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted -O-C3-C6 carbocyclyl, hydroxyl, optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , or R A3 and R A4 , together with the carbon atoms 20 is optionally substituted C2-C9 heterocyclyl, 26 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A4 is A 2 , or is substituted with A 2 .
  • each of R A1 , R A2 , R A3 , and R A4 is, independently, H, A 2 , F, , 5 C9 heterocyclyl, which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A4 is A 2 , or is substituted with A 2 .
  • R A1 is A 2 .
  • R A2 is A 2 .
  • R A3 is A 2 .
  • R A4 is A 2 .
  • R A5 is A 2 . 10
  • R A5 is H or optionally substituted C1-C6 alkyl.
  • R A5 is H or . In some embodiments, R A5 is H. In some embodiments, R A5 is . In some embodiments, the structure of Formula BY has the structure of Formula BY1: , 15 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula BY has the structure of Formula BY2: , Formula BY2 20 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula BY has the structure of Formula BY3: , Formula BY3 27 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula BY has the structure of Formula BY4: , 5 or a pharmaceutically acceptable salt thereof.
  • the structure of Formula BY is or . 10
  • the degradation moiety includes the structure of
  • L has the structure of Formula II: A 1 -(B 1 )f-(C 1 )g-(B 2 )h-(D)-(B Formula or a pharmaceutically acceptable salt thereof, wherein 15 A 1 is a bond between the linker and the EP300 binding moiety; A 2 is a bond between the degradation moiety and the linker; each of B 1 , B 2 , B 3 , and B 4 is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C10 arylene, optionally substituted C6-C10 aryl C1-4 alkylene, optionally substituted C2-C8 heterocyclyl C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C3-C10 20 cycloalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C
  • each of B 1 , B 2 , B 3 , and B 4 is, independently, optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2–C8 heteroarylene, optionally substituted C2-C8 heterocyclyl C1-C4 alkylene, or O.
  • B 1 or B 2 is optionally substituted C2-C8 heterocyclylene or optionally substituted C3-C10 cycloalkylene. 10 , In some embodiments, . In some embodiments, f is 0. 15 In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. 20 In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. 25 In some embodiments, k is 1.
  • D is D is optionally substituted C1–C10 alkylene, optionally substituted C2– C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C9 heterocyclylene, optionally substituted C2–C9 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2- C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene.
  • D is optionally substituted C2-C9 heterocyclylene.
  • D is 29 PATENT ATTORNEY DOCKET NO.: 51121-103WO2
  • D is optionally substituted C2–C8 heteroarylene.
  • D is optionally substituted C6–C12 arylene In some embodiments, D is optionally substituted C1-C10 alkylene. In some embodiments, D is optionally substituted C1-C10 heteroalkylene. 5 In some embodiments, the linker has the structure of: 10 30 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 31 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 32 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 33 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 35 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 36 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 37 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 38 PATENT ATTORNEY DOCKET NO.
  • the shortest chain of atoms connecting two valencies of the linker is 6 atoms long.
  • the compound is any one of compounds 1-30 in Table 1A. In some embodiments, the compound is any one of compounds 31-46, 49-58, 60-61, 63-64, 66- 10 70, and 72-234 in Table 1B. 42 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Table 1A.
  • the invention features a method of decreasing the levels and/or activity of EP300 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • 120 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 the invention features a method of decreasing the levels and/or activity of CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the invention features a method of decreasing the levels of or activity of a MYC 5 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the invention features a method of decreasing the levels of or activity of AR, i.e. androgen receptor, in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the cell is a cancer cell.
  • the invention features a method of treating a EP300-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the EP300-related disorder is cancer.
  • the invention features a method of inhibiting EP300, the method involving contacting a cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the cell is a cancer cell.
  • the disclosure features a method of inhibiting the level and/or activity of EP300 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, 20 or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the invention features a method of treating a disorder related to a EP300 loss of function mutation in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the disorder related to a EP300 loss of function mutation is cancer.
  • the subject is determined to have a EP300 loss of function disorder, for example, is determined to have a EP300 loss of function cancer (for example, the cancer has been determined to include cancer cells with loss of EP300 function).
  • the invention features a method of inducing apoptosis in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a 30 pharmaceutical composition thereof.
  • the cell is a cancer cell.
  • the invention features a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, 35 endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric cancer, urinary tract cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid 40 sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcom
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, 5 renal cell carcinoma, melanoma, neuroblastoma, or colorectal cancer.
  • the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer.
  • the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma. In some embodiemnts, the cancer is carcinoma. 10 In some embodiments, the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, myeloma, skin, endometrial, cervical, gastric, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, lymphoma, leukemia, esophogeal, stomach, or lung cancer. In some embodiments, the cancer is metastatic.
  • the cancer is metastatic.
  • the subject or cancer has a CBP loss of function mutation.
  • the method further comprises administering to the subject an anticancer therapy.
  • the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof.
  • the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, head and neck cancer, prostate cancer, acute leukemia, gastric cancer, or breast cancer.
  • the breast cancer is found to be ER positive i.e. the cancer cells contain estrogen receptors. 25 In some embodiments, the breast cancer is found to be ER negative i.e.
  • cancer cells do not contain estrogen receptors.
  • the prostate cancer is found to be AR positive i.e. cancer cells contain androgen receptors.
  • the prostate cancer is CRPC i.e. castration-resistant prostate cancer. 30
  • the prostate cancer is sensitive prostate cancer.
  • the cancer is lymphoma.
  • the lymphoma is Diffuse large B cell lymphoma (DLBCL).
  • the disclosure features a method of treating a EP300-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the 35 foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the EP300-related disorder is cancer.
  • the EP300- related disorder is infection.
  • the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, 40 breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's 122 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gli
  • Additional cancers which may be treated using the disclosed compounds according to the present invention include, for 10 example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast 15 cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2- negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor
  • the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta, abraxane, Adriamycin®, 35 gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, dema prior therapy
  • a prior therapy e.g
  • the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, 40 breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's 124 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendro
  • Additional cancers which may be treated using the disclosed compounds according to the present invention include, for 10 example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast 15 cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2- negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round 35 cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, 40 stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer.
  • the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s 126 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer.
  • the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma. In some embodiments of any of the foregoing methods, the cancer has or has been determined 5 to have EP300 mutations. In some embodiments of any of the foregoing methods, the EP300 mutations are homozygous. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an EP300 mutation.
  • EGFR epidermal growth factor receptor
  • the cancer does not 10 have, or has been determined not to have, a EP300 mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the foregoing methods, the cancer has, or has been determined to have, a KRAS mutation. In some embodiments of any of the foregoing methods, the CBP mutation is chromosomal translocation. 15 In another aspect, the disclosure provides a method treating a disorder related to EP300 (e.g., cancer or viral infections) in a subject in need thereof.
  • a disorder related to EP300 e.g., cancer or viral infections
  • the disorder is a viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency 20 virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simple
  • the disorder is Coffin Siris, Neurofibromatosis (e.g., NF-1, NF-2, or Schwannomatosis), or Multiple Meningioma.
  • the disclosure provides a method for treating a viral infection in a subject in 30 need thereof. This method includes administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions.
  • the viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), 35 Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicella-zoster virus), Papillomavi
  • HIV Human
  • the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, myeloma, skin, endometrial, esophageal, cervical, gastric, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the invention features a method of reducing tumor growth of melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the invention features a method of suppressing metastatic progression of melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the invention features a method of suppressing metastatic colonization of melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the invention features a method of reducing the level and/or activity of EP300 and/or CBP in a melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophageal, stomach, or hematologic cancer cell, the method including contacting the cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.
  • the melanoma, prostate cancer, breast cancer, bone cancer, myeloma, skin, endometrial, esophageal, cervical, gastric, renal cell carcinoma, osteosarcoma, neuroblastoma, esophagael, stomach, or hematologic cell is in a subject.
  • the effective amount of the compound reduces the level and/or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference.
  • the effective amount of the compound that reduces the level and/or activity of EP300 by at least 50% e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference.
  • the effective amount of the compound that reduces the level and/or activity of EP300 by at least 90% e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 35 99%.
  • the effective amount of the compound reduces the level of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to the percent of reduction of the level of CBP.
  • the effective amount of the compound that reduces 40 the level of EP300 by at least 50% e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to percent of reduction of the level of CBP.
  • the effective amount of the 128 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 compound that reduces the level of EP300 by at least 90% e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%
  • the effective amount of the compound reduces the level and/or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 5 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more).
  • 5% e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 5 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more).
  • the effective amount of the compound that reduces the level and/or activity of EP300 by at least 5% e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days 10 (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).
  • the effective amount of the compound reduces the level and/or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference.
  • the effective amount of the compound that reduces the level and/or 15 activity of CBP by at least 50% e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference.
  • the effective amount of the compound that reduces the level and/or activity of CBP by at least 90% e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • the effective amount of the compound reduces the level and/or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 20 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more).
  • the effective amount of the compound that reduces the level and/or activity of CBP by at least 5% e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days (e.g., 5 25 days, 6 days, 7 days, 14 days, 28 days, or more).
  • the subject has cancer.
  • the cancer expresses EP300 and/or CBP protein and/or the cell or subject has been identified as expressing EP300 and/or CBP.
  • the cancer expresses EP300 protein and/or the cell or subject has been identified as expressing EP300.
  • the cancer expresses CBP protein and/or the cell 30 or subject has been identified as expressing CBP.
  • the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma).
  • the cancer is prostate cancer.
  • the cancer is a hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell 35 lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.
  • hematologic cancer e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell 35 lymphom
  • the cancer is breast cancer (e.g., an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer).
  • the cancer is a bone cancer (e.g., Ewing’s sarcoma).
  • the cancer is a renal cell carcinoma 40 (e.g., a Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma (tRCC)).
  • the cancer is metastatic (e.g., the cancer has spread to the liver).
  • the metastatic 129 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 cancer can include cells exhibiting migration and/or invasion of migrating cells and/or include cells exhibiting endothelial recruitment and/or angiogenesis.
  • the migrating cancer is a cell migration cancer.
  • the cell migration cancer is a non-metastatic cell migration cancer.
  • the metastatic cancer can be a cancer spread via seeding the surface of the peritoneal, 5 pleural, pericardial, or subarachnoid spaces.
  • the metastatic cancer can be a cancer spread via the lymphatic system, or a cancer spread hematogenously.
  • the effective amount of an agent that reduces the level and/or activity of EP300 and/or CBP is an amount effective to inhibit metastatic colonization of the cancer to the liver.
  • the method further includes administering to the subject or contacting the 10 cell with an anticancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation.
  • an anticancer therapy e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation.
  • the anticancer therapy is a chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparagine- specific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA-Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase 15 inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor.
  • chemotherapeutic or cytotoxic agent e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparagine- specific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA-Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase 15 inhibitor, phosphinositide
  • Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum).
  • alkylating agents e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum.
  • paclitaxel paclitaxel
  • taxol docetaxel
  • taxotere cis-platinum
  • a list of additional compounds having anticancer activity can be found in L. Brunton, B. Chabner and B. Knollman (eds). Goodman and Gilman’s The Pharmacological Basis of 20 Therapeutics, Twelfth Edition, 2011, McGraw Hill Companies, New York, NY.
  • the anticancer therapy and the compound of the invention are administered within 28 days of each other and each in an
  • the cancer is resistant to one or more chemotherapeutic or cytotoxic 25 agents (e.g., the cancer has been determined to be resistant to chemotherapeutic or cytotoxic agents such as by genetic markers, or is likely to be resistant, to chemotherapeutic or cytotoxic agents such as a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic or cytotoxic agents.
  • the cancer is resistant or has failed to respond to dacarbazine, temozolomide, cisplatin, 30 treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and/or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).
  • a CTLA-4 inhibitor e.g., ipilimumab
  • a PD-1 inhibitor e.g., Nivolumab or pembr
  • alkyl refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms).
  • An alkylene is a divalent alkyl group.
  • alkenyl refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon 10 atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • alkynyl refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • amino represents –N(RN 1 )2, wherein each RN 1 is, independently, H, 15 OH, NO2, N(RN2)2, SO2ORN 2 , SO2RN 2 , SORN 2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN 1 groups can be optionally substituted; or two RN 1 combine to form an alkylene or heteroalkylene, and wherein each RN 2 is, independently, H, alkyl, or aryl.
  • each RN 1 is, independently, H, alkyl, or aryl.
  • the amino groups of the compounds described herein can be an unsubstituted amino (i.e., –NH2) or a substituted amino (i.e., –N(RN 1 )2).
  • aryl refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.
  • Carbocyclyl refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl 25 groups and unsaturated carbocyclyl radicals.
  • a carbocyclylene is a divalent carbocyclyl group.
  • halo means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl–O– (e.g., methoxy and ethoxy).
  • a heteroalkylene is a divalent heteroalkyl group.
  • heteroalkenyl refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the 35 heteroalkenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkenyl groups.
  • heteroalkenyl groups are an “alkenoxy” which, as used herein, refers alkenyl–O–.
  • a heteroalkenylene is a divalent heteroalkenyl group.
  • heteroalkynyl refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkynyl group 40 can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyl groups.
  • PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl–O–.
  • a heteroalkynylene is a divalent heteroalkynyl group.
  • heteroaryl refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, 5 and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.
  • heterocyclyl refers a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O or S, wherein no ring is 10 aromatic. Heterocyclyl rings may be spirocyclic or bridged. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.
  • a heterocyclylene is a divalent heterocyclyl group.
  • hydroxyl represents an —OH group.
  • thiol represents an —SH group.
  • carbonyl represents an —C(O)– group.
  • thiocarbonyl represents an —C(S)– group.
  • sulfonyl represents an —S(O)2– group.
  • phosphoryl represents an P(O) group.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl 20 groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified.
  • Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or 25 thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol.
  • alkyl e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo
  • Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).
  • Compounds described herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, 30 optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates.
  • optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. 35 Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable.
  • Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the 40 configuration of substituents around one or more chiral carbon atoms.
  • Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known 132 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 techniques and methods, such as, for example, chiral chromatography and separation methods based thereon.
  • the appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art.
  • Racemate or “racemic mixture” means a compound containing two enantiomers, wherein such mixtures exhibit no 5 optical activity; i.e., they do not rotate the plane of polarized light.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on 25 opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” 10 indicate configurations relative to the core molecule.
  • Certain of the disclosed compounds may exist in atropisomeric forms.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds described herein may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a 15 free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide 35 of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or 20 resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure.
  • the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure.
  • Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers.
  • the stereochemistry of a disclosed compound is named or depicted by structure, 30 the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure.
  • diastereomer When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percent purity by mole fraction is the 35 ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer.
  • the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and/or”; and (iii) the terms “including” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.
  • the terms “about” and “approximately” refer to a value that is within 10% above or 20 below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.
  • administration refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system.
  • Administration to an animal subject may be by any appropriate route.
  • administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.
  • EP300 refers to the EP300 protein in a human cell.
  • CBP refers to the CREB-binding protein in a human cell.
  • EP300-related disorder refers to a disorder that is caused or affected by the level of activity of CBP.
  • EP300 loss of function mutation refers to a mutation in EP300 that 35 leads to the protein having diminished activity (e.g., at least 1% reduction in EP300 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity).
  • Exemplary EP300 loss of function mutations include, but are not limited to, a homozygous EP300 mutation and chromosomal translocations.
  • EP300 loss of function disorder refers to a disorder (e.g., cancer) that 40 exhibits a reduction in EP300 activity (e.g., at least 1% reduction in EP300 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in EP300 activity).
  • cancer refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.
  • a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen 5 for a particular disease or condition.
  • the treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap.
  • the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated.
  • the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen.
  • 10 administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic).
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, 15 but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.
  • determining the level of a protein or RNA is meant the detection of a protein or an RNA, by 20 methods known in the art, either directly or indirectly.
  • Directly determining means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value.
  • Indirectly determining refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value).
  • Methods to measure protein level generally include, but are not limited to, western blotting, 25 immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, 30 as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners.
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • immunoprecipitation immunofluorescence
  • surface plasmon resonance chemiluminescence
  • fluorescent polarization fluorescent
  • RNA levels are known in the art.
  • the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and/or activity of EP300 (e.g., in a cell or a subject) described herein refer to a quantity sufficient to, when administered to the subject, including a human, effect 35 beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and/or activity of EP300 sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and/or activity of EP300.
  • a “therapeutically effective amount” of an agent that reduces the level and/or activity of EP300 of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to 5 a control.
  • a therapeutically effective amount of an agent that reduces the level and/or activity of EP300 of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.
  • the term “inhibitor” refers to any agent which reduces the level and/or activity of a 10 protein (e.g., EP300). Non-limiting examples of inhibitors include small molecule inhibitors, degraders, antibodies, enzymes, or polynucleotides (e.g., siRNA).
  • level is meant a level of a protein, or mRNA encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein.
  • a “decreased level” or an “increased level” of a protein or RNA is meant a decrease or increase, respectively, in a protein or RNA 15 level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as 20 compared to a reference; a decrease or an increase by less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1.2
  • a level of a protein may be expressed in mass/vol (e.g., g/dL, 25 mg/mL, ⁇ g/mL, ng/mL) or percentage relative to total protein in a sample.
  • decreasing the activity of EP300 is meant decreasing the level of an activity related to EP300, or a related downstream effect.
  • the activity level of a EP300 may be measured using any method known in the art, e.g., HiBit assay.
  • pharmaceutical composition represents a composition containing a 30 compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human.
  • a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for 35 topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.
  • a “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active 40 compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, 136 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, 5 croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), 10 stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin
  • the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, for example, any compound of Formula I.
  • Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue 15 toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or 20 separately by reacting a free base group with a suitable organic acid.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically 25 acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, 30 camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. 40
  • a “reference” is meant any useful reference used to compare protein or RNA levels.
  • the reference can be any sample, standard, standard curve, or level that is used for comparison purposes. 137 PATENT ATTORNEY DOCKET NO.: 51121-103WO2
  • the reference can be a normal reference sample or a reference standard or level.
  • a “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a 5 subject that is diagnosed with a disease, but not yet treated with a compound of the invention; a sample from a subject that has been treated by a compound of the invention; or a sample of a purified protein or RNA (e.g., any described herein) at a known normal concentration.
  • a control e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject
  • a sample from a normal healthy subject such as a normal cell or normal tissue
  • a sample e.g., a cell or tissue
  • reference standard or level is meant a value or number derived from a reference sample.
  • a “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a 10 normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”).
  • a subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker.
  • a normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound of the invention.
  • the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health.
  • a standard curve of levels of a purified protein or RNA, e.g., any described herein, within the normal reference range can also be used as a reference.
  • the term “subject” refers to any organism to which a composition in accordance 20 with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes.
  • Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans).
  • a subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • the terms "treat,” “treated,” or “treating” mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of 30 condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • Compounds of the invention may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder.
  • the terms “variant” and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein.
  • a variant or derivative of a compound, peptide, protein, or other substance 40 described herein may retain or improve upon the biological activity of the original material.
  • 138 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 The details of one or more embodiments of the invention are set forth in the description below.
  • the term “degrader” refers to a small molecule compound including a degradation 5 moiety, wherein the compound interacts with a protein (e.g., EP300) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of the level of the protein, e.g., in a cell or subject.
  • a protein e.g., EP300
  • degradation moiety refers to a moiety whose binding results in degradation of a protein, e.g., EP300.
  • the moiety binds to a protease or a ubiquitin ligase 10 that metabolizes the protein, e.g., EP300.
  • a protease or a ubiquitin ligase 10 that metabolizes the protein, e.g., EP300.
  • the present disclosure features compositions and methods useful for the treatment of EP300- related disorders (e.g., cancer and infection).
  • the disclosure further features compositions and methods 15 useful for inhibition of the level and/or activity of EP300, e.g., for the treatment of disorders such as cancer (e.g., sarcoma) and infection (e.g., viral infection), e.g., in a subject in need thereof.
  • A-L-B Formula I wherein A is an EP300 binding moiety has the structure of Formula IIIa: Formula IIIa wherein X 1’ is N or CR 6 ; 25 X 2’ is N, or CR 5 ; R 1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I,C(O)N(R a )2, S(O)N(R a )2, S(O)2N(R a )2, OR a , SR a , OC(O)R a , OC(O)OR a , C(O)R a , C(O)R a , C(
  • compositions described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the level, status, and/or activity of EP300, e.g., by inhibiting the activity or level of the EP300 in a cell within a mammal.
  • An aspect of the present invention relates to methods of treating disorders related to EP300 such as cancer in a subject in need thereof.
  • the compound is administered in an 25 amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject. Treating cancer can result in a reduction in size or volume of a tumor.
  • tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.
  • Size of a tumor may be measured by any reproducible means of measurement.
  • the size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer may further result in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment.
  • Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x). Treating cancer can result in a decrease in number of metastatic nodules in other tissues or 40 organs distant from the primary tumor site. For example, after treatment, the number of metastatic 141 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • 5% or greater e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater
  • the number of metastatic nodules may be measured by any reproducible means of measurement.
  • the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 5 50x).
  • Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average survival time of a population may be measured by any reproducible 10 means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.
  • 15 Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a 20 pharmaceutically acceptable salt of a compound described herein.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.
  • 25 Combination Therapies
  • a method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of therapies to treat cancer.
  • the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, 30 doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, dosages of the compounds when combined should provide a therapeutic effect.
  • the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer).
  • alkylating 35 agents include alkylating 35 agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog.
  • 5-fluorouracil 5-FU
  • 40 leucovorin (LV) irenotecan
  • oxaliplatin capecitabine
  • paclitaxel paclitaxel
  • doxetaxel chemotherapeutic agents
  • alkylating agents such as thiotepa and cyclosphosphamide
  • alkyl 142 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 sulfonates such as busulfan, improsulfan and piposulfan
  • aziridines such as benzodopa, carboquone, meturedopa, and uredopa
  • ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine
  • acetogenins especially bullatacin and bullatacinone
  • a camptothecin including the synthetic
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic 15 chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, 6-diazo- 5-oxo-L-nor
  • chemotherapeutic agents can be used in a cocktail to be administered in combination with the first 5 therapeutic agent described herein.
  • Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol.18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).
  • the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment.
  • cytokine e.g., interferon or an interleukin (e.g., IL-2)
  • the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®).
  • an anti-VEGF agent e.g., bevacizumab (AVASTIN®).
  • the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer.
  • Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); 15 SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-I- 131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (pan
  • the second agent may be a therapeutic agent which is a non-drug treatment.
  • the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue.
  • the second agent may be a checkpoint inhibitor.
  • the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody).
  • the antibody may 30 be, e.g., humanized or fully human.
  • the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein.
  • the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein.
  • the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein.
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule 35 inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion a protein such as ipilimumab/YERVOY® or tremelimumab).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; pidilizumab/CT-011).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; 40 BMS 936559).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/Ig fusion protein such as AMP 144 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 224).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof.
  • the anti-cancer therapy is a T cell adoptive transfer (ACT) therapy.
  • the T cell is an activated T cell.
  • the T cell may be modified to express a chimeric antigen receptor (CAR).
  • CAR modified T (CAR-T) cells can be generated by any method known in the art.
  • the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell.
  • a source of T cells Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject.
  • T cells can be obtained from a number of sources, including peripheral blood mononuclear 10 cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors.
  • any number of T cell lines available in the art may be used.
  • the T cell is an autologous T cell.
  • the T cells can be activated and expanded generally using methods as described, for example, in U.S. 15 Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and U.S. Patent Application Publication No.20060121005.
  • the first and second therapeutic agents are administered simultaneously or sequentially, in either order.
  • the first therapeutic agent may be 20 administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent.
  • compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.
  • the compounds described herein may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the methods described herein.
  • the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds described herein may be administered, for 35 example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
  • a compound described herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be 145 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 compressed into tablets, or it may be incorporated directly with the food of the diet.
  • a compound described herein may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.
  • a compound described herein may also be administered parenterally.
  • Solutions of a compound described 5 herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s 10 Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018.
  • compositions suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe.
  • Compositions for nasal administration may 15 conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non- aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an 20 aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as 25 sugar, acacia, tragacanth, gelatin, and glycerine.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.
  • a compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate.
  • a 30 compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals. In the case of surgical intervention, the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection.
  • Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature.
  • the compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
  • the dosage of the compounds described herein, and/or compositions including a compound described herein can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the 5 clearance rate of the compound in the animal to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.
  • kits including (a) a pharmaceutical composition including an agent that reduces the level and/or activity of EP300 in a cell or subject described herein, and (b) a package insert with instructions to perform any of the methods described herein.
  • the kit includes (a) a pharmaceutical composition including an agent that reduces the level and/or activity of 20 EP300 in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein.
  • a pharmaceutical composition including an agent that reduces the level and/or activity of 20 EP300 in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein.
  • Step 2 A solution of tert-butyl 4-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in dioxane was treated with7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline, XPhos Pd G3 and X Phos, and20 heated at 80 C for 8 h to give tert-butyl 4-(3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1H- pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in 76% yield.
  • Step 3 A solution of tert-butyl 4-(3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate in MeOH was treated with PtO2 and hydrogen at 25 C for 12 h to 149 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 give tert-butyl 4-(3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate which was used without purification.
  • Step 4 A solution of tert-butyl 4-(3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H- 5 pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in DCM was treated with acetic anhydride and triethylamine at 25 C for 1 h to give tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)- yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in 79% yield.
  • Step 6 A solution of tert-butyl 4-(5-acetyl-3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in dioxane was treated with cesium carbonate, Pd(dppf)Cl2 and bis(pinacolato)diboron at 100 C or 2 h to give tert-butyl 4-(5-acetyl-3- (7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7- 20 tetrahydr
  • Step 7 A solution of tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-25 carboxylate carboxylate in dioxane was treated with cesium carbonate, Pd(dppf)Cl2 and 3-bromo-1- methyl-1H-pyrrolo[3,2-c]pyridine at 80 C for 2 h to give tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-6-(1- methyl-1H-pyrrolo[3,2-c]pyridin-3-yl
  • Step 5 4-(4- ⁇ 5-acetyl-3-[7-(difluoromethyl)-6- ⁇ 1-methylpyrrolo[3,2-c]pyridin-3-yl ⁇ -3,4-dihydro-2H-quinolin- 1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ piperidin-1-yl)-N-(3- ⁇ [2-(2,6-dioxopiperidin-3-yl)-1,3- 20 dioxoisoindol-4-yl]oxy ⁇ phenyl)-4-oxobutanamide (Compound 14).
  • the crude 5 product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 13% B to 33% B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 8.33) to afford compound 14 (17.7 mg, 27.27%) as a light yellow solid.
  • Step 2 1- ⁇ 1-[1-(azetidine-3-carbonyl)piperidin-4-yl]-3-[7-(difluoromethyl)-6- ⁇ 1-methylpyrrolo[3,2-c]pyridin- 15 3-yl ⁇ -3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl ⁇ ethanone (Intermediate 3). A mixture of Intermediate 2 (40 mg, 0.054 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred at room temperature for 1 h.
  • the crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 12% B to 29% 10 B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 9.15). This resulted in compound 9 (10.6 mg, 12.52%) as a yellow solid.
  • the crude product (25 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 25 OBD Column 30*150mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 15% B to 32% B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 7.87) to afford compound Compound A (17.5 mg, 31.53%) as a off-white solid.
  • the mixture solution was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 10 OBD Column 30*150mm, 5 ⁇ m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 6% B to 23% B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 9.32) to afford compound 6 (5.2 mg, 16.67%) as a light yellow solid.
  • Step 1 5-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroquinolin- 5 1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 27).
  • Step 2 1- ⁇ 1-[1-(azetidin-3-yl)piperidin-4-yl]-3-[7-(difluoromethyl)-6- ⁇ 1-methylpyrrolo[3,2-c]pyridin-3-yl ⁇ -3,4- 25 dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl ⁇ ethanone (Intermediate 3).
  • DCM 3 mL
  • Step 3 5-[3-(4- ⁇ 5-acetyl-3-[7-(difluoromethyl)-6- ⁇ 1-methylpyrrolo[3,2-c]pyridin-3-yl ⁇ -3,4-dihydro-2H- quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ piperidin-1-yl)azetidin-1-yl]-2-(2,6-dioxopiperidin-3- 10 yl)isoindole-1,3-dione
  • Intermediate 3 28 mg, 0.046 mmol, 1 equiv
  • DIEA 29.43 mg, 0.230 mmol, 5 equiv
  • Step 1 5-(4- ⁇ 5-acetyl-3-[7-(difluoromethyl)-6- ⁇ 1-methylpyrrolo[3,2-c]pyridin-3-yl ⁇ -3,4-dihydro-2H-quinolin- 1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 26).
  • Step 1 tert-butyl 4- ⁇ 5-acetyl-3-[7-(difluoromethyl)-6- ⁇ 3,5-dimethylpyrrolo[3,2-c]pyridazin-7-yl ⁇ -3,4-dihydro- 2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ piperidine-1-carboxylate (Intermediate 2).
  • the resulting mixture was stirred at 40°C for 10 1h. Desired product could be detected by LCMS.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): isocratic 10%B to 22%B in 10min; Wave Length: 254nm/220 nm; RT1(min): 10.57) to afford compound 109 (10.1 mg, 30.23%) as a light yellow solid.
  • Step 2 Preparation of methyl 1- ⁇ 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyrazolo[4,3-c]pyridin-3-yl ⁇ -7- (difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylate (Intermediate 3).
  • Step 3 Preparation of methyl 1- ⁇ 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,5H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl ⁇ -7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylate (Intermediate 4).
  • Intermediate 4 To a solution of intermediate 3 (240 mg, 0.444 mmol, 1.00 equiv) in MeOH (9 mL) was added Platinum(IV)oxide (26.20 mg, 0.124 mmol, 0.34 equiv) at room temperature.
  • Step 4 Preparation of methyl 1- ⁇ 5-acetyl-1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl ⁇ -7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylate (Intermediate 5).
  • Step 5 Preparation of 1- ⁇ 5-acetyl-1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl ⁇ -7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid (Intermediate 6).
  • Step 2 Preparation of 2-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo [3,4-f]isoindol- 2(1H)-yl)acetic acid (Intermediate B).
  • Intermediate B A mixture of intermediate 2 (105 mg, 0.363 mmol, 1 equiv) in con.HCl (5 mL) and H2O (5 mL) was 5 stirred at room temperature for 0.5h. The resulting mixture was concentrated under reduced pressure to afford (126 mg, crude) as a white solid.
  • Step 1 tert-butyl 3-(3-bromopyridin-4-yl)-3-cyanoazetidine-1-carboxylate (Intermediate 2). 5 A solution of 3-bromo-4-fluoropyridine (1 g, 5.682 mmol, 1 equiv) and tert-butyl 3-cyanoazetidine-1- carboxylate (2.07 g, 11.364 mmol, 2 equiv) in THF (15 mL) was stirred for 30 min at -78°C under nitrogen atmosphere. To the above mixture was added LDA (in 2M THF) (1.22 g, 11.364 mmol, 2 equiv) in portions over 10 min at -78°C under nitrogen atmosphere.
  • LDA in 2M THF
  • Step 5 Preparation of tert-butyl 4- ⁇ 5-acetyl-3-[7-(difluoromethyl)-6- ⁇ 1-methyl-2'H-spiro[azetidine-3,3'- pyrrolo[2,3-c]pyridin]-1'-yl ⁇ -3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ piperidine- 1-carboxylate (Intermediate 6).
  • Step 6 Preparation of 1- ⁇ 3-[7-(difluoromethyl)-6- ⁇ 1-methyl-2'H-spiro[azetidine-3,3'-pyrrolo[2,3-c]pyridin]- 1'-yl ⁇ -3,4-dihydro-2H-quinolin-1-yl]-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl ⁇ ethanone (Intermediate 7). To a stirred solution of intermediate 6 (48 mg, 0.068 mmol, 1 equiv) in DCM (0.75 mL) was added 25 TFA (0.25 mL).
  • the resulting mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 11% B in 10 min; Wave Length: 254nm/220 nm; RT1(min): 10.87) to afford compound 86 (18.1 mg, 43.54%) as a light yellow solid.
  • Step 1 Preparation of methyl (1s,4s)-4-[(4-methylbenzenesulfonyl)oxy]cyclohexane-1-carboxylate (Intermediate 2).
  • methyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate (1 g, 6.321 mmol, 1 10 equiv) and TsCl (4.34 g, 22.757 mmol, 1.2 equiv) in DCM (40 mL) was added TEA (5.76 g, 56.892 mmol, 3 equiv) and DMAP (463.36 mg, 3.793 mmol, 0.2 equiv).
  • Step 6 Preparation of methyl (1r,4r)-4- ⁇ 5-acetyl-3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1- yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ cyclohexane-1-carboxylate (Intermediate 7).
  • 228 PATENT ATTORNEY DOCKET NO.: 51121-103WO2
  • NBS 136.08 mg, 0.765 mmol, 1 equiv
  • the resulting mixture was stirred at 10 40°C for 1h under argon atmosphere.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5 ⁇ m; Mobile Phase A: Water(0.1%FA, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17%B to 27% B in 10min; Wave Length: 254nm/220 nm; RT1(min): 9.7) to afford compound 74 (9 mg, 11.78%,) as a yellow solid.
  • Step 1 Preparation of methyl 3- ⁇ 6-[4-(dimethoxymethyl)piperidin-1-yl]-1-oxo-3H-isoindol-2-yl ⁇ piperidine- 2,6-dione (Intermediate 2).
  • Step2 Preparation of 1-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl] piperidine-4-carbaldehyde 10 (Intermediate 3).
  • Intermediate 2 100 mg, 0.319 mmol, 1 equiv
  • DMSO 1.2 mL
  • IBX 178.75 mg, 0.638 mmol, 2 equiv
  • the resulting mixture was stirred at room temperature for 2h. Desired product could be detected by LCMS.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient (B%): 8%B to 18%B in 10min; Wave Length: 254nm/220 nm; RT1(min): 9.32) to afford compound 118 (2.1 mg, 2.50%) as a yellow solid.
  • Step 2 Preparation of tert-butyl 4- ⁇ 5-acetyl-3-[7-(difluoromethyl)-6- ⁇ imidazo[1,2-a]pyridin-6-yl ⁇ -3,4- dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ piperidine-1-carboxylate (Intermediate 3).
  • Step 3 Preparation of 1- ⁇ 3-[7-(difluoromethyl)-6- ⁇ imidazo[1,2-a]pyridin-6-yl ⁇ -3,4-dihydro-2H-quinolin-1-yl]- 15 1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl ⁇ ethanone (Intermediate 4).
  • Intermediate 4 To a stirred mixture of intermediate 3 (113 mg, 0.175 mmol, 1 equiv) in DCM (0.9 mL) was added trifluoroacetic acid (0.3 mL) in portions at room temperature. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure.
  • Step 4 Preparation of t 4-( ⁇ 4-[(4- ⁇ 5-acetyl-3-[7-(difluoromethyl)-6- ⁇ imidazo[1,2-a]pyridin-6-yl ⁇ -3,4-dihydro- 2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ piperidin-1-yl)methyl]phenyl ⁇ amino)-2-(2,6- dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 125).
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; 10 Gradient: 10% B to 30% B in 10 min; Wave Length: 254nm/220nm; RT1(min): 9.1) to afford Compound 125. (7.1 mg, 14.24%) as a yellow solid.
  • Step 2 Preparation of 1- ⁇ 3-[2-(4- ⁇ 5-acetyl-3-[7-(difluoromethyl)-6- ⁇ 6-methoxyimidazo[1,2-a]pyridin-7-yl ⁇ - 3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl ⁇ piperidin-1-yl)-2-oxoethoxy]-2- methylphenyl ⁇ -1,3-diazinane-2,4-dione (Compound 142).
  • Step 1 tert-butyl 4-(5-acetyl-3- ⁇ [4-chloro-3-(difluoromethyl)phenyl]amino ⁇ -4H,6H,7H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 2).
  • Step 2 tert-butyl 4-(5-acetyl-3- ⁇ [4-chloro-3-(difluoromethyl)phenyl](methyl)amino ⁇ -4H,6H,7H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 3).
  • Intermediate 3 To a stirred solution of intermediate 2 (1.8 g, 3.435 mmol, 1 equiv) and NaH (164.87 mg, 6.870 mmol, 2 equiv) in DMF (10 mL) was added MeI (1.46 g, 10.305 mmol, 3.00 equiv) at 0°C.
  • Step 3 4-( ⁇ 5-acetyl-1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-3- yl ⁇ (methyl)amino)-2-(difluoromethyl)phenylboronic acid (Intermediate 4).
  • the resulting mixture was stirred at room temperature for additional 1h.
  • the 10 mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5 ⁇ m; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 10%B to 18%B in 10min; Wave Length: 254nm/220 nm; RT1(min): 7.82) to afford to afford compound 224 (20 mg, 32.23%) as a white solid.
  • the resulting mixture was stirred at 25°C for 1h.
  • the mixture was purified by Prep- HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5 ⁇ m; Mobile Phase A: 15 Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): isocratic 7% B to 18% B in 10min; Wave Length: 254 nm/220 nm; RT1(min): 11.73) to afford compound 190 (11.2 mg, 7.02%) as a yellow solid.
  • Step 1 Preparation of 3- ⁇ 5-[3-(4- ⁇ 5-acetyl-3-[7-(difluoromethyl)-6- ⁇ 6-methoxyimidazo[1,2- 5 258 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 1: Preparation of methyl 3- ⁇ 6-[4-(dimethoxymethyl)piperidin-1-yl]-1-oxo-3H-isoindol-2-yl ⁇ piperidine- 2,6-dione (Intermediate 2).
  • Step2 Preparation of 1-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl] piperidine-4-carbaldehyde (Intermediate 3).
  • Intermediate 2 100 mg, 0.319 mmol, 1 equiv
  • DMSO 1.2 mL
  • IBX 178.75 mg, 0.638 mmol, 2 equiv
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): isocratic 11% B to 23% B in10min; Wave Length: 254nm/220 nm; RT1(min): 8.03) to afford compound 165 (19.5 mg, 18.39%) as a 15 yellow solid.
  • Step 1 Preparation of Preparation of 3-(5-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(6-methoxyimidazo[1,2- a]pyridin-7-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 141). .
  • the resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. Desired product could be detected by LCMS.
  • the mixture solution was purified directly by Prep-HPLC with the 10 following conditions (Column: Xselect CSH Prep C18, 30*150mm 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 17%B to 27%B in10min; Wave Length: 254nm/220 nm; RT1(min): 10.73) to afford compound 141 (10.9 mg, 25.02%) as a white solid.
  • Step 3 Preparation of 3-chloro-7-methyl-7H-pyrrolo[2,3-c]pyridazine (Intermediate 4).
  • Intermediate 3 To a solution of KOH (367 mg, 6.568 mmol, 3 equiv) in DMF (2 mL) was treated with intermediate 3 (335 mg, 2.189 mmol, 1 equiv) for 1h at room temperature under nitrogen atmosphere followed by the addition of CH3I (310 mg, 2.189 mmol, 1.00 equiv) dropwise at room temperature. The resulting mixture 15 was stirred for overnight at room temperature.
  • Step 4 Preparation of tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-6-(7-methyl-7H-pyrrolo [2,3-c]pyridazin-3- yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 5).
  • Step 5 Preparation of 1-(3-(7-(difluoromethyl)-6-(7-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl) -3,4- 5 dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (Intermediate 6). To a solution of intermediate 5 (58 mg, 0.088 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) at room temperature. The resulting mixture was stirred for 1h at room temperature.
  • Step 6 Preparation of 6-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(7-methyl-7H-pyrrolo [2,3-c]pyridazin-3-yl)- 3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)- 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (Compound 121).
  • the mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Fluoro-Phenyl Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(0.1%FA, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10%B to 20% B in 10min; Wave Length: 254nm/220 nm; RT1(min): 11.11) 25 to afford compound 121 (27 mg, 84.10%) as a yellow solid.
  • Step 2 Preparation of tert-butyl 4-(3- ⁇ [5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino ⁇ pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 3).
  • Desired product could be detected by LCMS.
  • the resulting mixture was diluted with water (50 mL), extracted with EtOAc (3 x 200 mL). The combined organic layers were washed 10 with water (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in intermediate 3 (800 mg, 47.60%) as a yellow solid.
  • LCMS (ESI) m/z: [M+H] + 493.
  • Step 3 Preparation of tert-butyl 4-(3- ⁇ [5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino ⁇ -4H,5H,6H,7H- pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 4).
  • Step 4 Preparation of tert-butyl 4-(5-acetyl-3- ⁇ [5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino ⁇ - 4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 5).
  • Intermediate 5 To a stirred mixture of intermediate 4 (750.2 mg, 1.509 mmol, 1 equiv) and Acetic anhydride (308.1 mg, 3.018 mmol, 2 equiv) in DCM (10 mL) was added DIEA (390.0 mg, 3.018 mmol, 2 equiv) in portions 10 at room temperature.
  • Desired product could be detected by LCMS.
  • the resulting mixture was diluted with water (50 mL).
  • the resulting mixture was extracted with EtOAc (3 x 200 mL).
  • the combined 25 organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash 303 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in intermediate 6 (576 mg, 62.55%) as a yellow solid.
  • Step 3 Preparation of 1-(3-(3-hydroxyprop-1-yn-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 4).
  • Intermediate 4 To a stirred solution of intermediate 3 (200 mg, 0.606 mmol, 1 equiv) and trimethyl(prop-2-yn-1- yloxy)silane (116.54 mg, 0.909 mmol, 1.5 equiv) in DMF (2 mL) was added Pd(PPh3)2Cl2 (85.05 mg, 20 0.121 mmol, 0.2 equiv) and CuI (11.54 mg, 0.061 mmol, 0.1 equiv), Cs2CO3 (592.17 mg, 1.818 mmol, 3 equiv).
  • Step 4 Preparation of 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)propiolaldehyde (Intermediate 5).
  • Intermediate 4 To a stirred solution of intermediate 4 (60 mg, 0.232 mmol, 1 equiv) in DMSO (1 mL) was added 5 IBX (130.10 mg, 0.464 mmol, 2 equiv). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. Na2S2O3 (aq.) (10 mL) at 0 °C.
  • the resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 9%B to 20%B in10min; Wave Length: 254 nm/220 nm; RT1(min): 9.13) to afford 25 compound 213 (35.5 mg, 27.87%) as a yellow solid.
  • Step 1 Preparation of 1-(3-ethenyl-2-methylphenyl)-1,3-diazinane-2,4-dione (Intermediate 2).
  • Intermediate 1 300 mg, 0.909 mmol, 1 equiv
  • Pd(dppf)Cl2 66.49 mg, 0.091 mmol, 0.1 equiv
  • Cs2CO3 888.26 mg, 2.727 mmol, 3 equiv
  • Step 1 Preparation of 3-(benzyl(methyl)amino)piperidine-2,6-dione (Intermediate 2).
  • DMF dimethylbenzylamine
  • the resulting mixture was stirred at room temperature for 2 h.
  • the resulting mixture was diluted with water (60 mL).
  • the resulting mixture was 10 was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SO4.
  • Step 3 Preparation of 5-bromo-N-(2,6-dioxopiperidin-3-yl)-N-methylpicolinamide (Intermediate 4).
  • Intermediate 3 250 mg, 1.759 mmol, 1 equiv
  • 5-bromopyridine-2- carboxylic acid 355.25 mg, 1.759 mmol, 1 equiv
  • DMA 3 mL
  • HATU 2.638 mmol, 1.50 equiv
  • DIEA 681.88 mg, 5.277 mmol, 3.00 equiv
  • the resulting mixture was diluted with water (200 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with saturated brine (200 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product.
  • the crude product was purified by flash C18-flash chromatography, 10 elution gradient 0 to 100% MeCN in water (containing 0.05% TFA).
  • Step 7 Preparation of tert-butyl 4-(5-acetyl-3-(7-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-3,4-dihydroquinoxalin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1- carboxylate (Intermediate 8).
  • Step 8 Preparation of tert-butyl 4-(5-acetyl-3-(7-fluoro-6-(6-methoxyimidazo[1,2-a]pyridin-7-yl)-4-methyl- 25 3,4-dihydroquinoxalin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 9).
  • Step 9 Preparation of 1-(3-(7-fluoro-6-(6-methoxyimidazo[1,2-a]pyridin-7-yl)-4-methyl-3,4- dihydroquinoxalin-1(2H)-yl)-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1- one (Intermediate 10). To a stirred solution of intermediate 9 (90 mg, 0.137 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 15 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere.
  • Step 10 Preparation of 3-(5-(4-(5-acetyl-3-(7-fluoro-6-(6-methoxyimidazo[1,2-a]pyridin-7-yl)-4-methyl-3,4- dihydroquinoxalin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 201).
  • Desired product could be detected by LCMS.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): isocratic 17%B to 28%B in 10min; Wave Length: 254nm/220 nm; RT1(min): 8.22) to afford compound 201 (11 mg, 10 19.18%) as a yellow solid.
  • Cells were incubated in primary antibody (either CREBBP or EP300 specific antibody) over night at 4°C. Cells were washed three times with PBS-0.1% Tween20. Cells were then incubated in secondary antibody conjugated with Alexa 488 30 fluorophore appropriately diluted in PBS-0.1% Tween20 for 1 hour at room temperature. A DAPI stain solution (0.1ug/ml) was added to stain the cell nuclei for 5 minutes at room temperature. Cells were washed three times with PBS-0.1% Tween20 and finally 80ul of PBS-only were added to the well. Cells were imaged with a high content imager at 20X magnification and fluorescence was quantified with the imager analyses software.
  • primary antibody either CREBBP or EP300 specific antibody
  • cells were seeded in 30 ⁇ L phenol-free RPMI media supplemented with 10% FBS into each well of 384-well cell culture plates. The seeding density was 5000 cells/well.
  • cells were treated with 90 nL DMSO or 90 nL of 3-fold serially DMSO-diluted compounds (10 points in duplicates with 30 ⁇ M as final top dose). Subsequently plates were incubated for 24 hours in a standard tissue culture incubator. After the 24 hours incubation, 10 medium was removed and cells were fixed with a solution of 4% paraformaldehyde for 20 minutes at room temperature.
  • U2OS CREBBP HiBiT line was stained with a CREBBP specific primary antibody and U2OS EP300 HiBiT line was stained with a EP300 specific primary antibody.
  • Cells were 20 washed three times with PBS-0.1% Tween20. Cells were then incubated in secondary antibody conjugated with Alexa 488 fluorophore appropriately diluted in PBS-0.1% Tween20 for 1 hour at room temperature. A DAPI stain solution (0.1ug/ml) was added to stain the cell nuclei for 5 minutes at room temperature. Cells were washed three times with PBS-0.1% Tween20 and finally 80ul of PBS-only were added to the well.
  • a compound having the structure of Formula I: A-L-B Formula I, wherein A is an EP300 binding moiety has the structure of Formula III: 5 Formula III wherein R 1 is halo, C1-4 alkyl, wherein any C1-4 alkyl is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I,—C(O)—N(R a )2, —S(O)—N(R a )2, —S(O)2—10 N(R a )2, —O—R a , —S—R a , —O—C(O)—R a , —O—C(O)—O—R a , —C(O)—O—R a , —C(O)—O—R a , —S(O)— R a , —S(O)2—R a , —O—C(O)—N(R a
  • the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel- Lindau (VHL) ligands, or derivatives or analogs thereof.
  • IAP Inhibitors of Apoptosis
  • MDM2 mouse double minute 2 homolog
  • VHL von Hippel- Lindau
  • each of R A1 , R A2 , R A3 , and R A4 is, independently, H, A 2 , halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2- C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , and/or R A3 and R A4 , together with the carbon atoms to which each is attached, combine to form optionally substituted C6-C10 aryl, optionally substituted C
  • each R A1 , R A2 , R A3 , and R A4 is, independently, A 2 , H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, hydroxyl, optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , or R A3 and R A4 , together with the carbon atoms to which each is attached, combine to form optionally substituted C2-C9 heterocyclyl.
  • E11 The compound of embodiment 9, wherein R A5 is H.
  • E12 The compound of any one of embodiments 9 to 11, wherein Y 1 is .
  • E13. The compound of embodiment 12, wherein Y 1 is .
  • L has the structure of Formula II: A 1 -(B 1 )f-(C 1 )g-(B 2 )h-(D)-(B Formula or a pharmaceutically acceptable salt thereof, wherein 5 A 1 is a bond between the linker and the EP300 binding moiety; A 2 is a bond between the degradation moiety and the linker; each of B 1 , B 2 , B 3 , and B 4 is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C10 arylene, optionally substituted C6-C10 aryl C1-4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C3-C10 cycloalkylene, optionally substituted C2-C8 heterocyclylene, 10 optionally substituted C2-C8 heteroarylene, optionally substituted C6–12 arylene, O, S, S(O)2, or NR N ; each R N is, independently, H,
  • each of B 1 , B 2 , B 3 , and B 4 is, independently, optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2–C8 heteroarylene, or O. 25 E21.
  • the method of embodiment 48 wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myeloma, skin, endometrial, esophageal, cervical, gastric, lymphoma, leukemia, esophogeal, stomach, lung cancer, or non-small cell lung cancer.
  • 25 E50. The method of embodiment 48 or 49, wherein the cancer is metastatic.
  • E51 The method of any one of embodiments 48 to 50, wherein the subject or cancer has a CBP loss of function mutation.
  • 30 E52 The method of any one of embodiments 48 to 51, wherein the cancer is prostate cancer.

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Abstract

The present disclosure features compounds useful for the treatment of EP300-related disorders.

Description

PATENT ATTORNEY DOCKET NO.: 51121-103WO2 COMPOUNDS AND USES THEREOF BACKGROUND OF THE INVENTION EP300 is a histone acetyltransferase that regulates transcription of genes via chromatin 5 remodeling. EP300 is involved in regulating cell growth and division. The present invention is related to useful compositions and methods for the treatment of EP300-related disorders, such as cancer and infection. SUMMARY EP300 is an intracellular protein that regulates cell growth and division. EP300 is overexpressed 10 in multiple cancer cell lines. Accordingly, agents that reduce the levels and/or activity of EP300 may provide new methods for the treatment of disease and disorders, such as cancer and infection. The inventors have found that depleting EP300 results in the downregulation/depletion of MYC in those cells. Thus, agents that degrade EP300 (e.g., compounds) are useful in the treatment of disorders (e.g., cancers or infections) related to EP300 and/or MYC. 15 The present disclosure features compounds and methods useful for treating EP300-related disorders (e.g., cancer or infection). In an aspect, the disclosure features A compound having the structure of Formula I: A-L-B Formula I, wherein A is an EP300 binding moiety has the structure of Formula IIIa: 20 Formula IIIa wherein X1’ is N or CR6; X2’ is N, or CR5; R1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, 25 S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra’)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; and R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally 1 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; 5 R3 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, or optionally substituted C1-4 alkyl C2-C9 heteroaryl, wherein each C1-C4 alkyl, C1-C4 alkoxy, C3-C10 carbocyclyl, C2-C9 heterocyclyl, C6-C10 aryl, or C2-C9 heteroaryl, C1-C4 alkyl C2-C9 heterocyclyl, or C1-4 alkyl C2-C9 heteroaryl is optionally 10 substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C4 alkoxy, C1-C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl that is optionally substituted with one or more groups independently selected from C1-C3 alkyl, C3-C10 carbocyclyl, or halo; R4 is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, is optionally substituted with one or more groups independently selected from oxo, 15 halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo, or R5 and R4 of Formula (IIIa) taken together with the atoms to which they are attached form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups of Re; R5 is H, C1-C3 alkyl, or C1-C3 alkoxy, or R5 and R4 of Formula (IIIa) taken together with the atoms 20 to which they are attached form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups of Re; R6 is H, halo, C1-C3 alkyl, or C1-C3 alkoxy; each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4alkenyl, or C2-C4alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups 25 independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; each Re is, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, 30 N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, carbocycle, and C1-C6 alkyl that is optionally 35 substituted with one or more groups independently selected from oxo and halo; each Rf is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, 40 OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, which carbocyclyl and C1-C6 alkyl are optionally substituted with one or more groups 2 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, ORg, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; each Rg is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 5 C3-12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and C1- C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg are taken together with the nitrogen to which they are attached to form a heterocyclyl (e.g. C3-C12 heterocyclyl) that is optionally substituted with one or more groups independently selected from 10 oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and each Rh is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl 15 that is optionally substituted with one or more groups independently selected from halo; B is a degradation moiety; and L is a linker between the EP300 binding moiety and the degradation moiety. In any of the aspects described herein, each Re is, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, 20 S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, carbocycle, and C1-C6 25 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In any of the aspects described herein, each Rf is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rg)2, CN, 30 C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, which carbocyclyl and C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, ORg, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl. 35 In any of the aspects described herein, each Rg is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups 40 independently selected from oxo and halo; or two Rg are taken together with the nitrogen to which they 3 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 are attached to form a C3-C12 heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In some embodiments, the EP300 binding moiety has the structure of Formula IIIb: 5 Formula IIIb wherein X3 is O, NRN2’ or CR7, wherein RN2’ is C1-C3 alkyl or H, 10 R1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I,C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; and 15 R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, 20 N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; R3 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, or optionally substituted C1-C4 alkyl C2-C9 heteroaryl, wherein each C1-C4 alkyl, C1-C4 alkoxy, C3-C10 carbocyclyl, C2-C9 25 heterocyclyl, C6-C10 aryl, or C2-C9 heteroaryl, C1-4 alkyl C2-C9 heterocyclyl, or C1-C4 alkyl C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C4 alkoxy, C1-C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl that is optionally substituted with one or more groups independently selected from C1-C3 alkyl, C3-C10 carbocyclyl, or halo; R7 is H, halo, or C1-C3 alkyl; 30 each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and each Rh is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, 35 wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with 4 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo. In some embodiments, R2 has the structure: . 5 In some embodiments, R1’ is H, halo, C1-C3 alkoxy, or C1-C4 alkyl optionally substituted with one or more substituent groups independently selected from F. In some embodiments, X3 is CH2, NCH3, or O. In some embodiments, the EP300 binding moiety has the structure: 10 . In some embodiments, the EP300 binding moiety has the structure of Formula IIIc: 15 Formula IIIc wherein X1’ is N or CR6, wherein R6 is H, halo, C1-C3 alkyl, or C1-C3 alkoxy; X2’ is N, or CR5, wherein R5 is H, C1-C3 alkyl, or C1-C3 alkoxy; 5 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 R1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or 5 N(Ra)S(O)2N(Ra)2; and R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, 10 OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; R3 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, or optionally substituted 15 C1-C4 alkyl C2-C9 heteroaryl, wherein each C1-C4 alkyl, C1-C4 alkoxy, C3-C10 carbocyclyl, C2-C9 heterocyclyl, C6-C10 aryl, or C2-C9 heteroaryl, C1-C4 alkyl C2-C9 heterocyclyl, or C1-C4 alkyl C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C4 alkoxy, C1-C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl that is optionally substituted with one or more groups independently selected from C1-C3 alkyl, C3-C10 carbocyclyl, or halo; 20 R4 is hydrogen or methyl; each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and 25 each Rh is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo. In some embodiments, R2 has the structure: 30 . In some embodiments, R1’ is H, halo, C1-C3 alkoxy, or C1-C4 alkyl optionally substituted with one or more substituent groups independently selected from F. In some embodiments, X1 is CH, C1-C3 alkoxy, or N. 35 In some embodiments, X2 is CH or N. In some embodiments, R4 is hydrogen. In some embodiments, R4 is methyl. In some embodiments, the EP300 binding moiety has the structure: 6 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, R3 is optionally substituted C2-C9 heteroaryl, wherein the C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from halo, C1-C4 alkoxy, C1- 5 C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl, that is optionally substituted with one or more groups independently selected from halo, C1-C3 alkyl or C3-C10 carbocyclyl. 10 7 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 5 , In some embodiments, . In some embodiments, R3 is optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, wherein the C1- C4 alkyl C2-C9 heteroaryl is optionally substituted with one or more groups independently selected with one or more groups independently selected from oxo, and C1-C3 alkyl. 10 In some embodiments, R3 is: , , , 8 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, the the EP300 binding moiety has the structure: In some embodiments, the EP300 binding moiety of Formula IIIa has the structure of Formula IIID: 5 wherein X1 is NRN, CH2, or O; RN is C1-C3 alkyl or H; R1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, 10 S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; and R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally 15 substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; 9 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and 5 each Rh is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo. In some embodiments, R1’ is C1-C4 alkyl optionally substituted with one or more F groups. 10 In some embodiments, R1’ is difluroromethyl. In some embodiments, R2 has the structure: . In some embodiments, X1 is CH2. In some embodiments, the EP300 binding moiety has the structure: . 15 In some embodiments, the EP300 binding moiety has the structure of Formula IV: wherein R7 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each alkyl, alkenyl, alkynyl, 3-12 membered carbocycle, and 3-12 membered 20 heterocycle of R3 is optionally substituted with A1 and/or C1-C6 alkyl; R8 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each alkyl, alkenyl, alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with A1 and/or C1-C6 alkyl; R9 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered 25 heterocycle, wherein each alkyl, alkenyl, alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with A1 and/or C1-C6 alkyl; R2a is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6- 10 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 C20 aryl)(C1-C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1 and/or one or more substituent groups independently selected from Rc, oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, 5 N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3a is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C 12 alkynyl, 3-12 membered carbocycle, and 3- 12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups of Re; or R2a and R3a of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 10 membered heterocycle that is optionally substituted with A1 and/or one or more groups of Re; each Ra is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocyclyl, heterocyclyl, or C1-C6 alkyl that is optionally substituted with A1 and/or one or more groups 15 independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl (e.g. C3-C12 heterocyclyl) that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and each Re is, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 20 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rf)2, wherein any alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, 25 N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 30 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, which carbocyclyl and C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, ORg, heterocyclyl, and carbocyclyl that 35 is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; each Rg is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and C1- 40 C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg are taken together with the nitrogen to which they are attached to form a C3-C12 heterocyclyl that 11 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and wherein one and only one of R2a or R3a comprises A1. In some embodiments, NR2aR3a taken together has the structure: 5 . In some embodiments, NR2aR3a taken together has the structure: , , 10 In some embodiments, R3a is methyl. In some embodiments, the EP300 binding moiety has the structure: Formula I, wherein A is an EP300 binding moiety has the structure of Formula III: 12 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Formula III wherein R1 is halo, C1-C4 alkyl, wherein any C1-C4 alkyl is optionally substituted with one or more 5 substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; and R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally 10 substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- 15 C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; X1 is NRN, CH2, or O; and RN is C1-C3 alkyl or H; 20 B is a degradation moiety; and L is a linker between the EP300 binding moiety and the degradation moiety. In some embodiments, R1 is C1-C4 alkyl optionally substituted with one or more F groups. In some embodiments, R1 is difluroromethyl. In some embodiments, R2 has the structure: 25 . In some embodiments, X1 is CH2. In some embodiments, the EP300 binding moiety has the structure: 13 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 . In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety. In some embodiments, the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof. In some embodiments, the degradation moiety includes the structure of Formula Y: Formula Y, 5 where A2 is a bond between the degradation moiety and the linker; v1 is 0, 1, 2, 3, 4, or 5; u1 is 1, 2, or 3; 10 R5A is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each RJ1 is, independently, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; JA is absent, O, optionally substituted amino, optionally substituted C1-C6 alkyl, or optionally 15 substituted C1-C6 heteroalkyl; and J is absent, optionally substituted C3-C10 carbocyclylene, optionally substituted C6-C10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene, or a pharmaceutically acceptable salt thereof. 14 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, T2 is . In some embodiments, T2 is or . so e e o e s, s . In some embodiments, T2 is . In some embodiments, the structure of Formula Y has the structure of Formula Y1: 5 Formula Y1, or a pharmaceutically acceptable salt thereof. In some embodiments, T1 is a bond. In some embodiments, . In some embodiments, the structure of Formula Y has the structure of Formula Y2: 10 Formula Y2, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula Y has the structure of Formula Z: Formula Z, 15 or a pharmaceutically acceptable salt thereof. In some embodiments, u1 is 1. In some embodiments, u1 is 2. In some embodiments u1 is 3. In some embodiments, the structure of Formula Z has the structure of Formula AA0: Formula AA0, 15 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula Z has the structure of Formula AB: Formula AB, 5 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula Z has the structure of Formula AC: Formula AC, or a pharmaceutically acceptable salt thereof. 10 In some embodiments, JA is absent. In some embodiments, JA is optionally substituted C1-C6 alkyl. In some embodiments, JA is optionally substituted C1-C6 heteroalkyl. In some embodiments, JA is O or optionally substituted amino. In some embodiments, . In some embodiments, the structure of Formula AA0 has the structure of Formula AA0: 15 Formula AA, or a pharmaceutically acceptable salt thereof. In some embodiments, v1 is 0, 1, 2, or 3. In some embodiments, v1 is 0. In some embodiments, v1 is 1. In some embodiments, v1 is 2. In some embodiments, v1 is 3. 20 In some embodiments, the structure of Formula AA has the structure of Formula AA1: Formula AA1, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AB has the structure of Formula AB1: 16 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Formula AB1, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AC has the structure of Formula AC1: 5 Formula AC1, or a pharmaceutically acceptable salt thereof. In some embodiments, J is absent. In some embodiments, J is optionally substituted C3-C10 carbocyclylene or optionally substituted C6-C10 arylene. In some embodiments, J is optionally substituted 10 C2-C9 heterocyclylene or optionally substituted C2-C9 heteroarylene. In some embodiments, J is optionally substituted heterocyclylene. In some embodiments, J is optionally substituted C6-C10 arylene. In some embodiments, . In some embodiments, the structure of Formula AA has the structure of Formula AA2: 15 Formula AA2, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AA has the structure of Formula AA3: Formula AA3, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AA has the structure of Formula AA4: Formula AA4, or a pharmaceutically acceptable salt thereof. In some embodiments, RA5 is H or optionally substituted C1-C6 alkyl. In some embodiments, RA5 is optionally substituted C1-C6 heteroalkyl. 17 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, RA5 is H or methyl. In some embodiments, RA5 is H. In some embodiments, RA5 is methyl. In some embodiments, RA5 is . In some embodiments, T1 is a bond. In some embodiments, T2 is , In some embodiments, RA5 is H. In some embodiments, JA is absent. In some embodiments, J is absent. 5 In some embodiments, the structure of Formula . In some embodiments, J is optionally substituted C2-C9 heteroarylene or optionally substituted C6- C10 arylene. In some embodiments, the structure of Formula , . 10 In some embodiments, the structure of Formula Y is In some embodiments, the structure of Formula Y is . 15 18 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, . In some embodiments, J is optionally substituted C6-C10 arylene. In some embodiments, the structure of Formula Y is 5 In some embodiments, the structure of Formula AA has the structure of Formula AY: , 10 RA5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RA6 is H or optionally substituted C1-C6 alkyl; and RA7 is H or optionally substituted C1-C6 alkyl; or RA6 and RA7, together with the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl; or RA6 and RA7, together with the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or 15 optionally substituted C2-C5 heterocyclyl; 19 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 RA8 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each of RA1, RA2, RA3, and RA4 is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally 5 substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or RA1 and RA2, RA2 and RA3, and/or RA3 and RA4, together with the carbon atoms to which each is attached, combine to form ; and is optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is optionally substituted with A2, where one of RA1, RA2, 10 RA3, and RA4 is A2, or is substituted with A2, or a pharmaceutically acceptable salt thereof. In some embodiments, each of RA1, RA2, RA3, and RA4 is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, 15 or optionally substituted amino; or RA1 and RA2, RA2 and RA3, and/or RA3 and RA4, together with the carbon atoms to which each is attached, combine to form ; a is optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is optionally substituted with A2, where one of RA1, RA2, RA3, and RA4 is A2, is substituted with A2, or a pharmaceutically acceptable salt thereof. 20 In some embodiments, each of RA1, RA2, RA3, and RA4 is, H, A2, halogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted -O-C3-C6 carbocyclyl, hydroxyl, optionally substituted amino; or RA1 and RA2, RA2 and RA3, or RA3 and RA4, together with the carbon atoms to which each is attached, combine to form ; a is optionally substituted C2-C9 heterocyclyl, which is optionally substituted with A2, where one of RA1, RA2, RA3, and RA4 is A2, or is substituted 25 with A2. In some embodiments, each of RA1, RA2, RA3, and RA4 is, independently, H, A2, F, , together with the carbon atoms to which each is attached, combine to form is optionally substituted C2- C9 heterocyclyl, which is optionally substituted with A2, where one of RA1, RA2, RA3, 30 is substituted with A2. 20 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, RA1 is A2. In some embodiments, RA2 is A2. In some embodiments, RA3 is A2. In some embodiments, RA4 is A2. In some embodiments, RA5 is A2. In some embodiments, RA5 is H or optionally substituted C1-C6 alkyl. In some embodiments, RA5 is H or . In some embodiments, RA5 is H. In some 5 embodiments, . . In some embodiments, . In some embodiments, each of RA6 and RA7 is, independently, H, F, , , ; or RA6 and RA7, together with the carbon atom to which each is bound, combine to form 10 s , In some embodiments, the structure of Formula AY has the structure of Formula A1: 15 , Formula AY1 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A2: , 20 Formula AY2 or a pharmaceutically acceptable salt thereof. 21 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, the structure of Formula AY has the structure of Formula A3: , Formula AY3 or a pharmaceutically acceptable salt thereof. 5 In some embodiments, the structure of Formula AY has the structure of Formula A4: , Formula AY4 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A5: 10 , or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A6: , 15 Formula AY6 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A7: , Formula AY7 20 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A8: 22 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , Formula AY8 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A9: 5 , Formula AY9 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AY has the structure of Formula A10: , 10 Formula AY10 or a pharmaceutically acceptable salt thereof. 23 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 In some embodiments, the structure of Formula , or derivative or analog thereof. In some embodiments, the structure of Formula AY is 24 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, the structure of Formula derivative or an analog thereof. In some embodiments, the structure of Formula . , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. 5 In some embodiments, RA9 is H, A2, or optionally substituted C1-C6 alkyl. In some embodiments, RA9 is H, A2, or methyl. In some embodiments, R9A is H. In some embodiments, R9A is methyl. In some embodiments, RA9 is A2. 25 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, the structure of Formula . In some embodiments, the structure of Formula . In some embodiments, the structure of Formula AA has the structure of Formula BY: , 5 Formula BY where RA5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each of RA1, RA2, RA3, and RA4 is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted 10 C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 15 RA3, and RA4 is A2, or is substituted with A2, or a pharmaceutically acceptable salt thereof. In some embodiments, each of RA1, RA2, RA3, and RA4 is, H, A2, halogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted -O-C3-C6 carbocyclyl, hydroxyl, optionally substituted amino; or RA1 and RA2, RA2 and RA3, or RA3 and RA4, together with the carbon atoms 20 is optionally substituted C2-C9 heterocyclyl, 26 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 which is optionally substituted with A2, where one of RA1, RA2, RA3, and RA4 is A2, or is substituted with A2. In some embodiments, each of RA1, RA2, RA3, and RA4 is, independently, H, A2, F, , 5 C9 heterocyclyl, which is optionally substituted with A2, where one of RA1, RA2, RA3, and RA4 is A2, or is substituted with A2. In some embodiments, RA1 is A2. In some embodiments, RA2 is A2. In some embodiments, RA3 is A2. In some embodiments, RA4 is A2. In some embodiments, RA5 is A2. 10 In some embodiments, RA5 is H or optionally substituted C1-C6 alkyl. In some embodiments, RA5 is H or . In some embodiments, RA5 is H. In some embodiments, RA5 is . In some embodiments, the structure of Formula BY has the structure of Formula BY1: , 15 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula BY has the structure of Formula BY2: , Formula BY2 20 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula BY has the structure of Formula BY3: , Formula BY3 27 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula BY has the structure of Formula BY4: , 5 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula BY is or . 10 In some embodiments, the degradation moiety includes the structure of In some embodiments, L has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D)-(B Formula or a pharmaceutically acceptable salt thereof, wherein 15 A1 is a bond between the linker and the EP300 binding moiety; A2 is a bond between the degradation moiety and the linker; each of B1, B2, B3, and B4 is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C10 arylene, optionally substituted C6-C10 aryl C1-4 alkylene, optionally substituted C2-C8 heterocyclyl C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C3-C10 20 cycloalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2-C8 heteroarylene, optionally substituted C6–12 arylene, O, S, S(O)2, or NRN; each RN is, independently, H, optionally substituted C1–C4 alkylene, optionally substituted C2–C4 alkenylene, optionally substituted C2–C4 alkynylene, optionally substituted C2–C6 heterocyclylene, optionally substituted C2–C6 heteroarylene, or optionally substituted C1–C7 heteroalkylene; 25 each of C1 and C2 is, independently, carbonylene, thiocarbonylene, sulphonylene, or phosphorylene; each of f, g, h, i, j, and k is, independently, 0 or 1; and 28 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C9 heterocyclylene (e.g. C2-C8 heterocyclylene), optionally substituted C2–C9 heteroarylene (e.g. C2-C8 heteroarylene), optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene. 5 In some embodiments, each of B1, B2, B3, and B4 is, independently, optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2–C8 heteroarylene, optionally substituted C2-C8 heterocyclyl C1-C4 alkylene, or O. In some embodiments, B1 or B2 is optionally substituted C2-C8 heterocyclylene or optionally substituted C3-C10 cycloalkylene. 10 , In some embodiments, . In some embodiments, f is 0. 15 In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. 20 In some embodiments, i is 0. In some embodiments, i is 1. In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. 25 In some embodiments, k is 1. In some embodiments, D is D is optionally substituted C1–C10 alkylene, optionally substituted C2– C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C9 heterocyclylene, optionally substituted C2–C9 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2- C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene. 30 In some embodiments, D is optionally substituted C2-C9 heterocyclylene. In some embodiments, D is 29 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, D is optionally substituted C2–C8 heteroarylene. In some embodiments, D is optionally substituted C6–C12 arylene In some embodiments, D is optionally substituted C1-C10 alkylene. In some embodiments, D is optionally substituted C1-C10 heteroalkylene. 5 In some embodiments, the linker has the structure of: 10 30 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 31 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 32 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 33 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 35 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 36 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 37 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 38 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 40 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 41 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In some embodiments, the shortest chain of atoms connecting two valencies of the linker is 2 to 5 10 atoms long. In some embodiments, the shortest chain of atoms connecting two valencies of the linker is 6 atoms long. In some embodiments, the compound is any one of compounds 1-30 in Table 1A. In some embodiments, the compound is any one of compounds 31-46, 49-58, 60-61, 63-64, 66- 10 70, and 72-234 in Table 1B. 42 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Table 1A. Compounds 1-30 of the invention 43 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 44 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 45 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 46 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 47 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 48 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 49 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 50 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 51 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 52 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Table 1B. Compounds 31-46, 49-58, 60-61, 63-64, 66-70, and 72-234 53 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 54 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 56 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 57 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 58 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 59 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 60 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 61 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 62 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 63 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 65 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 66 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 67 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 68 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 70 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 71 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 72 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 73 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 74 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 75 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 76 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 103 77 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 78 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 79 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 80 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 81 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 82 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 83 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 84 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 85 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 86 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 87 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 88 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 89 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 90 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 91 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 92 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 93 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 94 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 95 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 96 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 97 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 98 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 99 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 101 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 102 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 103 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 105 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 106 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 107 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 108 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 109 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 110 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 111 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 112 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 113 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 114 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 115 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 116 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 117 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 118 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 119 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In another aspect, the disclosure features a pharmaceutical composition including any of the foregoing compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. 5 In another aspect, the invention features a method of decreasing the levels and/or activity of EP300 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. 120 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In another aspect, the invention features a method of decreasing the levels and/or activity of CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In another aspect, the invention features a method of decreasing the levels of or activity of a MYC 5 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In another aspect, the invention features a method of decreasing the levels of or activity of AR, i.e. androgen receptor, in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. 10 In some embodiments, the cell is a cancer cell. In another aspect, the invention features a method of treating a EP300-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the EP300-related disorder is cancer. 15 In a further aspect, the invention features a method of inhibiting EP300, the method involving contacting a cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell. In an aspect, the disclosure features a method of inhibiting the level and/or activity of EP300 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, 20 or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. In another aspect, the invention features a method of treating a disorder related to a EP300 loss of function mutation in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the disorder related to a EP300 loss of function mutation is cancer. In 25 other embodiments, the subject is determined to have a EP300 loss of function disorder, for example, is determined to have a EP300 loss of function cancer (for example, the cancer has been determined to include cancer cells with loss of EP300 function). In another aspect, the invention features a method of inducing apoptosis in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a 30 pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell. In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, 35 endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric cancer, urinary tract cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid 40 sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade 121 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, myeloma, skin, endometrial, esophageal, cervical, gastric, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, 5 renal cell carcinoma, melanoma, neuroblastoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma. In some embodiemnts, the cancer is carcinoma. 10 In some embodiments, the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, myeloma, skin, endometrial, cervical, gastric, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, lymphoma, leukemia, esophogeal, stomach, or lung cancer. In some embodiments, the cancer is metastatic. 15 In some embodiments, the subject or cancer has a CBP loss of function mutation. In some embodiments, the method further comprises administering to the subject an anticancer therapy. In some embodiment, the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof. 20 In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, head and neck cancer, prostate cancer, acute leukemia, gastric cancer, or breast cancer. In some embodiments, the breast cancer is found to be ER positive i.e. the cancer cells contain estrogen receptors. 25 In some embodiments, the breast cancer is found to be ER negative i.e. cancer cells do not contain estrogen receptors. In some embodiments, the prostate cancer is found to be AR positive i.e. cancer cells contain androgen receptors. In some embodiments, the prostate cancer is CRPC i.e. castration-resistant prostate cancer. 30 In some embodiments, the prostate cancer is sensitive prostate cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the lymphoma is Diffuse large B cell lymphoma (DLBCL). In an aspect, the disclosure features a method of treating a EP300-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the 35 foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. In some embodiments, the EP300-related disorder is cancer. In some embodiments, the EP300- related disorder is infection. In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, 40 breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's 122 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, 5 meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for 10 example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast 15 cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2- negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, 20 progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, 25 fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltrating 30 breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic 35 melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, 40 osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic 123 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, 5 rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, Diffuse large B cell lymphoma (DLBCL), testicular cancer, throat cancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, 10 undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute 15 promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cell prolymphocytic 20 leukemia; splenic lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell/histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly;25 primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B- cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B- cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. 30 In some embodiments of any of the foregoing methods, the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta, abraxane, Adriamycin®, 35 gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, demcizumab, fosbretabulin, or a PDL1 inhibitor). In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, 40 breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's 124 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, 5 meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for 10 example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast 15 cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2- negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, 20 progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, 25 fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltrating 30 breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, myeloma, skin, endometrial, esophageal, cervical, gastric, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, 35 mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, 40 oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal 125 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, 5 renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, 10 ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a 15 subtype of AML), large granular lymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); Diffuse large B cell lymphoma (DLBCL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cell 20 prolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell/histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus 25 (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. 30 In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round 35 cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, 40 stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s 126 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma. In some embodiments of any of the foregoing methods, the cancer has or has been determined 5 to have EP300 mutations. In some embodiments of any of the foregoing methods, the EP300 mutations are homozygous. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an EP300 mutation. In some embodiments of any of the foregoing methods, the cancer does not 10 have, or has been determined not to have, a EP300 mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the foregoing methods, the cancer has, or has been determined to have, a KRAS mutation. In some embodiments of any of the foregoing methods, the CBP mutation is chromosomal translocation. 15 In another aspect, the disclosure provides a method treating a disorder related to EP300 (e.g., cancer or viral infections) in a subject in need thereof. This method includes contacting a cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the disorder is a viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency 20 virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicella-zoster virus), Papillomaviridae 25 family (e.g., Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g., Parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), Togaviridae family (e.g., Rubella virus). In some embodiments, the disorder is Coffin Siris, Neurofibromatosis (e.g., NF-1, NF-2, or Schwannomatosis), or Multiple Meningioma. In another aspect, the disclosure provides a method for treating a viral infection in a subject in 30 need thereof. This method includes administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), 35 Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicella-zoster virus), Papillomaviridae family (e.g., Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g., Parvovirus B19), Polyomaviridae family (e.g., 40 JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), or Togaviridae family (e.g., Rubella virus). 127 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, myeloma, skin, endometrial, esophageal, cervical, gastric, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof. 5 In another aspect, the invention features a method of reducing tumor growth of melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof. 10 In another aspect, the invention features a method of suppressing metastatic progression of melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof. 15 In another aspect, the invention features a method of suppressing metastatic colonization of melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof. 20 In another aspect, the invention features a method of reducing the level and/or activity of EP300 and/or CBP in a melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophageal, stomach, or hematologic cancer cell, the method including contacting the cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof. 25 In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, myeloma, skin, endometrial, esophageal, cervical, gastric, renal cell carcinoma, osteosarcoma, neuroblastoma, esophagael, stomach, or hematologic cell is in a subject. In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and/or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or activity of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or activity of EP300 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 35 99%). In some embodiments of any of the above aspects, the effective amount of the compound reduces the level of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to the percent of reduction of the level of CBP. In some embodiments, the effective amount of the compound that reduces 40 the level of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to percent of reduction of the level of CBP. In some embodiments, the effective amount of the 128 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 compound that reduces the level of EP300 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) as compared to the percent of reduction of the level of CBP. In some embodiments, the effective amount of the compound reduces the level and/or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 5 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the compound that reduces the level and/or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days 10 (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more). In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and/or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or 15 activity of CBP by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or activity of CBP by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%). In some embodiments, the effective amount of the compound reduces the level and/or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 20 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the compound that reduces the level and/or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days (e.g., 5 25 days, 6 days, 7 days, 14 days, 28 days, or more). In some embodiments, the subject has cancer. In some embodiments, the cancer expresses EP300 and/or CBP protein and/or the cell or subject has been identified as expressing EP300 and/or CBP. In some embodiments, the cancer expresses EP300 protein and/or the cell or subject has been identified as expressing EP300. In some embodiments, the cancer expresses CBP protein and/or the cell 30 or subject has been identified as expressing CBP. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell 35 lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments, the cancer is breast cancer (e.g., an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer). In some embodiments, the cancer is a bone cancer (e.g., Ewing’s sarcoma). In some embodiments, the cancer is a renal cell carcinoma 40 (e.g., a Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). The metastatic 129 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 cancer can include cells exhibiting migration and/or invasion of migrating cells and/or include cells exhibiting endothelial recruitment and/or angiogenesis. In other embodiments, the migrating cancer is a cell migration cancer. In still other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. The metastatic cancer can be a cancer spread via seeding the surface of the peritoneal, 5 pleural, pericardial, or subarachnoid spaces. Alternatively, the metastatic cancer can be a cancer spread via the lymphatic system, or a cancer spread hematogenously. In some embodiments, the effective amount of an agent that reduces the level and/or activity of EP300 and/or CBP is an amount effective to inhibit metastatic colonization of the cancer to the liver. In some embodiments, the method further includes administering to the subject or contacting the 10 cell with an anticancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation. In some embodiments, the anticancer therapy is a chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparagine- specific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA-Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase 15 inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor. Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum). A list of additional compounds having anticancer activity can be found in L. Brunton, B. Chabner and B. Knollman (eds). Goodman and Gilman’s The Pharmacological Basis of 20 Therapeutics, Twelfth Edition, 2011, McGraw Hill Companies, New York, NY. In some embodiments, the anticancer therapy and the compound of the invention are administered within 28 days of each other and each in an amount that together are effective to treat the subject. In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic 25 agents (e.g., the cancer has been determined to be resistant to chemotherapeutic or cytotoxic agents such as by genetic markers, or is likely to be resistant, to chemotherapeutic or cytotoxic agents such as a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the cancer is resistant or has failed to respond to dacarbazine, temozolomide, cisplatin, 30 treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and/or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196). 35 Chemical terms The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting. For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be 40 understood, other atoms, such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group 130 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 has the formula –CH2CH3. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring. 5 The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). An alkylene is a divalent alkyl group. The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon 10 atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms). The term “alkynyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms). The term “amino,” as used herein, represents –N(RN1)2, wherein each RN1 is, independently, H, 15 OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN1 groups can be optionally substituted; or two RN1 combine to form an alkylene or heteroalkylene, and wherein each RN2 is, independently, H, alkyl, or aryl. The amino groups of the compounds described herein can be an unsubstituted amino (i.e., –NH2) or a substituted amino (i.e., –N(RN1)2). 20 The term “aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl. The term “carbocyclyl,” as used herein, refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl 25 groups and unsaturated carbocyclyl radicals. A carbocyclylene is a divalent carbocyclyl group. The term “halo,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical. The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some 30 embodiments, the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl–O– (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group. The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the 35 heteroalkenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroalkenyl groups are an “alkenoxy” which, as used herein, refers alkenyl–O–. A heteroalkenylene is a divalent heteroalkenyl group. The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group 40 can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyl groups. 131 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl–O–. A heteroalkynylene is a divalent heteroalkynyl group. The term “heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, 5 and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl. The term “heterocyclyl,” as used herein, refers a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O or S, wherein no ring is 10 aromatic. Heterocyclyl rings may be spirocyclic or bridged. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. A heterocyclylene is a divalent heterocyclyl group. The term “hydroxyl,” as used herein, represents an –OH group. The term “thiol,” as used herein, represents an –SH group. 15 The term “carbonyl,” as used herein, represents an –C(O)– group. The term “thiocarbonyl,” as used herein, represents an –C(S)– group. The term “sulfonyl,” as used herein, represents an –S(O)2– group. The term “phosphoryl,” as used herein, represents an P(O) group. The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl 20 groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or 25 thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)). Compounds described herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, 30 optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. 35 Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the 40 configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known 132 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, wherein such mixtures exhibit no 5 optical activity; i.e., they do not rotate the plane of polarized light. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on 25 opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," 10 indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds described herein may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a 15 free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide 35 of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or 20 resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. 25 When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, 30 the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percent purity by mole fraction is the 35 ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound 40 free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or 133 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the 5 other diastereomer(s), or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials 10 known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Definitions 15 In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and/or”; and (iii) the terms “including” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps. As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or 20 below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM. As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in 25 some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal. 30 As used herein, the term “EP300” refers to the EP300 protein in a human cell. As used herein, the term “CBP” refers to the CREB-binding protein in a human cell. As used herein, the term “EP300-related disorder” refers to a disorder that is caused or affected by the level of activity of CBP. As used herein, the term “EP300 loss of function mutation” refers to a mutation in EP300 that 35 leads to the protein having diminished activity (e.g., at least 1% reduction in EP300 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity). Exemplary EP300 loss of function mutations include, but are not limited to, a homozygous EP300 mutation and chromosomal translocations. As used herein, the term “EP300 loss of function disorder” refers to a disorder (e.g., cancer) that 40 exhibits a reduction in EP300 activity (e.g., at least 1% reduction in EP300 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in EP300 activity). 134 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 The term “cancer” refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas. As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen 5 for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, 10 administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, 15 but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally. By “determining the level of a protein” or RNA is meant the detection of a protein or an RNA, by 20 methods known in the art, either directly or indirectly. “Directly determining” means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value. “Indirectly determining” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Methods to measure protein level generally include, but are not limited to, western blotting, 25 immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, 30 as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners. Methods to measure RNA levels are known in the art. As used herein, the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and/or activity of EP300 (e.g., in a cell or a subject) described herein refer to a quantity sufficient to, when administered to the subject, including a human, effect 35 beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and/or activity of EP300 sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and/or activity of EP300. The amount of a given agent that reduces the level and/or 40 activity of EP300 described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the 135 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 type of disease or disorder, the identity of the subject (e.g., age, sex, and/or weight) or host being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. Also, as used herein, a “therapeutically effective amount” of an agent that reduces the level and/or activity of EP300 of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to 5 a control. As defined herein, a therapeutically effective amount of an agent that reduces the level and/or activity of EP300 of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response. As used herein, the term “inhibitor” refers to any agent which reduces the level and/or activity of a 10 protein (e.g., EP300). Non-limiting examples of inhibitors include small molecule inhibitors, degraders, antibodies, enzymes, or polynucleotides (e.g., siRNA). By “level” is meant a level of a protein, or mRNA encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a protein or RNA is meant a decrease or increase, respectively, in a protein or RNA 15 level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as 20 compared to a reference; a decrease or an increase by less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). A level of a protein may be expressed in mass/vol (e.g., g/dL, 25 mg/mL, μg/mL, ng/mL) or percentage relative to total protein in a sample. By “decreasing the activity of EP300” is meant decreasing the level of an activity related to EP300, or a related downstream effect. The activity level of a EP300 may be measured using any method known in the art, e.g., HiBit assay. The term “pharmaceutical composition,” as used herein, represents a composition containing a 30 compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human. Typically, a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for 35 topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation. A “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active 40 compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, 136 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, 5 croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), 10 stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, for example, any compound of Formula I. Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue 15 toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or 20 separately by reacting a free base group with a suitable organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically 25 acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, 30 camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, 35 pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. 40 By a “reference” is meant any useful reference used to compare protein or RNA levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. 137 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a 5 subject that is diagnosed with a disease, but not yet treated with a compound of the invention; a sample from a subject that has been treated by a compound of the invention; or a sample of a purified protein or RNA (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a 10 normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound of the invention. In preferred 15 embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein or RNA, e.g., any described herein, within the normal reference range can also be used as a reference. As used herein, the term “subject” refers to any organism to which a composition in accordance 20 with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition. 25 As used herein, the terms "treat," "treated," or "treating" mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of 30 condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. 35 Compounds of the invention may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder. As used herein, the terms “variant” and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance 40 described herein may retain or improve upon the biological activity of the original material. 138 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. As used herein, the term “degrader” refers to a small molecule compound including a degradation 5 moiety, wherein the compound interacts with a protein (e.g., EP300) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of the level of the protein, e.g., in a cell or subject. As used herein, the term “degradation moiety” refers to a moiety whose binding results in degradation of a protein, e.g., EP300. In one example, the moiety binds to a protease or a ubiquitin ligase 10 that metabolizes the protein, e.g., EP300. DETAILED DESCRIPTION OF THE INVENTION The present disclosure features compositions and methods useful for the treatment of EP300- related disorders (e.g., cancer and infection). The disclosure further features compositions and methods 15 useful for inhibition of the level and/or activity of EP300, e.g., for the treatment of disorders such as cancer (e.g., sarcoma) and infection (e.g., viral infection), e.g., in a subject in need thereof. Compounds Compounds described herein reduce the level of an activity related to EP300, or a related downstream effect, or reduce the level of EP300 in a cell or subject. Exemplary compounds described 20 herein have the structure according to Formula I. A-L-B Formula I, wherein A is an EP300 binding moiety has the structure of Formula IIIa: Formula IIIa wherein X1’ is N or CR6; 25 X2’ is N, or CR5; R1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I,C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or 30 N(Ra)S(O)2N(Ra)2; and 139 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, — S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, 5 OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; R3 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, or optionally substituted 10 C1-C4 alkyl C2-C9 heteroaryl, wherein each C1-C4 alkyl, C1-C4 alkoxy, C3-C10 carbocyclyl, C2-C9 heterocyclyl, C6-C10 aryl, or C2-C9 heteroaryl, C1-C4 alkyl C2-C9 heterocyclyl, or C1-C4 alkyl C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C4 alkoxy, C1-C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl that is optionally substituted with one or more groups independently selected from C1-C3 alkyl, C3-C10 carbocyclyl, or halo; 15 R4 is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo, or R5 and R4 of Formula (IIIa) taken together with the atoms to which they are attached form a 3-12 membered heterocyclyl that is optionally substituted with one or more 20 groups of Re; R5 is H, C1-C3 alkyl, or C1-C3 alkoxy, or R5 and R4 of Formula (IIIa) taken together with the atoms to which they are attached form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups of Re; R6 is H, halo, C1-C3 alkyl, or C1-C3 alkoxy; 25 each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4alkenyl, or C2-C4alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; each Re is, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 30 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, 35 N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 40 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, 140 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, which carbocyclyl and C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, ORg, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; 5 each Rg is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and C1- C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; 10 or two Rg are taken together with the nitrogen to which they are attached to form a C3-C12 heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and each Rh is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with 15 one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; B is a degradation moiety; and L is a linker between the EP300 binding moiety and the degradation moiety. Pharmaceutical Uses 20 The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the level, status, and/or activity of EP300, e.g., by inhibiting the activity or level of the EP300 in a cell within a mammal. An aspect of the present invention relates to methods of treating disorders related to EP300 such as cancer in a subject in need thereof. In some embodiments, the compound is administered in an 25 amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject. Treating cancer can result in a reduction in size or volume of a tumor. For example, after 30 treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor. Treating cancer may further result in a decrease in number of tumors. For example, after 35 treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x). Treating cancer can result in a decrease in number of metastatic nodules in other tissues or 40 organs distant from the primary tumor site. For example, after treatment, the number of metastatic 141 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 5 50x). Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible 10 means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein. 15 Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a 20 pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein. 25 Combination Therapies A method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of therapies to treat cancer. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, 30 doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, dosages of the compounds when combined should provide a therapeutic effect. In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating 35 agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), 40 leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl 142 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue 5 topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, 10 phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed Engl.33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic 15 chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, 20 peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; 25 androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as 30 maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; 35 mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum 40 coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; 143 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first 5 therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol.18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000). In some embodiments, the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some 10 embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); 15 SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-I- 131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); 20 SOLIRIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado- trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody-drug conjugates. 25 The second agent may be a therapeutic agent which is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue. The second agent may be a checkpoint inhibitor. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may 30 be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule 35 inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion a protein such as ipilimumab/YERVOY® or tremelimumab). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; pidilizumab/CT-011). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; 40 BMS 936559). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/Ig fusion protein such as AMP 144 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 224). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the anti-cancer therapy is a T cell adoptive transfer (ACT) therapy. In 5 some embodiments, the T cell is an activated T cell. The T cell may be modified to express a chimeric antigen receptor (CAR). CAR modified T (CAR-T) cells can be generated by any method known in the art. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear 10 cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art, may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. 15 Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and U.S. Patent Application Publication No.20060121005. In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be 20 administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent. 25 Pharmaceutical Compositions The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. 30 The compounds described herein may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the methods described herein. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds described herein may be administered, for 35 example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. 40 A compound described herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be 145 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound described herein may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. A compound described herein may also be administered parenterally. Solutions of a compound described 5 herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s 10 Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe. Compositions for nasal administration may 15 conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non- aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an 20 aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as 25 sugar, acacia, tragacanth, gelatin, and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. A compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate. A 30 compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals. In the case of surgical intervention, the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection. Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature. 35 The compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice. 40 Dosages 146 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 The dosage of the compounds described herein, and/or compositions including a compound described herein, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the 5 clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.01 mg and 3000 mg (measured as the solid form). 10 Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg). Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-50 mg/kg (e.g., 0.25-25 mg/kg). 15 Kits The invention also features kits including (a) a pharmaceutical composition including an agent that reduces the level and/or activity of EP300 in a cell or subject described herein, and (b) a package insert with instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent that reduces the level and/or activity of 20 EP300 in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein. 147 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Examples Definitions used in the following Schemes and elsewhere herein are: ACN or MeCN acetonitrile Ac2O acetic anhydride 5 tBuOK potassium tert-butoxide DCM dichloromethane DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide 10 dppf bis(diphenylphosphino)ferrocene dtbpf di-tert-butylphosphino)ferrocene ESI electrospray ionization Et N or TEA triethylamine 3 EtOAc ethyl acetate 15 EtOH ethyl alcohol FA formic acid FCC flash column chromatography h hours HATU 2-(3H-[ 1,2,3 ]triazolo[ 4,5-b ]pyridin-3-yl)-l, 1,3 ,3- 20 tetramethylisouronium HPLC high performance liquid chromatography KOAC potassium acetate L liter LCMS liquid chromatography / mass spectrometry 25 LiHMDS lithium hexamethyldisilazide MeOH methyl alcohol mL milliliter mmol millimole mg milligrams 30 MHz megahertz MS mass spectrometry MTBE methyl t-butylether m/z mass/charge ratio NBS N-bromosuccinimide 35 nm nanometer NMR nuclear magnetic resonance ppm parts per million rt room temperature RT retention time 40 Ruphos Pd 3G (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′- 148 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 amino-1,1′-biphenyl)]palladium(II) methanesulfonate SFC supercritical fluid chromatography TFA trifluoroacetic acid THF tetrahydrofuran 5 XPhos Pd 3G (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II) methanesulfonate Materials Unless otherwise noted, all materials were obtained from commercial suppliers and were used without 10 further purification. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere. Preparation of Intermediates Step 1: A solution of 3-bromo-1H-pyrazolo[4,3-c]pyridine in DMF was treated with cesium carbonate and15 tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate and heated at 120 C for 2 h to give tert-butyl 4- (3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in 47% yield. Step 2: A solution of tert-butyl 4-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in dioxane was treated with7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline, XPhos Pd G3 and X Phos, and20 heated at 80 C for 8 h to give tert-butyl 4-(3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1H- pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in 76% yield. Step 3: A solution of tert-butyl 4-(3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate in MeOH was treated with PtO2 and hydrogen at 25 C for 12 h to 149 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 give tert-butyl 4-(3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate which was used without purification. Step 4: A solution of tert-butyl 4-(3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H- 5 pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in DCM was treated with acetic anhydride and triethylamine at 25 C for 1 h to give tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)- yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in 79% yield. LC/MS (ESI) m/z [M + H]+ 488.4. 10 Step 5: A solution of tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in DMF was treated with N- Bromosuccinimide at 0 C for 1 h to give tert-butyl 4-(5-acetyl-3-(6-bromo-7-(difluoromethyl)-3,4- dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in 83% yield. LC/MS (ESI) m/z [M + Na]+ 552.3. 15 Step 6: A solution of tert-butyl 4-(5-acetyl-3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in dioxane was treated with cesium carbonate, Pd(dppf)Cl2 and bis(pinacolato)diboron at 100 C or 2 h to give tert-butyl 4-(5-acetyl-3- (7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7- 20 tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in 82% yield. LC/MS (ESI) m/z [M + Na]+ 630.2. Step 7: A solution of tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-25 carboxylate carboxylate in dioxane was treated with cesium carbonate, Pd(dppf)Cl2 and 3-bromo-1- methyl-1H-pyrrolo[3,2-c]pyridine at 80 C for 2 h to give tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-6-(1- methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate in 58% yield. LC/MS (ESI) m/z [M + H]+ 656.4. 30 Step 8: A solution of tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)- 3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate in dioxane was treated with HCl in dioxane at 30 C for 2 h to give 1-(3-(7-(difluoromethyl)-6-(1-methyl-1H- pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one in 67% yield. LC/MS (ESI) m/z [M + H]+ 560.4. 35 Example 1. Preparation of 4-((4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrrolo[3,2- c]pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1- 150 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 yl)piperidine-1-carbonyl)phenyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 15). 5 To a stirred solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (150 mg, 0.445 mmol, 1 equiv) and tert-butyl 4-aminobenzoate (85.98 mg, 0.445 mmol, 1 equiv) in 1,4-dioxane (0.5 mL) were added K2CO3 (184.48 mg, 1.335 mmol, 3 equiv) and XPhos (42.42 mg, 0.089 mmol, 0.2 equiv) 10 ,Pd2(dba)3 (40.74 mg, 0.045 mmol, 0.1 equiv) in portions at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 3h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 100% gradient in 20 min; detector, UV 254 nm. to afford Intermediate 2 (163 mg, 15 90%purity) as a green solid. LCMS (ESI) m/z [M-H]- = 448. To a stirred solution of Intermediate 2 (25 mg, 0.056 mmol, 1 equiv) in DCM (0.3 mL) was added 20 trifluoroacetic acid (0.1 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 1h under nitrogen atmosphere. The resulting mixture was concentrated under reduced 151 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 pressure to afford Intermediate 3 (50 mg, crude) as a yellow oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 394. 5 To a stirred solution of 1-methyl-1H-imidazole (20.87 mg, 0.255 mmol, 5 equiv) and 1-{3-[7- (difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro-2H-quinolin-1-yl]-1-(piperidin-4-yl)- 10 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (28.46 mg, 0.051 mmol, 1 equiv) in DMF (0.5 mL) were added Intermediate 3 (20 mg, 0.051 mmol, 1.00 equiv) and TCFH (28.53 mg, 0.102 mmol, 2 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1h under nitrogen atmosphere. The residue was purified by reverse phase flash with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: 15 ACN; Flow rate: 60 mL/min mL/min; Gradient: 18% B to 37% B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 7.42) to afford compound 15 as a yellow solid.1H NMR (300 MHz, Acetonitrile-d3) δ 8.95 (s, 1H), 8.82 – 8.74 (m, 1H), 8.29 (d, J = 6.6 Hz, 1H), 8.16 (s, 1H), 7.81 – 7.73 (m, 1H), 7.60 – 7.53 (m, 2H), 7.50 (d, J = 5.5 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.37 – 7.31 (m, 2H), 7.28 – 7.24 (m, 1H), 7.20 (s, 1H), 6.94 (d, J = 4.7 Hz, 1H), 6.56 (t, J = 55.3 Hz, 1H), 5.05 – 4.93 (m, 1H), 4.43 – 4.37 (m, 1H), 4.36 – 4.29 20 (m, 1H), 4.25 (s, 2H), 3.94 (s, 3H), 3.85 – 3.82 (m, 1H), 3.80 – 3.74 (m, 1H), 3.73 – 3.65 (m, 2H), 3.65 – 3.62 (m, 1H), 3.28 – 3.01 (m, 4H), 2.94 – 2.85 (m, 3H), 2.82 – 2.76 (m, 1H), 2.74 – 2.58 (m, 5H), 2.13 – 2.08 (m, 1H), 2.08 – 2.03 (m, 3H), 2.01 – 1.95 (m, 2H). LCMS (ESI) m/z [M+H]+ =935.35. The following compounds in TABLE 1C were prepared using standard chemical manipulations and 25 procedures that are the same or similar to those used for the preparation of Compound 15 in Example 1. TABLE 1C 152 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 153 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.77 – 39 907.45 6.72 (m, 1H), 6.66– 6.62 (m, 1H), 5.16 – 4.99 (m, 1H), 4.34 (s, 4-((3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl- 1H), 4.28 – 4.19 (m, 1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroquinolin- 2H), 4.01 – 3.99 (m, 1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- 3H), 3.82 – 3.71 (m, c]pyridin-1-yl)piperidin-1-yl)phenyl)amino)-2-(2,6- 2H), 3.65 – 3.56 (m, dioxopiperidin-3-yl)isoindoline-1,3-dione 2H), 3.04 – 2.76 (m, 8H), 2.74 – 2.62 (m, 3H), 2.15 – 2.11 (m, 2H), 2.10 – 1.86 (m, 8H). 154 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 155 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 156 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Compound LRMS # Structure 1HNMR (ESI) 1H NMR (400 MHz, DMSO-d6) δ 10.96 - dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy}phenyl)-4-oxobutanamide (Compound 14). 157 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 1: tert-butyl N-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy}phenyl) carbamate (Intermediate 2). 5 To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (600 mg, 2.172 mmol, 1 equiv) and tert-butyl N-(3-hydroxyphenyl)carbamate (454.51 mg, 2.172 mmol, 1 equiv) in DMSO (10 mL) was added K2CO3 (1.20 g, 8.688 mmol, 4 equiv). The resulting mixture was stirred at 60 °C for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After10 filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 60% gradient in 10 min; detector, UV 254 nm) afford intermediate 2 (208 mg, 20.43%) as a light yellow solid. LCMS (ESI) m/z [M+H]+ =466. 15 To a stirred solution of intermediate 2 (200 mg, 0.430 mmol, 1 equiv) in DCM (4.5 mL) was added TFA (1.5 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated to afford intermediate 3 (147 mg, crude) as a light yellow solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ =366. 20 Step 3: tert-butyl 3-[(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4- yl]oxy}phenyl)carbamoyl]propanoate (Intermediate 4). 158 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred solution of intermediate 3 (137 mg, 0.375 mmol, 1 equiv) and 4-(tert-butoxy)-4- oxobutanoic acid (78.39 mg, 0.450 mmol, 1.2 equiv) in DMF (2 mL) was added HATU (285.17 mg, 0.750 mmol, 2 equiv) and DIPEA (242.33 mg, 1.875 mmol, 5 equiv). The resulting mixture was stirred at room 5 temperature for 1 h. The crude product was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford intermediate 4 (114 mg, 58.29%) as a light yellow solid. LCMS (ESI) m/z [M+H]+ =522. Step 4: 3-[(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy}phenyl)carbamoyl]propanoic acid 10 (Intermediate 5). To a stirred solution of intermediate 4 (60 mg, 0.115 mmol, 1 equiv) in DCM (0.3 mL) was added TFA (0.1 mL, 0.001 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash 15 chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford intermediate 5 (45 mg, 84.04%) as a light yellow solid. LCMS (ESI) m/z [M+H]+ =466. Step 5: 4-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro-2H-quinolin- 1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)-N-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3- 20 dioxoisoindol-4-yl]oxy}phenyl)-4-oxobutanamide (Compound 14). 159 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred solution of intermediate 5 (30 mg, 0.064 mmol, 1 equiv) and R23-24-071 (36.08 mg, 0.064 mmol, 1 equiv) in DMF (1 mL) was added TCFH (36.17 mg, 0.128 mmol, 2 equiv) and NMI (26.46 mg, 0.320 mmol, 5 equiv). The resulting mixture was stirred at room temperature for 1 h. The crude 5 product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 13% B to 33% B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 8.33) to afford compound 14 (17.7 mg, 27.27%) as a light yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.97 (s, 1H), 8.72 (s, 1H), 8.28 (d, J = 5.8 Hz, 1H), 7.91 – 7.76 (m, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.54 – 10 7.46 (m, 2H), 7.46 – 7.30 (m, 3H), 7.29 – 7.14 (m, 2H), 6.98 – 6.39 (m, 3H), 5.22 – 5.01 (m, 1H), 4.61 – 4.30 (m, 2H), 4.23 (s, 2H), 4.17 – 3.94 (m, 1H), 3.86 (s, 3H), 3.82 – 3.69 (m, 2H), 3.63 (t, J = 5.7 Hz, 2H), 3.35 – 3.18 (m, 1H), 3.01 – 2.73 (m, 6H), 2.75 – 2.50 (m, 6H), 2.22 – 1.70 (m, 10H). LCMS (ESI) m/z [M+H]+ =1007.25. 15 Example 3. Preparation of 5-[3-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3- yl}-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1- carbonyl)azetidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 9). 160 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 1: tert-butyl 3-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro-2H- quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carbonyl)azetidine-1-carboxylate (Intermediate 2). 5 To a solution of 1-{3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro- 2H-quinolin- 1-yl]-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (40 mg, 0.071 mmol, 1 equiv) and 1- (tert-butoxycarbonyl)azetidine-3-carboxylic acid (14.38 mg, 0.071 mmol, 1 equiv) in DMF (1 mL) was added HATU (32.61 mg, 0.085 mmol, 1.2 equiv) and DIEA (37.35 uL, 0.213 mmol, 3.0 equiv) at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 1 h. The residue was 10 purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 30 min; detector, UV 220 nm. This resulted in Intermediate 2 (43 mg, 80.99%) as a yellow oil. LCMS (ESI) m/z: [M+H]+ = 743. Step 2: 1-{1-[1-(azetidine-3-carbonyl)piperidin-4-yl]-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin- 15 3-yl}-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (Intermediate 3). A mixture of Intermediate 2 (40 mg, 0.054 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. This resulted in Intermediate 3 (63 mg, crude) 20 as a yellow oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ =643. 161 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 3: 5-[3-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro-2H- quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carbonyl)azetidin-1-yl]-2-(2,6- dioxopiperidin-3-yl)isoindole-1,3-dione ( Compound 9). 5 To a stirred solution of Intermediate 3 (25.78 mg, 0.093 mmol, 1.0 equiv) in DMSO (0.5 mL) was added DIEA (48.78 uL, 0.279 mmol, 3.0 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred at 60 °C for 4 h under nitrogen atmosphere. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 12% B to 29% 10 B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 9.15). This resulted in compound 9 (10.6 mg, 12.52%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.71 (s, 1H), 8.33 – 8.12 (m, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 5.7 Hz, 1H), 7.33 (s, 1H), 7.20 (s, 1H), 6.95 (s, 1H), 6.89 – 6.49 (m, 3H), 5.01 (dd, J = 12.3, 5.5 Hz, 1H), 4.47 – 4.34 (m, 2H), 4.33 – 4.24 (m, 4H), 4.22 – 4.14 (m, 2H), 4.05 – 3.95 (m, 1H), 3.86 (s, 3H), 3.81 – 3.74 (m, 2H), 3.65 (t, J = 5.7 Hz, 2H), 2.94 – 2.82 (m, 7H), 2.67 – 2.54 15 (m, 3H), 2.12 – 1.93 (m, 10H). LCMS (ESI) m/z [M+H]+ =898.25. The following compounds in TABLE 2 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 9 in Example 3. TABLE 2 162 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 163 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 164 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 165 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 166 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 167 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 168 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroquinolin- 3.70 – 3.50 (m, 5H), 1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- 3.27 – 3.01 (m, 3H), c]pyridin-1-yl)piperidine-1-carbonyl)-2- 2.97 – 2.74 (m, 4H), methoxyphenyl)dihydropyrimidine-2,4(1H,3H)- 2.67 (t, J = 6.7 Hz, dione 2H), 2.09 (s, 2H), 2.07 – 1.80 (m, 7H). 1H NMR (300 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.04 (s, 1H), 8.49 (d, J = 6.8 Hz, 1H), 8.21 – 8.09 (m, 2H), 7.85 (s, 1H), 7.26 – 7.17 (m, 3H), 6.99 – 6.89 (m, 1H), 52 861.45 6.76 – 6.52 (m, 3H), 4.59 – 4.44 (m, 1H), 4.42 – 4.36 (m, 1H), 4.29 – 4.20 (m, 3H), 4.20 – 4.15 (m, 1H), 4.05 (s, 3H), 3.98 – 3.87 (m, 1H), 3.79 – 3.73 (m, 2H), 3.66 (t, 169 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Compound LRMS # Structure 1HNMR (ESI) (2S)-2-((4-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1- J = 5.7 Hz, 2H), 3.20 methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4- – 3.06 (m, 2H), 2.95 dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H- – 2.89 (m, 3H), 2.76 170 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 171 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 172 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 4. Preparation of 4-{4-[4-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3- yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl]-4- oxobutoxy}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound A). 5 A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione (2 g, 7.293 mmol, 1 equiv),10 NaHCO3 (919.00 mg, 10.940 mmol, 1.5 equiv), KI (121.07 mg, 0.729 mmol, 0.1 equiv) and tert-butyl 4- 173 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 bromobutanoate (1.95 g, 8.752 mmol, 1.2 equiv) in DMF (20 mL) was stirred at 70 °C for 5 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 30 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in intermediate 2 (1.82 g, 5 53.93%) as a off-white solid. LCMS (ESI) m/z [M+H ]+ =417. A mixture of Intermediate 2 (1.82 g, 4.563 mmol, 1 equiv) in HCl (gas) in 1,4-dioxane (20 mL) was 10 stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 25 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in intermediate 3 (1.1775 g, 69.48%) as a white solid. LCMS (ESI) m/z [M+H]+ =361. 15 20 A mixture of intermediate 3 (20 mg, 0.056 mmol, 1 equiv), HATU (42.21 mg, 0.112 mmol, 2 equiv), DIEA (21.52 mg, 0.168 mmol, 3 equiv) and 1-{3-[7-(difluoromethyl)-6-[1-(piperidin-4-yl)pyrrolo[3,2- c]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (34.96 mg, 0.056 mmol, 1 equiv) in DMF (1 mL) was stirred at room temperature for 2 h. The crude product (25 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 25 OBD Column 30*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 15% B to 32% B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 7.87) to afford compound Compound A (17.5 mg, 31.53%) as a off-white solid.1H NMR (400 MHz, DMSO-d6) δ 174 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 11.10 (s, 1H), 8.72 (d, J = 6.7 Hz, 1H), 8.31 - 8.27 (m, 1H), 7.87 - 7.76 (m, 1H), 7.69 (d, J = 5.9 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 5.9 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.21 (s, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.87 - 6.57 (m, 1H), 5.10 - 5.03 (m, 1H), 4.83 - 4.70 (m, 1H), 4.64 (d, J = 12.7 Hz, 1H), 4.36 - 4.22 (m, 3H), 4.18 (s, 1H), 4.09 (d, J = 13.6 Hz, 1H), 4.01-3.91 (m, 2H), 3.79 - 3.75 (m, 1H), 3.74 - 3.69 5 (m, 1H), 3.65 - 3.60 (m, 2H), 3.51 - 3.42 (m, 3H), 3.26 (d, J = 11.6 Hz, 2H), 2.93 - 2.84 (m, 4H), 2.83 - 2.73 (m, 2H), 2.66 - 2.56 (m, 2H), 2.49 - 2.42 (m, 1H), 2.09 (s, 2H), 2.05 - 1.9 (m, 11H), 1.84 (d, J = 13.5 Hz, 3H). LCMS (ESI) m/z [M+H]+ =972.50. The following compounds in TABLE 3 were prepared using standard chemical manipulations and 10 procedures that are the same or similar to those used for the preparation of Compound A in Example 4. TABLE 3 175 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 176 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 177 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 178 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 179 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 180 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 181 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 182 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 5. Preparation of 2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrrolo[3,2-c]pyridin- 3-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)- N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (Compound 6). 5 A solution of pomalidomide (200 mg, 0.732 mmol, 1 equiv) and chloroacetyl chloride (82.66 mg, 10 0.732mmol, 1 equiv) in THF (2mL) was stirred at 80oC for 1h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in Intermediate 2 (286 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 350. 183 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 To a stirred solution of 2-chloro-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]acetamide (15.00 mg, 0.043 mmol, 1.2 equiv) and R23-24-071 (20 mg, 0.036 mmol, 1.00 equiv) in DMF (0.5 mL) was added DIEA (13.86 mg, 0.108 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1h. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture solution was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 10 OBD Column 30*150mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 6% B to 23% B in 8 min; Wave Length: 254nm/220nm nm; RT1(min): 9.32) to afford compound 6 (5.2 mg, 16.67%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.71 (s, 1H), 8.28 (d, J = 5.8 Hz, 1H), 7.61 – 7.46 (m, 2H), 7.33 (s, 1H), 7.20 (s, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.94 – 6.85 (m, 1H), 6.75 – 6.46 (m, 2H), 5.03 (dd, J = 12.3, 5.4 Hz, 1H), 15 4.57 – 4.27 (m, 2H), 4.22 (s, 2H), 4.14 – 3.88 (m, 1H), 3.86 (s, 3H), 3.75 (s, 2H), 3.71 – 3.67 (m, 2H), 3.63 (t, J = 5.2 Hz, 5H), 3.59 – 3.39 (m, 7H), 2.96 – 2.87 (m, 4H), 2.87 – 2.69 (m, 2H), 2.63 (dt, J = 6.6, 2.1 Hz, 1H), 2.59 – 2.56 (m, 2H), 2.18 – 1.97 (m, 6H), 1.92 (s, 4H). LCMS (ESI) m/z: [M+H]+ = 872.93. 184 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 6. Preparation of 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 27). Step 1: 5-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroquinolin- 5 1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 27). To a stirred solution of 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (15 mg, 0.043 mmol, 1 equiv) and 1-{3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro-2H-quinolin- 10 1-yl]-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (23.91 mg, 0.043 mmol, 1 equiv) in DMF (1 mL) was added K2CO3 (11.81 mg, 0.086 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at 60°C for 2h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 15 60 mL/min mL/min; Gradient: 35% B to 53% B in 13 min; Wave Length: 254nm/220nm nm; RT1(min): 6.35) to afford compound 27 (5.4 mg, 14.49%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 11.12 185 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 (s, 1H), 8.73 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 5.8 Hz, 1H), 7.93 – 7.80 (m, 3H), 7.53 (d, J = 5.8 Hz, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 6.91 (d, J = 3.5 Hz, 1H), 6.72 (d, J = 3.3 Hz, 1H), 5.15 (dd, J = 12.8, 5.3 Hz, 1H), 4.20 (d, J = 9.7 Hz, 2H), 4.07 (s, 1H), 3.85 (s, 3H), 3.72 (d, J = 9.3 Hz, 4H), 3.62 (t, J = 5.5 Hz, 3H), 2.94 (d, J = 4.7 Hz, 6H), 2.76 – 2.54 (m, 3H), 2.20 (t, J = 9.5 Hz, 2H), 2.11 – 1.96 (m, 8H), 1.97 - 1.81(m, 5 2H). LCMS (ESI) m/z [M+H]+ = 830.45. Example 7. Preparation of 5-[3-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3- yl}-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)azetidin-1-yl]- 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 8). 10 15 To a stirred solution of 1-{3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro-2H- quinolin-1-yl]-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (30 mg, 0.054 mmol, 1 equiv) and tert-butyl 3-oxoazetidine-1-carboxylate (18.35 mg, 0.108 mmol, 2 equiv) in MeOH (1 mL) and Acetic acid (0.1 mL) was added 2-methylpyridine borane (11.47 mg, 0.108 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at 60°C for 2h. The resulting mixture was concentrated 20 under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford Intermediate 2 (23 mg, 60.02%) as a white solid. LCMS (ESI) m/z [M+H]+ =714. Step 2: 1-{1-[1-(azetidin-3-yl)piperidin-4-yl]-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4- 25 dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (Intermediate 3). 186 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred solution of Intermediate 2 (23 mg, 0.032 mmol, 1 equiv) in DCM (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in Intermediate 3 (31 5 mg, 153.6%) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ =614. Step 3: 5-[3-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro-2H- quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)azetidin-1-yl]-2-(2,6-dioxopiperidin-3- 10 yl)isoindole-1,3-dione To a stirred solution of Intermediate 3 (28 mg, 0.046 mmol, 1 equiv) and DIEA (29.43 mg, 0.230 mmol, 5 equiv) in DMSO (1 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (12.58 mg, 0.046 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at 100°C for 1h. The 15 crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 8% B to 21%B in 10 min; Wave Length: 254nm/220nm nm; RT1(min): 8.7) to afford compound 8 (3.6 mg, 9.07%yield, 97.9%purity) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.75 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 5.9 Hz, 20 1H), 7.39 (d, J = 3.2 Hz, 1H), 7.22 (s, 1H), 6.91 (d, J = 3.5 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.76 – 6.54 (m, 2H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.27 – 4.08 (m, 5H), 3.89 – 3.84 (m, 5H), 3.79 – 3.71 (m, 2H), 187 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 3.67 – 3.57 (m, 2H), 3.37 – 3.32 (m, 2H), 2.92 – 2.77 (m, 7H), 2.62 – 2.54 (m, 2H), 2.11 – 2.08 (m, 3H), 2.07 – 1.93 (m, 8H). LCMS (ESI) m/z [M+H]+ =871.35. The following compounds in TABLE 4 were prepared using standard chemical manipulations and 5 procedures that are the same or similar to those used for the preparation of Compound 8 in Example 7. TABLE 4 188 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 189 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 190 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 191 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 192 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 193 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 194 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 195 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 196 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 197 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Compound LRMS # Structure 1HNMR (ESI) 1H NMR (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 10.15 (s, 1H), 9.06 (s, 2H), 8.74 (s, 1H), 8.28 (d, J = 5.8 Hz, 1H), 7.69 – 7.47 (m, 2H), 7.45 – 7.38 198 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 199 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 200 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 8. Preparation of 5-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3- yl}-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 26). 5 Step 1: 5-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro-2H-quinolin- 1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 26). To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (10 mg, 0.036 mmol, 110 equiv) and 1-{3-[7-(difluoromethyl)-6-{1-methylpyrrolo[3,2-c]pyridin-3-yl}-3,4-dihydro-2H-quinolin-1-yl]-1- (piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (20.26 mg, 0.036 mmol, 1 equiv) in DMSO (1 mL) was added DIEA (14.04 mg, 0.108 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 60°C for overnight. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% 15 gradient in 10 min; detector, UV 254 nm. To afford compound 26 (13.6 mg, 45.35%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.75 (s, 1H), 8.27 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.53 (dd, J = 5.9, 1.0 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.37 – 7.27 (m, 2H), 7.20 (s, 1H), 6.95 – 6.35 (m, 2H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.46 (s, 1H), 4.22 (d, J = 13.5 Hz, 4H), 3.85 (s, 3H), 3.74 (s, 2H), 201 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 3.63 (s, 2H), 3.23 (d, J = 9.2 Hz, 2H), 2.98 (s, 4H), 2.60 (s, 2H), 2.11 (s, 2H), 2.00 (s, 8H), 1.24 (s, 1H). LCMS (ESI) m/z [M+H]+ = 816.30. The following compounds in TABLE 5 were prepared using standard chemical manipulations and 5 procedures that are the same or similar to those used for the preparation of Compound 26 in Example 8. TABLE 5 202 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 9.3-(5-{4-[(4-{5-acetyl-3-[7-(difluoromethyl)-6-{3,5-dimethylpyrrolo[3,2-c]pyridazin-7-yl}- 3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)methyl]piperidin- 1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione; formic acid (Compound 109). 5 Step 1: tert-butyl 4-{5-acetyl-3-[7-(difluoromethyl)-6-{3,5-dimethylpyrrolo[3,2-c]pyridazin-7-yl}-3,4-dihydro- 2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (Intermediate 2). 203 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a mixture of 7-bromo-3,5-dimethylpyrrolo[3,2-c]pyridazine (13.8 mg, 0.061 mmol, 1 equiv) and tert-butyl 4-{5-acetyl-3-[7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro- 2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (60.1 mg, 0.092 mmol, 1.5 5 equiv) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was added Cs2CO3 (59.6 mg, 0.183 mmol, 3.0 equiv), XPhos Pd G3 (5.2 mg, 0.006 mmol, 0.1 equiv) and XPhos (5.8 mg, 0.012 mmol, 0.2 equiv) and CuBr (0.9 mg, 0.006 mmol, 0.1 equiv) in portions at room temperature. The resulting mixture was stirred at 80°C for 4h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 x 50 mL). The combined 10 organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column: C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 25% to 50% gradient in 10 min; detector, UV 254 nm) to afford intermediate 2 (27 mg, 65.55%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 675. 15 A solution of intermediate 2 (27.0 mg, 0.040 mmol, 1 equiv) in DCM (2 mL) was added trifluoroacetic 20 acid (0.4 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 3h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 28% gradient in 10min; detector, UV 254 nm. This resulted in to afford intermediate 3 (22 mg, 95.68%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 575. 204 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 To a solution of intermediate 3 (20.0 mg, 0.035 mmol, 1 equiv) in DMF (1 mL) was treated with 1-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]piperidine-4-carbaldehyde (18.5 mg, 0.053 mmol, 1.5 equiv) and AcOH (one drop) at room temperature for 10 min followed by the addition of STAB (14.7 mg, 0.070 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at 40°C for 10 1h. Desired product could be detected by LCMS. The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): isocratic 10%B to 22%B in 10min; Wave Length: 254nm/220 nm; RT1(min): 10.57) to afford compound 109 (10.1 mg, 30.23%) as a light yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.50 (d, J = 15 8.7 Hz, 1H), 7.40 (s, 1H), 7.27 – 6.80 (m, 4H), 5.06 – 4.96 (m, 1H), 4.39 – 4.18 (m, 4H), 4.13 – 3.98 (m, 2H), 3.92 – 3.80 (m, 4H), 3.74 (s, 2H), 3.69 – 3.61 (m, 2H), 3.03 – 2.94 (m, 3H), 2.93 – 2.80 (m, 7H), 2.76 (s, 3H), 2.69 – 2.56 (m, 3H), 2.42 – 2.30 (m, 1H), 2.29 – 2.18 (m, 3H), 2.17 – 1.95 (m, 8H), 1.92 – 1.72 (m, 3H), 1.30 – 1.16 (m, 2H). LCMS (ESI) m/z: [M+H]+ = 914.45. 20 The following compounds in TABLE 6 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 109 in Example 9. 205 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 TABLE 6 206 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 207 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 208 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 209 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 210 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 211 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 10. Preparation of 3-{6-[2-(4-{5-acetyl-3-[7-(difluoromethyl)-6-(morpholine-4-carbonyl)-3,4- dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)-2-oxoethyl]-1,3- dioxo-5H,7H-pyrrolo[3,4-f]isoindol-2-yl}piperidine-2,6-dione（Compound 69） 5 Preparation of 1-{5-acetyl-1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl}- 7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid (Intermediate A). 212 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 1: Preparation of tert-butyl 4-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 2). 5 To a stirred solution of 3-bromo-1H-pyrazolo[4,3-c]pyridine (1.00 g, 5.005 mmol, 1 equiv) and 1-Boc- 4-methanesulfonyloxypiperidine (1.34 g, 6.565 mmol, 1.30 equiv) in DMF (10 mL) was added Cs2CO3 (4.94 g, 15.150 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for 2h at 120°C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture 10 was extracted with CH2Cl2 (3 x 50mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in intermediate 2 (1.05 g, 54.53%) as a white solid. LCMS (ESI) m/z [M+H]+ = 381. 15 Step 2: Preparation of methyl 1-{1-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyrazolo[4,3-c]pyridin-3-yl}-7- (difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylate (Intermediate 3). 213 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred solution of intermediate 7 (200 mg, 0.829 mmol, 1.00 equiv) and intermediate 2 (316.10 mg, 0.829 mmol, 1.00 equiv) in toluene (2 mL) was added RuPhos (58.03 mg, 0.125mmol, 0.15 equiv), Cs2CO3 (540.25 mg, 1.658 mmol, 2.00 equiv) and RuPhos Pd G3 (104.01 mg, 0.125 mmol, 0.15 equiv) in portions at room temperature. The resulting mixture was stirred for 2h at 80°C under nitrogen 5 atmosphere. The resulting mixture was diluted with water (10 mL), extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford methyl intermediate 3 (240 mg, 29.51%) as a white solid. LCMS (ESI) m/z [M+H]+ = 542. 10 Step 3: Preparation of methyl 1-{1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,5H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylate (Intermediate 4). To a solution of intermediate 3 (240 mg, 0.444 mmol, 1.00 equiv) in MeOH (9 mL) was added Platinum(IV)oxide (26.20 mg, 0.124 mmol, 0.34 equiv) at room temperature. The mixture was 15 hydrogenated at room temperature under 30 psi of hydrogen pressure for 16h, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford intermediate 4 (200 mg, 69.48%) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 546. 20 Step 4: Preparation of methyl 1-{5-acetyl-1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylate (Intermediate 5). To a stirred solution of intermediate 4 (200 mg, 0.0.366 mmol, 1 equiv) in DCM (10 mL) was added Acetic anhydride (74.84 mg, 0.733 mmol, 2 equiv) and Et3N (148.37 mg, 1.466 mmol, 4 equiv) dropwise 25 at room temperature. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford intermediate 5 (189 mg, 87.58%) as a yellow solid. LCMS (ESI) m/z [M+H]+ =588. 214 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 5: Preparation of 1-{5-acetyl-1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid (Intermediate 6). To a stirred solution of methyl intermediate 5 (264 mg, 0.450 mmol, 1.00 equiv) in MeOH:THF:H2O 5 (8:8:1) (1 mL) was added LiOH (107.58 mg, 4.500 mmol, 10 equiv) at room temperature. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 15 min; detector, UV 254 nmto afford intermediate A (168 mg, 59.98%) as a white 10 solid. LCMS (ESI) m/z [M+H]+ = 574. 15 To a stirred solution of 3-{1,3-dioxo-5H,6H,7H-pyrrolo[3,4-f]isoindol-2-yl}piperidine-2,6-dione (120 mg, 0.401 mmol, 1 equiv) and tert-butyl 2-bromoacetate (58.45 uL, 0.401 mmol, 1 equiv) in DMF (1 mL) was 20 added DIEA (209.52 uL, 1.203 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1h. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm. to afford intermediate 2 (105 mg, 84.54%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 414. 25 215 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 2: Preparation of 2-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo [3,4-f]isoindol- 2(1H)-yl)acetic acid (Intermediate B). A mixture of intermediate 2 (105 mg, 0.363 mmol, 1 equiv) in con.HCl (5 mL) and H2O (5 mL) was 5 stirred at room temperature for 0.5h. The resulting mixture was concentrated under reduced pressure to afford (126 mg, crude) as a white solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 358. 10 To a stirred solution of 1-{5-acetyl-1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid (45 mg, 0.078 mmol, 1 equiv) 15 and HATU (59.66 mg, 0.156 mmol, 2 equiv) in DMF (0.5 mL) was added DIEA (40.56 mg, 0.312 mmol, 4 equiv) and morpholine (10.25 mg, 0.117 mmol, 1.5 equiv) The resulting mixture was stirred at 20°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 20 254 nm. This resulted in intermediate 2 (33.2 mg, 65.85%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 643. 216 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 2: 1-{3-[7-(difluoromethyl)-6-(morpholine-4-carbonyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(piperidin-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethenone (Intermediate 3) To a stirred solution of tert-butyl 4-{5-acetyl-3-[7-(difluoromethyl)-6-(morpholine-4-carbonyl)-3,4- 5 dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (30 mg, 0.05 mmol, 1 equiv) in DCM (1 mL) was added trifluoroacetic acid (0.3 mL).The resulting mixture was stirred at 20°C for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in intermediate 3 (29 mg, crude) as brown oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 543. 10 Step 3: 3-{6-[2-(4-{5-acetyl-3-[7-(difluoromethyl)-6-(morpholine-4-carbonyl)-3,4-dihydro-2H-quinolin-1-yl]- 4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)-2-oxoethyl]-1,3-dioxo-5H,7H-pyrrolo[3,4-f]isoindol-2- yl}piperidine-2,6-dione (Compound 69). 15 To a stirred solution of 1-{3-[7-(difluoromethyl)-6-(morpholine-4-carbonyl)-3,4-dihydro-2H-quinolin-1-yl]-1- (piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (29 mg, 0.053 mmol, 1 equiv) and [6-(2,6- dioxopiperidin-3-yl)-5,7-dioxo-1H,3H-pyrrolo[3,4-f]isoindol-2-yl]acetic acid (19.10 mg, 0.053 mmol, 1 equiv) in DMF (2 mL) was added TCFH (29.99 mg, 0.106 mmol, 2 equiv) and 1-methyl-1H-imidazole 20 (13.16 mg, 0.159 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 1h under nitrogen atmosphere. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in compound 69 (8.0 mg, 16.97%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 882.94.1H NMR (300 MHz, DMSO-d6) 7.79 (s, 2H), 7.12 – 6.50 (m, 217 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 3H), 5.13 (dd, J = 12.8, 1H), 4.40 (m, 2H), 4.13 (m, 7H), 3.62 (m, 12H), 3.23 (m, 3H), 2.86 (m, 6H), 2.60 (m, J = 20.2 Hz, 2H), 2.08 (s, 3H), 1.96 (m, 6H), 1.77 (m, 1H). The following compounds in TABLE 7 were prepared using standard chemical manipulations and 5 procedures that are the same or similar to those used for the preparation of Compound 69 in Example 10. TABLE 7 218 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 11. Preparation of 4-{4-[(4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methyl-2'H-spiro[azetidine- 3,3'-pyrrolo[2,3-c]pyridin]-1'-yl}-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1- 219 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 yl}piperidin-1-yl)methyl]piperidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione; formic acid (Compound 86). Step 1: tert-butyl 3-(3-bromopyridin-4-yl)-3-cyanoazetidine-1-carboxylate (Intermediate 2). 5 A solution of 3-bromo-4-fluoropyridine (1 g, 5.682 mmol, 1 equiv) and tert-butyl 3-cyanoazetidine-1- carboxylate (2.07 g, 11.364 mmol, 2 equiv) in THF (15 mL) was stirred for 30 min at -78°C under nitrogen atmosphere. To the above mixture was added LDA (in 2M THF) (1.22 g, 11.364 mmol, 2 equiv) in portions over 10 min at -78°C under nitrogen atmosphere. The resulting mixture was stirred for overnight at room 10 temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford intermediate 2 (1.2 g, 62.44%) as a yellow oil. LCMS (ESI) m/z [M+H]+ =338/340. 220 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 2: tert-butyl 3-(aminomethyl)-3-(3-bromopyridin-4-yl)azetidine-1-carboxylate (Intermediate 3). To a solution of intermediate 2 (6 g, 17.74 mmol, 1 equiv) in THF (10 mL) was added Lithium aluminum hydride (2.0 M in THF) (17.8 mL, 35.48 mmol, 2 equiv) at -10°C under nitrogen atmosphere. 5 The resulting mixture stirred at -10°C for 1h under nitrogen atmosphere. The reaction was quenched with Water/Ice at 0°C.The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 100% gradient in 20 min; detector, UV 254 nm.to afford intermediate 3 (400 mg, 6.59%) as a white solid. LCMS (ESI) m/z [M+H]+ =342/344. 10 Step 3: tert-butyl 1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1-carboxylate (Intermediate 4). To a stirred solution of intermediate 3 (120 mg, 0.351 mmol, 1 equiv) and Pd-PEPPSI-IPentCl 2- methylpyridine (68.29 mg, 0.070 mmol, 0.2 equiv) in 1,4-dioxane (4 mL) was added Cs2CO3 (342.73 mg, 15 1.053 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 10% to 100% gradient in 20 min; detector, UV 254 nm.to afford Intermediate 4 (52 mg, 56.76%) as a white solid. LCMS 20 (ESI) m/z [M+H]+ =262. Step 4: Preparation of 1-methyl-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine] (Intermediate 5). 25 To a stirred solution of tert-butyl 1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1-carboxylate (250 mg, 0.957 mmol, 1 equiv) in THF (10 mL) was added LiAlH4(2.4 M in THF) (1.2 mL, 3.000 mmol, 3.14 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2h. The reaction was quenched by the addition of MeOH (1 mL) at 0°C. The resulting mixture was 30 concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography 221 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford intermediate 5 (85 mg, 50.70%) as a light yellow semi-solid. LCMS (ESI) m/z [M+H]+ =176. 5 Step 5: Preparation of tert-butyl 4-{5-acetyl-3-[7-(difluoromethyl)-6-{1-methyl-2'H-spiro[azetidine-3,3'- pyrrolo[2,3-c]pyridin]-1'-yl}-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl} piperidine- 1-carboxylate (Intermediate 6). To a stirred solution of intermediate 5 (25 mg, 0.143 mmol, 1 equiv) and tert-butyl 4-{5-acetyl-3-[6-10 bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1- carboxylate (86.82 mg, 0.143 mmol, 1 equiv) in toluene (1 mL) was added RuPhos Pd G3 (11.93 mg, 0.014 mmol, 0.1 equiv), RuPhos (13.31 mg, 0.029 mmol, 0.2 equiv) and t-BuONa (41.13 mg, 0.429 mmol, 3 equiv). The resulting mixture was stirred at 100°C for 1h under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic 15 layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford intermediate 6 (63 mg, 62.83%) as a light yellow solid. LCMS (ESI) m/z [M+H]+ =703. 20 Step 6: Preparation of 1-{3-[7-(difluoromethyl)-6-{1-methyl-2'H-spiro[azetidine-3,3'-pyrrolo[2,3-c]pyridin]- 1'-yl}-3,4-dihydro-2H-quinolin-1-yl]-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (Intermediate 7). To a stirred solution of intermediate 6 (48 mg, 0.068 mmol, 1 equiv) in DCM (0.75 mL) was added 25 TFA (0.25 mL). The resulting mixture was stirred at 25°C for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the 222 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford intermediate 7 (35 mg, 85.03%) as a light yellow solid. LCMS (ESI) m/z [M+H]+ =603. 5 To a stirred solution of intermediate 7 (25 mg, 0.041 mmol, 1 equiv) and intermediate 8 (15.32 mg, 10 0.041 mmol, 1 equiv) in DMF (0.5 mL) was added STAB (26.37 mg, 0.123 mmol, 3 equiv). The resulting mixture was stirred at 25°C for 1h. The resulting mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 11% B in 10 min; Wave Length: 254nm/220 nm; RT1(min): 10.87) to afford compound 86 (18.1 mg, 43.54%) as a light yellow solid.1H 15 NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.16 (s, 1H, FA salt), 8.01 (d, J = 4.6 Hz, 1H), 7.73 – 7.61 (m, 1H), 7.51 (d, J = 4.7 Hz, 1H), 7.39 (s, 1H), 7.32 (t, J = 8.5 Hz, 2H), 7.12 – 6.72 (m, 3H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 4.27 – 4.14 (m, 2H), 4.12 – 3.98 (m, 1H), 3.99 – 3.83 (m, 2H), 3.81 – 3.65 (m, 5H), 3.66 – 3.53 (m, 3H), 3.55 – 3.50 (m, 2H), 3.05 – 2.94 (m, 2H), 2.94 – 2.84 (m, 4H), 2.85 – 2.69 (m, 3H), 2.65 – 2.51 (m, 2H), 2.38 (s, 3H), 2.27 (d, J = 6.9 Hz, 2H), 2.19 – 2.06 (m, 4H), 2.07 – 1.91 (m, 6H), 1.90 – 1.79 20 (m, 4H), 1.78 – 1.68 (m, 1H), 1.41 – 1.21 (m, 2H). LCMS (ESI) m/z [M+H]+ =956.55. The following compounds in TABLE 8 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 86 in Example 11. TABLE 8 223 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 224 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 225 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 12. Preparation of 3-(1,3-dioxo-6-{[(1r,4r)-4-{5-acetyl-3-[7-(difluoromethyl)-6-(1- methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1- yl}cyclohexyl]methyl}-5H,7H-pyrrolo[3,4-f]isoindol-2-yl)piperidine-2,6-dione (Compound 74). 5 Step 1: Preparation of methyl (1s,4s)-4-[(4-methylbenzenesulfonyl)oxy]cyclohexane-1-carboxylate (Intermediate 2). To a stirred solution of methyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate (1 g, 6.321 mmol, 1 10 equiv) and TsCl (4.34 g, 22.757 mmol, 1.2 equiv) in DCM (40 mL) was added TEA (5.76 g, 56.892 mmol, 3 equiv) and DMAP (463.36 mg, 3.793 mmol, 0.2 equiv). The resulting mixture was stirred at room temperature for overnight. The resulting mixture was concentrated under reduced pressure. The residue 226 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford intermediate 2 (1.5 g, 75.96%) as a light yellow oil. LCMS (ESI) m/z [M+H]+ =313. Step 2: Preparation of methyl (1r,4r)-4-{3-bromopyrazolo[4,3-c]pyridin-1-yl}cyclohexane-1-carboxylate 5 (Intermediate 3). To a stirred solution of intermediate 2 (5.68 g, 18.180 mmol, 3 equiv) and 3-bromo-1H-pyrazolo[4,3- c]pyridine (1.2 g, 6.060 mmol, 1 equiv) in DMSO (15 mL) was added Cs2CO3 (5.92 g, 18.180 mmol, 3 equiv). The resulting mixture was stirred at 80°C for 2h. The resulting mixture was filtered, the filter cake 10 was washed with DMSO (3 x 3 mL). The filtrate was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 0% to 50% gradient in 30 min; detector, UV 254 nm) to afford intermediate 3 (1.5 g, 73.19%) as an off-white solid. LCMS (ESI) m/z [M+H]+ =338. 15 To a stirred solution of intermediate 3 (500 mg, 1.478 mmol, 1 equiv) and 7-(difluoromethyl)-1,2,3,4- tetrahydroquinoline (270.84 mg, 1.478 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added Pd2(dba)3 20 (270.76 mg, 0.296 mmol, 0.2 equiv), XantPhos (342.18 mg, 0.591 mmol, 0.4 equiv) and K3PO4 (941.43 mg, 4.434 mmol, 3 equiv). The resulting mixture was stirred at 80oC for overnight under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The 25 residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 50% gradient in 30 min; detector, UV 254 nm) to afford intermediate 4 (485 mg, 74.48%) as a light yellow solid. LCMS (ESI) m/z [M+H]+ =441. 227 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a solution of intermediate 4 (475 mg, 1.078 mmol, 1 equiv) in MeOH (5 mL) was added PtO2 5 (122.43 mg, 0.539 mmol, 0.5 equiv) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for 2h, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford intermediate 5 (452 mg, 94.29%) as a white solid. LCMS (ESI) m/z [M+H]+ =445. 10 To a stirred solution of intermediate 5 (447 mg, 1.006 mmol, 1 equiv) in DCM (5 mL) was added TEA 15 (305.27 mg, 3.018 mmol, 3 equiv) and Ac2O (112.92 mg, 1.107 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford intermediate 6 (382 mg, 78.08%) as a white solid. LCMS (ESI) m/z [M+H]+ =487. 20 Step 6: Preparation of methyl (1r,4r)-4-{5-acetyl-3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1- yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}cyclohexane-1-carboxylate (Intermediate 7). 228 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred solution of intermediate 6 (372 mg, 0.765 mmol, 1 equiv) in ACN (5 mL) was added NBS (136.08 mg, 0.765 mmol, 1 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:4) to afford intermediate 7 (431 mg, 99.69%) as 5 a white solid. LCMS (ESI) m/z [M+H]+ =566. 10 To a stirred solution of intermediate 7 (557 mg, 0.985 mmol, 1 equiv)) in MeOH (5 mL) was added NaBH4 (186.32 mg, 4.925 mmol, 5 equiv) at 0°C. The resulting mixture was stirred at 25°C for 1h. The reaction was quenched by the addition of AcOH (0.2 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford intermediate 8 (371 mg, 70.08%) as a light yellow solid. LCMS 15 (ESI) m/z [M+H]+ =537. 20 To a stirred solution of methyl (1r,4r)-4-{5-acetyl-3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H- quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}cyclohexane-1-carboxylate (50 mg, 0.088 mmol, 1 25 equiv) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (91.99 mg, 0.440 mmol, 5 equiv) in 1,4-dioxane (500 uL) and H2O (100 uL) was added XPhos Pd G3 (7.48 mg, 0.009 mmol, 0.1 equiv)and Cs2CO3 (86.43 mg, 0.264 mmol, 3 equiv) in portions at 25°C under argon atmosphere. The resulting mixture was stirred at 80°C for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) 30 to afford Intermediate 9 (45 mg, 90.24%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 567. 229 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 A solution of methyl (1r,4r)-4-{5-acetyl-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H- quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}cyclohexane-1-carboxylate (50 mg, 0.088 mmol, 1 equiv) and NaBH4 (16.69 mg, 0.440 mmol, 5 equiv) in THF (3 mL) was stirred at 0°C for 6h. The reaction was quenched by the addition of AcOH (0.1 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following 10 conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 0% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in Intermediate 10 (40 mg, 84.16%) as a colorless solid. LCMS (ESI) m/z: [M+H]+ = 539. 15 A solution of 1-{3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[(1r,4r)-4- (hydroxymethyl)cyclohexyl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (30 mg, 0.056 mmol, 1 equiv) and 1,1-bis(acetyloxy)-3-oxo-3H-1l^[5],2-benziodaoxol-1-yl acetate (23.62 mg, 0.056 mmol, 1 equiv) in 20 DCM (3 mL) was stirred at 25°C for 1h. The mixture was neutralized to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in Intermediate 11 (30 mg, crude) as a yellow oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 537. 25 230 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 To a stirred solution of (1r,4r)-4-{5-acetyl-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H- quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}cyclohexane-1-carbaldehyde (50 mg, 0.093 mmol, 1 equiv) and 3-{1,3-dioxo-5H,6H,7H-pyrrolo[3,4-f]isoindol-2-yl}piperidine-2,6-dione (27.89 mg, 0.093 mmol, 1.00 equiv) in DMF (1 mL) was added HOAc (11.19 uL, 0.195 mmol, 2.10 equiv) and STAB (19.75 mg, 0.093 mmol, 1 equiv) in portions at 25°C under argon atmosphere. The resulting mixture was stirred at 10 40°C for 1h under argon atmosphere. The mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water(0.1%FA, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17%B to 27% B in 10min; Wave Length: 254nm/220 nm; RT1(min): 9.7) to afford compound 74 (9 mg, 11.78%,) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.84 – 7.70 (m, 3H), 7.50 (s, 1H), 7.11 (s, 1H), 6.98 – 6.60 (m, 2H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 15 4.21 – 4.09 (m, 2H), 4.08 – 4.01 (m, 1H), 3.97 (s, 4H), 3.87 (s, 3H), 3.78 – 3.64 (m, 2H), 3.64 – 3.53 (m, 2H), 2.96 – 2.80 (m, 4H), 2.78 – 2.66 (m, 1H), 2.65 – 2.54 (m, 4H), 2.12 – 2.02 (m, 3H), 2.02 – 1.88 (m, 7H), 1.87 – 1.77 (m, 2H), 1.57 (s, 1H), 1.20 – 1.05 (m, 2H). LCMS (ESI) m/z: [M+H]+ = 820.40. The following compounds in TABLE 9 were prepared using standard chemical manipulations and 20 procedures that are the same or similar to those used for the preparation of Compound 74 in Example 12. 231 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 TABLE 9 Example 13. Preparation of 3-{5-[4-({4-[5-acetyl-3-(6-{3,5-dimethylpyrrolo[3,2-c]pyridazin-7-yl}-3,4- dihydro-2H-quinolin-1-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]piperidin-1-yl}methyl)piperidin-1- yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (Compound 114) 5 10 To a stirred solution of 3,4,6-trichloropyridazine (2 g, 10.904 mmol, 1.00 equiv), DIEA (4.23 g, 32.712 mmol, 3 equiv) in DMF (20 mL) was added methanamine, hydrochloride (1.10 g, 16.356 mmol, 1.5 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 3h. The 232 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 resulting mixture was diluted with H2O (40 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3:1) to afford Intermediate 2 (1.1 g, 56.67%) as a white 5 solid. LCMS (ESI) m/z [M+H]+ =178. To a stirred solution of Intermediate 2 (1.09 g, 6.123 mmol, 1.00 equiv), 2-[(E)-2-ethoxyethenyl]- 10 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.46 g, 7.348 mmol, 1.2 equiv), Pd(dppf)Cl2 (0.31 g, 0.429 mmol, 0.07 equiv) in 1,4-dioxane (12 mL) and H2O (2.4 mL) was added Na2CO3 (1.30 g, 12.246 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at 80°C for 4h under argon atmosphere. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over 15 anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford Intermediate 3 (837 mg, 63.98%) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 214. 20 To a stirred solution of Intermediate 3 (807 mg, 3.777 mmol, 1.00 equiv), trimethyl-1,3,5,2,4,6- trioxatriborinane (4741.08 mg, 18.885 mmol, 5 equiv, 50%) , XPhos Pd G3 (223.79 mg, 0.264 mmol, 0.07 equiv), XPhos (252.07 mg, 0.529 mmol, 0.14 equiv) in 1,4-dioxane (10 mL) was added CsF (1147.44 mg, 7.554 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at 80°C for 25 overnight under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford Intermediate 4 (710 mg, 97.28%) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 194. 30 To a stirred solution of Intermediate 4 (739 mg, 3.824 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added HCl in 1,4-dioxane (4.0 M) (10 mL) in portions at room temperature. The resulting mixture was 233 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 stirred at 60°C for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in Intermediate 5 (601 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 148. 5 To a stirred solution of Intermediate 5 (601 mg, 4.083 mmol, 1 equiv) in DMF (6 mL) was added NBS (654.11 mg, 3.675 mmol, 0.9 equiv) in DMF (6 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1h under nitrogen atmosphere. The precipitated solids were 10 collected by filtration and washed with MTBE (3 x 10 mL). This resulted in Intermediate 6 (671 mg, 72.68%) as a light yellow solid. LCM 15 To a stirred solution of tert-butyl 4-[5-acetyl-3-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate (179 mg, 0.320 mmol, 1 equiv) and 234 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 bis(pinacolato)diboron (122.0 mg, 0.480 mmol, 1.5 equiv) in 1,4-dioxane (5 mL) was added XPhos Pd G3 (27.1 mg, 0.032 mmol, 0.1 equiv) and AcOK (62.9 mg, 0.640 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL), extracted with EtOAc (3 x 50 mL). The combined organic 5 layers were washed with brine (2 x 30 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 0% to 45% gradient in 20 min; detector, UV 254 nm. This resulted in intermediate 2 (178 mg, 91.71%) as a red solid. LCMS (ESI) m/z: [M+H]+ = 606. 10 To a stirred solution of intermediate 2 (134 mg, 0.221 mmol, 1 equiv), Cs2CO3 (144.1 mg, 0.442 mmol, 15 2 equiv) and 7-bromo-3,5-dimethylpyrrolo[3,2-c]pyridazine (50.0 mg, 0.221 mmol, 1 equiv) in 1,4-dioxane (10 mL) and H2O (2 mL) was added XPhos Pd G3 (18.7 mg, 0.022 mmol, 0.1 equiv) and XPhos (21.1 mg, 0.044 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL), extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over 20 anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in intermediate 3 (132 mg, 95.48%) as a red solid. LCMS (ESI) m/z: [M+H]+ = 625. 25 235 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 A solution of intermediate 3 (132 mg, 0.211 mmol, 1 equiv) and TFA (3 mL) in DCM (9 mL) was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 35% gradient in 15 min; detector, UV 254 nm. This 5 resulted in intermediate 4 (88.7 mg, 80.02%) as a red solid. LCMS (ESI) m/z: [M+H]+ = 525. 10 To a stirred solution of intermediate 4 (30 mg, 0.057 mmol, 1 equiv) and 1-[2-(2,6-dioxopiperidin-3-yl)- 1-oxo-3H-isoindol-5-yl]piperidine-4-carbaldehyde (20.3 mg, 0.057 mmol, 1 equiv) in DMF (3 mL) was added STAB (24.2 mg, 0.114 mmol, 2 equiv) and HOAc (10 uL) at room temperature. The resulting mixture was stirred at room temperature for 1h. The mixture was purified by Prep-HPLC with the following conditions 15 (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient (B%): 10% B to 25% B in 10 min; Wave Length: 254nm/220nm nm; RT1(min): 9.1) to afford compound 114 (10.8 mg, 21.86%) as a red solid. [M+H]+ = 864.50.1H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.18 (s, TFA, 1H), 7.94 (s, 2H), 7.82 (dd, J = 8.5, 2.2 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.07 – 6.98 (m, 2H), 6.55 (d, J = 8.5 Hz, 1H), 5.01 (dd, 20 J = 13.1, 5.2 Hz, 1H), 4.39 – 4.19 (m, 3H), 4.18 (s, 2H), 4.08 – 3.97 (m, 1H), 3.91 – 3.82 (m, 2H), 3.81 – 3.79 (m, 4H), 3.78 – 3.75 (m, 2H), 3.61 (t, J = 5.6 Hz, 2H), 2.99 – 2.94 (m, 2H), 2.93 – 2.80 (m, 6H), 2.75 (s, 3H), 2.68 – 2.60 (m, 1H), 2.59 – 2.53 (m, 1H), 2.43 – 2.28 (m, 1H), 2.23 (d, J = 6.5 Hz, 2H), 2.19 – 1.93 (m, 9H), 1.91 – 1.70 (m, 5H), 1.37 – 1.08 (m, 1H). 25 The following compounds in TABLE 10 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 114 in Example 13. 236 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 TABLE 10 Example 14. Preparation of 3-{5-[3-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{3,5-dimethylpyrrolo[3,2- c]pyridazin-7-yl}-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1- yl)prop-1-yn-1-yl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl}piperidine-2,6-dione (Compound 118). 5 Step 1: Preparation of methyl 3-{6-[4-(dimethoxymethyl)piperidin-1-yl]-1-oxo-3H-isoindol-2-yl}piperidine- 2,6-dione (Intermediate 2). 10 To a stirred mixture of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (300 mg, 0.887 mmol, 1 equiv) and trimethyl(prop-2-yn-1-yloxy)silane (227.55 mg, 1.774 mmol, 2 equiv) in DMF (5 mL) was added CuI (16.90 mg, 0.089 mmol, 0.1 equiv), Cs2CO3 (578.10 mg, 1.774 mmol, 2 equiv) and dichlorobis(triphenylphosphine)palladium(II) (62.27 mg, 0.089 mmol, 0.1 equiv) in portions at room 237 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 temperature. The resulting mixture was stirred at 80°C for 2h under argon atmosphere. The mixture was diluted with H2O (30 mL), extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following 5 conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 40 min; detector, UV 254 nm. This resulted in Intermediate 2 (114 mg, 41.01%) as a white solid. LCMS (ESI) m/z: [M+H]+ = 314. Step2: Preparation of 1-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl] piperidine-4-carbaldehyde 10 (Intermediate 3). To a stirred mixture of Intermediate 2 (100 mg, 0.319 mmol, 1 equiv) in DMSO (1.2 mL) was added IBX (178.75 mg, 0.638 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 2h. The mixture was purified by reversed-phase flash chromatography with the 15 following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 40 min; detector, UV 254 nm. This resulted in Intermediate 3 (85 mg, 85.55%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 312. 20 To a stirred solution of intermediate 1 (44.3 mg, 0.077 mmol, 0.80 equiv) and intermediate 2 (30.0 mg, 0.096 mmol, 1.00 equiv) in DMSO (1.5 mL) was added STAB (40.8 mg, 0.192 mmol, 2.00 equiv) in portions 25 at room temperature. The resulting mixture was stirred at room temperature for 2h. Desired product could be detected by LCMS. The mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient (B%): 8%B to 18%B in 10min; Wave Length: 254nm/220 nm; RT1(min): 9.32) to afford compound 118 (2.1 mg, 2.50%) as a yellow solid. LCMS (ESI) m/z: [M-H]+ = 238 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 868.35.1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.70 (d, J = 5.0 Hz, 1H), 7.67 (s, 1H), 7.39 (d, J = 5.8 Hz, 1H), 7.32 (s, 1H), 7.21 – 7.07 (m, 2H), 6.97 (t, J = 55.5 Hz, 1H), 6.93 (s, 1H), 5.39 (dd, J = 12.7, 5.4 Hz, 1H), 4.29 – 4.12 (m, 2H), 4.11 – 3.93 (m, 1H), 3.83 (s, 3H), 3.79 – 3.67 (m, 2H), 3.66 – 3.60 (m, 2H), 3.58 (s, 2H), 3.31 (s, 3H), 3.02 – 2.94 (m, 2H), 2.93 – 2.82 (m, 4H), 2.80 – 2.70 (m, 4H), 2.69 – 2.58 (m, 5 2H), 2.46 – 2.35 (m, 2H), 2.08 (s, 3H), 2.06 – 1.96 (m, 5H), 1.95 – 1.83 (m, 2H). Example 15. Preparation of 4-((4-((4-(5-acetyl-3-(7-(difluoromethyl)-6-(imidazo[1,2-a]pyridin-6-yl)- 3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)methyl)phenyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 125). 10 To a stirred mixture of 6-bromoimidazo[1,2-a]pyridine (200 mg, 1.015 mmol, 1 equiv) and 15 bis(pinacolato)diboron (257.76 mg, 1.015 mmol, 1 equiv) in 1,4-dioxane (4 mL) was added Pd(dppf)Cl2CH2Cl2 (82.89 mg, 0.101 mmol, 0.1 equiv) and AcOK (298.86 mg, 3.045 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile 20 phase, MeCN in Water (0.1% FA), 20% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in intermediate 2 (135 mg, 94%) as a brown oil. LCMS (ESI) m/z [M+H]+ = 163. 239 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 2: Preparation of tert-butyl 4-{5-acetyl-3-[7-(difluoromethyl)-6-{imidazo[1,2-a]pyridin-6-yl}-3,4- dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (Intermediate 3). To a stirred mixture of intermediate 2 (30 mg, 0.185 mmol, 1 equiv) and tert-butyl 4-{5-acetyl-3-[6- 5 bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1- carboxylate (112.72 mg, 0.185 mmol, 1 equiv) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was added Cs2CO3 (181.06 mg, 0.555 mmol, 3 equiv) and Pd(dppf)Cl2CH2Cl2 (15.13 mg, 0.018 mmol, 0.1 equiv) in portions at room temperature. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified 10 by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in intermediate 3 (113 mg, 57%) as a brown solid. LCMS (ESI) m/z [M+H]+ = 646. Step 3: Preparation of 1-{3-[7-(difluoromethyl)-6-{imidazo[1,2-a]pyridin-6-yl}-3,4-dihydro-2H-quinolin-1-yl]- 15 1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (Intermediate 4). To a stirred mixture of intermediate 3 (113 mg, 0.175 mmol, 1 equiv) in DCM (0.9 mL) was added trifluoroacetic acid (0.3 mL) in portions at room temperature. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The crude was 20 purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 80% gradient in 30 min; detector, UV 254 nm. This resulted in intermediate 4 (55 mg, 57.60%) as off-white solid. LCMS (ESI) m/z [M+H]+ = 546. 240 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 4: Preparation of t 4-({4-[(4-{5-acetyl-3-[7-(difluoromethyl)-6-{imidazo[1,2-a]pyridin-6-yl}-3,4-dihydro- 2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)methyl]phenyl}amino)-2-(2,6- dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 125). 5 To a stirred mixture of intermediate 4 (30 mg, 0.055 mmol, 1 equiv) and intermediate 5 in DMF (1 mL) was added HOAc (0.2 mL, 0.018 mmol, 0.10 equiv) and STAB (17.48 mg, 0.082 mmol, 1.50 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 2h. The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; 10 Gradient: 10% B to 30% B in 10 min; Wave Length: 254nm/220nm; RT1(min): 9.1) to afford Compound 125. (7.1 mg, 14.24%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.99 – 10.77 (m, 1H), 9.03 (s, 1H), 8.51 – 8.20 (m, 1H), 7.94 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.62 – 7.50 (m, 2H), 7.42 – 7.26 (m, 4H), 7.25 – 7.15 (m, 3H), 7.12 (s, 1H), 6.97 – 6.52 (m, 2H), 5.11 – 4.98 (m, 1H), 4.21 (s, 2H), 4.14 – 3.99 (m, 1H), 3.83 – 3.70 (m, 2H), 3.68 – 3.58 (m, 2H), 3.58 – 3.49 (m, 2H), 3.02 – 2.93 (m, 2H), 2.92 – 2.81 (m, 15 5H), 2.78 – 2.57 (m, 2H), 2.30 – 2.12 (m, 2H), 2.11 – 1.84 (m, 10H). LCMS (ESI) m/z [M+H]+ =907.50. Preparation of 4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino} benzaldehyde (Intermediate A). 20 241 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 1: Preparation of 4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}benzaldehyde (Intermediate A). To a stirred solution of 4-aminobenzaldehyde (500 mg, 4.127 mmol, 1 equiv) and 4-bromo-2-(2,6- 5 dioxopiperidin-3-yl)isoindole-1,3-dione (1391.50 mg, 4.127 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added XPhos Pd G3 (698.75 mg, 0.825 mmol, 0.2 equiv), XPhos (787.08 mg, 1.651 mmol, 0.4 equiv) and Cs2CO3 (2689.63 mg, 8.254 mmol, 2 equiv). The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; 10 mobile phase, MeCN in Water 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in intermediate A (448 mg, 28.76%) as a yellow solid. LCMS (ESI) m/z [M+H]+ =378. The following compounds in TABLE 11 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 125 in Example 15 15. TABLE 11 242 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 16. Preparation of 1-(3-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(6-methoxyimidazo[1,2- a]pyridin-7-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1- yl)piperidin-1-yl)-2-oxoethoxy)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 5 A solution of tert-butyl 2-[3-(2,4-dioxo-1,3-diazinan-1-yl)-2-methylphenoxy]acetate (70 mg, 0.209 mmol, 1 10 equiv) in HCl in 1,4-dioxane (4.0 M) (3 mL) was stirred at room temperature for 3h. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. This resulted in 3-(2,4-dioxo- 1,3-diazinan-1-yl)-2-methylphenoxyacetic acid (50 mg, 85.83%) as a white solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 279. 243 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 2: Preparation of 1-{3-[2-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{6-methoxyimidazo[1,2-a]pyridin-7-yl}- 3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-1-yl)-2-oxoethoxy]-2- methylphenyl}-1,3-diazinane-2,4-dione (Compound 142). 5 To a stirred solution of 3-(2,4-dioxo-1,3-diazinan-1-yl)-2-methylphenoxyacetic acid (20 mg, 0.072 mmol, 1 equiv) and 1-{3-[7-(difluoromethyl)-6-{6-methoxyimidazo[1,2-a]pyridin-7-yl}-3,4-dihydro-2H-quinolin-1-yl]- 1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (41.38 mg, 0.072 mmol, 1 equiv) in DMF (1 mL) was added TCFH (30.25 mg, 0.108 mmol, 1.5 equiv) and 1-methyl-1H-imidazole (17.70 mg, 0.216 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred at room 10 temperature for overnight. The mixture solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 00% to 50% gradient in 30 min; detector, UV 254 nm. To afford compound 142 (13.4 mg, 22.30%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.53 (s, 1H), 7.30 (s, 1H), 7.16 (t, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.87 (dd, J = 8.3, 4.4 Hz, 2H), 6.79 (d, J = 6.8 Hz, 1H), 6.53 (d, 15 J = 4.4 Hz, 1H), 4.94 – 4.89 (m, 2H), 4.42 (d, J = 15.0 Hz, 2H), 4.21 (d, J = 10.3 Hz, 2H), 4.01 (s, 1H), 3.70 (d, J = 2.5 Hz, 7H), 3.61 (s, 3H), 3.51 (s, 2H), 2.92 – 2.82 (m, 4H), 2.78 (s, 2H), 2.74 (s, 1H), 2.07 (d, J = 18.0 Hz, 2H), 2.02 (s, 3H), 2.00 (s, 5H), 1.80 (s, 1H). LCMS (ESI) m/z: [M+H]+ = 836.45. The following compounds in TABLE 12 were prepared using standard chemical manipulations and 20 procedures that are the same or similar to those used for the preparation of Compound 142 in Example TABLE 12 244 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 245 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 246 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 ), . . (m, 6-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(6- 4H), 3.64 – 3.55 (m, methylimidazo[1,2-a]pyridin-7-yl)-3,4-dihydroquinolin- 2H), 3.26 – 3.14 (m, 1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1- 1H), 2.97 – 2.72 (m, yl)piperidin-1-yl)-2-oxoethyl)-2-(2,6-dioxopiperidin-3-yl)- 6H), 2.68 – 2.54 (m, 6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione 2H), 2.15 – 1.88 (m, 12H), 1.87 – 1.72 (m, 1H). 1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.62 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 1.6 Hz, 3H), 7.33 (s, 1H), 232 984.40 7.19 (s, 1H), 6.92 – 6.47 (m, 2H), 5.14 (dd, J = 12.6, 5.4 Hz, 1H), 4.72 (s, 4H), 4.56 – 4.36 (m, 4H), 4.23 (d, J = 15.8 Hz, 1H), 4.02 (d, J = 15.4 247 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 17. Preparation of 3-[4-(4-{[4-(5-acetyl-3-{[3-(difluoromethyl)-4-{6-methoxyimidazo[1,2- a]pyridin-7-yl}phenyl](methyl)amino}-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl]methyl}piperidin-1-yl)phenyl]piperidine-2,6-dione). (Compound 224). 5 Step 1: tert-butyl 4-(5-acetyl-3-{[4-chloro-3-(difluoromethyl)phenyl]amino}-4H,6H,7H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 2). 248 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred solution of tert-butyl 4-{5-acetyl-3-iodo-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1- carboxylate (4 g, 8.433 mmol, 1 equiv) and intermediate 7 (1.50 g, 8.433 mmol, 1 equiv) in 1,4-dioxane (40 mL) was added BrettPhos Pd G3 (1.53 g, 1.687 mmol, 0.2 equiv) and dicyclohexyl[3,6-dimethoxy-2',4',6'- tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (1.81 g, 3.373 mmol, 0.4 equiv) and Cs2CO3 (8.24 g, 25.299 5 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford intermediate 2 (1.8 g, 40.73%) as a white solid. LCMS (ESI) m/z: [M+H]+ = 524. 10 Step 2: tert-butyl 4-(5-acetyl-3-{[4-chloro-3-(difluoromethyl)phenyl](methyl)amino}-4H,6H,7H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 3). To a stirred solution of intermediate 2 (1.8 g, 3.435 mmol, 1 equiv) and NaH (164.87 mg, 6.870 mmol, 2 equiv) in DMF (10 mL) was added MeI (1.46 g, 10.305 mmol, 3.00 equiv) at 0°C. The resulting mixture 15 was stirred at room temperature for 2h. The reaction was quenched with water (1 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford tert-butyl intermediate 3 (1.31 g, 70.88%) as a white solid. LCMS (ESI) m/z: [M+H]+ = 538. 20 Step 3: 4-({5-acetyl-1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-3- yl}(methyl)amino)-2-(difluoromethyl)phenylboronic acid (Intermediate 4). To a stirred mixture of intermediate 3 (1.3 g, 2.232 mmol, 1 equiv) and bis(pinacolato)diboron (1.13 g, 4.464 mmol, 2 equiv) in 1,4-dioxane (10 mL) was added XPhos Pd G3 (188.91 mg, 0.223 mmol, 0.1 equiv) 25 and AcOK (657.10 mg, 6.696 mmol, 3 equiv). The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford intermediate 4 (698 mg, 57.14%) as a white solid. LCMS (ESI) m/z: [M+H]+ = 548. 249 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred mixture of intermediate 4 (690 mg, 1.260 mmol, 1 equiv) and intermediate 8 (276.21 mg, 5 1.512 mmol, 1.2 equiv) in 1,4-dioxane (12 mL) and H2O (1 mL) was added XPhos Pd G3 (106.69 mg, 0.126 mmol, 0.1 equiv) and K3PO4 (535.11 mg, 2.520 mmol, 2 equiv). The resulting mixture was stirred at 80°C for 8h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford intermediate 5 (481 mg, 58.73%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+ = 650. 10 To a stirred mixture of intermediate 5 (470 mg, 0.724 mmol, 1 equiv) in DCM (4.5 mL) was added TFA 15 (1.5 mL). The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford intermediate 6 (351 mg, 88.15%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 550. 20 250 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 To a solution of Intermediate 1 (40 mg, 0.073 mmol, 1 equiv) and 1-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidine-4-carbaldehyde (28.42 mg, 0.095 mmol, 1.3 equiv) in DMF (1 mL) was added HOAc (8.74 mg, 0.146 mmol, 2 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30min. To the above mixture was added STAB (30.85 mg, 0.146 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for additional 1h. The 10 mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 10%B to 18%B in 10min; Wave Length: 254nm/220 nm; RT1(min): 7.82) to afford to afford compound 224 (20 mg, 32.23%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.31 (s, 1H), 8.15 (s, 1H, FA), 7.89 (s, 1H), 7.54 (s, 1H), 7.31 (s, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.11 – 7.02 (m, 3H), 7.01 – 6.94 15 (m, 1H), 6.92 – 6.86 (m, 2H), 6.65 (t, J = 55.1 Hz, 1H), 4.18 (s, 2H), 4.13 – 3.97 (m, 1H), 3.79 – 3.72 (m, 4H), 3.72 – 3.60 (m, 3H), 3.08 – 2.95 (m, 2H), 2.92 – 2.80 (m, 1H), 2.79 – 2.72 (m, 1H), 2.71 – 2.55 (m, 3H), 2.47 – 2.39 (m, 2H), 2.30 (d, J = 6.9 Hz, 2H), 2.26 – 2.12 (m, 3H), 2.12 – 1.96 (m, 7H), 1.95 – 1.76 (m, 4H), 1.76 – 1.62 (m, 1H), 1.36 – 1.15 (m, 3H).. LCMS (ESI) m/z: [M+H]+ = 834.55. 20 The following compounds in TABLE 13 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 224 in Example 17. TABLE 13 251 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 252 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 18. Preparation of 6-(((1r,4r)-4-(5-acetyl-3-(6-(6-methoxyimidazo[1,2-a]pyridin-7-yl)-3,4- dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)methyl)-2- (2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dionee (Compound 190). 5 Step 1: 3-(1,3-dioxo-6-{[(1r,4r)-4-[5-acetyl-3-(6-{6-methoxyimidazo[1,2-a]pyridin-7-yl}-3,4-dihydro-2H- quinolin-1-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]cyclohexyl]methyl}-5H,7H-pyrrolo[3,4-f]isoindol-2- yl)piperidine-2,6-dione To a stirred solution of (1r,4r)-4-[5-acetyl-3-(6-{6-methoxyimidazo[1,2-a]pyridin-7-yl}-3,4-dihydro-2H- 10 quinolin-1-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl]cyclohexane-1-carbaldehyde (100 mg, 0.181 mmol, 1 equiv) and 3-[1-oxo-5-(piperazin-1-yl)-3H-isoindol-2-yl]piperidine-2,6-dione (54.07 mg, 0.181 mmol, 1 equiv) in DMF (1 mL) was added STAB (76.70 mg, 0.362 mmol, 2 equiv) and AcOH (1.09 mg, 0.018 mmol, 0.1 equiv). The resulting mixture was stirred at 25°C for 1h. The mixture was purified by Prep- HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: 15 Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): isocratic 7% B to 18% B in 10min; Wave Length: 254 nm/220 nm; RT1(min): 11.73) to afford compound 190 (11.2 mg, 7.02%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.28 (s, 1H), 7.85 – 7.75 (m, 3H), 7.48 (s, 1H), 7.35 (s, 1H), 7.24 (d, J = 2.2 Hz, 1H), 7.19 – 7.09 (m, 1H), 6.53 – 6.39 (m, 1H), 5.18 - 5.09 (m, 1H), 4.17 (d, J = 5.7 Hz, 2H), 4.08 – 3.91 (m, 5H), 3.83 – 3.74 (m, 4H), 3.71 (t, J = 5.6 Hz, 1H), 3.62 – 3.55 (m, 20 2H), 2.96 – 2.80 (m, 4H), 2.76 – 2.66 (m, 1H), 2.64 – 2.53 (m, 4H), 2.13 – 2.04 (m, 3H), 2.03 – 1.77 (m, 9H), 1.65 – 1.51 (m, 1H), 1.20 – 1.04 (m, 2H). LCMS (ESI) m/z [M+H]+ =836.45. 253 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 The following compounds in TABLE 14 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 190 in Example 17. TABLE 14 254 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 255 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 256 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 257 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 19. Preparation of 3-{5-[3-(4-{5-acetyl-3-[7-(difluoromethyl)-6-{6-methoxyimidazo[1,2- 5 258 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 1: Preparation of methyl 3-{6-[4-(dimethoxymethyl)piperidin-1-yl]-1-oxo-3H-isoindol-2-yl}piperidine- 2,6-dione (Intermediate 2). To a stirred mixture of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (300 mg, 5 0.887 mmol, 1 equiv) and trimethyl(prop-2-yn-1-yloxy)silane (227.55 mg, 1.774 mmol, 2 equiv) in DMF (5 mL) was added CuI (16.90 mg, 0.089 mmol, 0.1 equiv), Cs2CO3 (578.10 mg, 1.774 mmol, 2 equiv) and dichlorobis(triphenylphosphine)palladium(II) (62.27 mg, 0.089 mmol, 0.1 equiv) in portions at room temperature. The resulting mixture was stirred at 80°C for 2h under argon atmosphere. The mixture was diluted with H2O (30 mL), extracted with EtOAc (3 x 10 mL). The combined organic layers were washed 10 with brine (1 x 10 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 40 min; detector, UV 254 nm. This resulted in Intermediate 2 (114 mg, 41.01%) as a white solid. LCMS (ESI) m/z: [M+H]+ = 314. 15 Step2: Preparation of 1-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl] piperidine-4-carbaldehyde (Intermediate 3). To a stirred mixture of Intermediate 2 (100 mg, 0.319 mmol, 1 equiv) in DMSO (1.2 mL) was added 20 IBX (178.75 mg, 0.638 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 2h. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 100% gradient in 40 min; detector, UV 254 nm. This resulted in Intermediate 3 (85 mg, 85.55%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 312. 25 259 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 To a stirred mixture of Intermediate 3 (36 mg, 0.116 mmol, 1 equiv) and 1-(3-(7-(difluoromethyl)-6-(6- methoxyimidazo[1,2-a]pyridin-7-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (79.89 mg, 0.139 mmol, 1.2 equiv) in methanol (1 mL) was added HOAc (20.83 mg, 0.348 mmol, 3 equiv) in portions at 0°C. The resulting mixture was stirred at 0°C for 30min. To the above mixture was added STAB (24.74 mg, 0.232 mmol, 2 equiv) in portions at 0°C. The 10 resulting mixture was stirred at room temperature for additional 2h. The resulting mixture was concentrated under reduced pressure. The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): isocratic 11% B to 23% B in10min; Wave Length: 254nm/220 nm; RT1(min): 8.03) to afford compound 165 (19.5 mg, 18.39%) as a 15 yellow solid.1H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.30 (s, 1H, FA salt), 7.89 (s, 1H), 7.53 (s, 1H), 7.33 – 7.25 (m, 2H), 7.21 – 7.08 (m, 2H), 6.99 (s, 1H), 6.91 – 6.82 (m, 1H), 6.75 – 6.29 (m, 1H), 5.39 (dd, J = 12.7, 5.4 Hz, 1H), 4.29 – 4.15 (m, 2H), 4.13 – 3.97 (m, 1H), 3.81 – 3.66 (m, 5H), 3.66 – 3.54 (m, 4H), 3.35 (s, 3H), 3.05 – 2.92 (m, 2H), 2.92 – 2.81 (m, 4H), 2.80 – 2.70 (m, 2H), 2.70 – 2.63 (m, 1H), 2.62 – 2.58 (m, 1H), 2.46 – 2.33 (m, 2H), 2.13 – 2.06 (m, 2H), 2.05 – 1.95 (m, 5H), 1.95 – 1.83 (m, 2H). LCMS 20 (ESI) m/z: [M+H]+ = 871.45. The following compounds in TABLE 15 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 165 in Example 19. 25 TABLE 15 260 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 261 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 262 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 263 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 264 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 265 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 20. Preparation of 3-(5-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(6-methoxyimidazo[1,2- a]pyridin-7-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1- yl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 141). 5 Step 1: Preparation of Preparation of 3-(5-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(6-methoxyimidazo[1,2- a]pyridin-7-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 141). . 266 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred mixture of 1-{3-[7-(difluoromethyl)-6-{6-methoxyimidazo[1,2-a]pyridin-7-yl}-3,4-dihydro-2H- quinolin-1-yl]-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (30 mg, 0.052 mmol, 1 5 equiv) and 3-(5-bromo-6-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (17.7 mg, 0.052 mmol, 1 equiv) in 1, 4-dioxane (2 mL) was added Cs2CO3 (33.9 mg, 0.104 mmol, 2 equiv) and 3-chloropyridine; {1,3- bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloropalladium (7.6 mg, 0.008 mmol, 0.15 equiv). The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture solution was purified directly by Prep-HPLC with the 10 following conditions (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 17%B to 27%B in10min; Wave Length: 254nm/220 nm; RT1(min): 10.73) to afford compound 141 (10.9 mg, 25.02%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.28 (s, 1H), 7.87 (s, 1H), 7.52 (s, 1H), 7.40 (d, J = 11.7 Hz, 1H), 7.33 – 7.24 (m, 2H), 7.00 (s, 1H), 6.87 (s, 1H), 6.53 (t, J = 55.3 Hz, 1H), 5.05 (dd, J = 13.1, 5.2 Hz, 1H), 15 4.45 – 4.20 (m, 5H), 3.86 – 3.71 (m, 5H), 3.70 – 3.59 (m, 4H), 3.11 – 2.99 (m, 2H), 2.97 – 2.78 (m, 5H), 2.77 – 2.58 (m, 1H), 2.44 – 2.32 (m, 1H), 2.31 – 2.13 (m, 2H), 2.12 – 1.98 (m, 8H). LCMS (ESI) m/z: [M+H]+ = 836.50. The following compounds in TABLE 16 were prepared using standard chemical manipulations and 20 procedures that are the same or similar to those used for the preparation of Compound 141 in Example 20. TABLE 16 267 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 268 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 269 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 270 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 271 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 272 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 273 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 274 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 275 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 276 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 277 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 278 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 279 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 280 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 281 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 282 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 283 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 284 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 285 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 286 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 287 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 288 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 289 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 290 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 291 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 292 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 293 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 294 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 295 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 21. Preparation of 6-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(7-methyl-7H-pyrrolo[2,3- c]pyridazin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1- 296 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 yl)piperidin-1-yl)-2-oxoethyl)-2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole- 1,3(2H,5H)-di 5 Step 1: Preparation of 3-chloro-5H,6H,7H-pyrrolo[2,3-c]pyridazine (Intermediate 2). To a stirred solution of but-3-yn-1-amine hydrochloride (10 g, 94.724 mmol, 1 equiv) and dichloro- 1,2,4,5-tetrazine (14.30 g, 94.724 mmol, 1 equiv) in THF (150 mL) was added DIEA (49.50 mL, 284.172 mmol, 3.00 equiv) dropwise at 0°C under argon atmosphere. The resulting mixture was stirred for 2h at 10 80°C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 0% to 40% gradient in 30 min; detector, UV 254 nm. This resulted in intermediate 2 (7 g, 85%) as an orange solid. LCMS (ESI) m/z [M+H]+ =156. 297 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 2: Preparation of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (Intermediate 3). A mixture of intermediate 2 (500 mg, 3.214 mmol, 1 equiv) and MnO2 (1.68 g, 19.284 mmol, 6 equiv) in toluene (5 mL) was stirred at 60°C for 3h. The resulting mixture was filtered, the filter cake was washed 5 with MeOH (3 x 3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 00% to 50% gradient in 20 min; detector, UV 254 nm. to afford intermediate 3 (340 mg, 89.16%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 154. 10 Step 3: Preparation of 3-chloro-7-methyl-7H-pyrrolo[2,3-c]pyridazine (Intermediate 4). To a solution of KOH (367 mg, 6.568 mmol, 3 equiv) in DMF (2 mL) was treated with intermediate 3 (335 mg, 2.189 mmol, 1 equiv) for 1h at room temperature under nitrogen atmosphere followed by the addition of CH3I (310 mg, 2.189 mmol, 1.00 equiv) dropwise at room temperature. The resulting mixture 15 was stirred for overnight at room temperature. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in intermediate 4 (286 mg, 49.45%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 168. 20 Step 4: Preparation of tert-butyl 4-(5-acetyl-3-(7-(difluoromethyl)-6-(7-methyl-7H-pyrrolo [2,3-c]pyridazin-3- yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 5). To a stirred solution of intermediate 4 (35 mg, 0.209 mmol, 1 equiv) and intermediate 6 (205.36 mg, 25 0.314 mmol, 1.5 equiv) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added XPhos Pd G3 (17.68 mg, 0.021 mmol, 0.1 equiv), XPhos (19.91 mg, 0.042 mmol, 0.2 equiv) and Cs2CO3 (204.12 mg, 0.627 mmol, 3 equiv) in portions. The resulting mixture was stirred for 1h at 80°C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, 298 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 eluted with CH2Cl2 / MeOH (20:1) to afford intermediate 5 (60 mg, 43.85%) as a yellow oil. LCMS (ESI) m/z: [M+H]+ = 661. Step 5: Preparation of 1-(3-(7-(difluoromethyl)-6-(7-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl) -3,4- 5 dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (Intermediate 6). To a solution of intermediate 5 (58 mg, 0.088 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) at room temperature. The resulting mixture was stirred for 1h at room temperature. The resulting mixture was 10 concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 00% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in intermediate 6 (30 mg, 60.96%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 561. 15 Step 6: Preparation of 6-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(7-methyl-7H-pyrrolo [2,3-c]pyridazin-3-yl)- 3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-2-oxoethyl)- 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (Compound 121). To a stirred solution of intermediate 6 (20 mg, 0.036 mmol, 1 equiv) and compound 126 (12.75 mg, 20 0.036 mmol, 1.00 equiv) in DMF (0.5 mL) was added TCFH (20.02 mg, 0.072 mmol, 2.00 equiv) and NMI (8.79 mg, 0.108 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2h. The mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Fluoro-Phenyl Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10%B to 20% B in 10min; Wave Length: 254nm/220 nm; RT1(min): 11.11) 25 to afford compound 121 (27 mg, 84.10%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 299 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 7.95 (d, J = 4.1 Hz, 1H), 7.88 (d, J = 3.4 Hz, 1H), 7.77 (s, 2H), 7.34 – 6.96 (m, 2H), 6.91 (s, 1H), 6.57 (d, J = 3.3 Hz, 1H), 5.16 – 5.02 (m, 1H), 4.57 – 4.30 (m, 2H), 4.19 (s, 2H), 4.14 (s, 4H), 4.01 (s, 3H), 3.85 – 3.56 (m, 7H), 2.98 – 2.85 (m, 4H), 2.85 – 2.71 (m, 2H), 2.67 – 2.55 (m, 2H), 2.07 (s, 3H), 2.05 – 1.99 (m, 4H), 1.98 – 1.87 (m, 4H). LCMS (ESI) m/z: [M+H]+ = 900.55. 5 The following compounds in TABLE 17 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 121 in Example 21. TABLE 17 10 Example 22. Preparation of 1-(3-(4-((4-(5-acetyl-3-((4-(difluoromethyl)-5-(6-methoxyimidazo[1,2- a]pyridin-7-yl)pyridin-2-yl)(methyl)amino)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1- 300 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compo 5 Step 1: Preparation of tert-butyl 4-{3-bromopyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (Intermediate 2). To a stirred mixture of 3-bromo-1H-pyrazolo[4,3-c]pyridine (2.1 g, 10.100 mmol, 1 equiv) and tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (3.1 g, 11.110 mmol, 1.1 equiv) in DMF (20 mL) was 10 added Cs2CO3 (6.58 g, 20.200 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at 60°C for 2h. Desired product could be detected by LCMS. The mixture was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in intermediate 2 (1.3 g, 33.76%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 381/383. 15 301 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 2: Preparation of tert-butyl 4-(3-{[5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino}pyrazolo[4,3- c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 3). To a stirred mixture of intermediate 2 (1.3 g, 3.410 mmol, 1 equiv) and 5-chloro-4-(difluoromethyl)-N- 5 methylpyridin-2-amine (656.6 mg, 3.410 mmol, 1 equiv) in 1,4-dioxane (15 mL) was added XantPhos Pd G4 (492.2 mg, 0.511 mmol, 0.15 equiv), XantPhos (295.9 mg, 0.511 mmol, 0.15 equiv) and t-BuONa (655.3 mg, 6.820 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (50 mL), extracted with EtOAc (3 x 200 mL). The combined organic layers were washed 10 with water (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in intermediate 3 (800 mg, 47.60%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 493. 15 Step 3: Preparation of tert-butyl 4-(3-{[5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino}-4H,5H,6H,7H- pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 4). To a stirred mixture of intermediate 3 (800.9 mg, 1.623 mmol, 1 equiv) and KI (134.7 mg, 0.811 mmol, 0.5 20 equiv) in HCOOH (14 mL) and TEA (10 mL) was added Pentamethylcyclopentadienylrhodium(III) chloride dimer (100.3 mg, 0.162 mmol, 0.1 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for 1h. Desired product could be detected by LCMS. The reaction was quenched by the addition of sat. sodium hyposulfite (aq.) (100mL) at 0°C. The aqueous layer was extracted with EtOAc (3 x 302 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 100 mL). The resulting mixture was concentrated under reduced pressure. This resulted in intermediate 4 (760 mg, 94.23%) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 497. 5 Step 4: Preparation of tert-butyl 4-(5-acetyl-3-{[5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino}- 4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 5). To a stirred mixture of intermediate 4 (750.2 mg, 1.509 mmol, 1 equiv) and Acetic anhydride (308.1 mg, 3.018 mmol, 2 equiv) in DCM (10 mL) was added DIEA (390.0 mg, 3.018 mmol, 2 equiv) in portions 10 at room temperature. The resulting mixture was stirred at room temperature for 2h. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in intermediate 5 (710 mg, 87.29%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ =539. 15 To a stirred mixture of intermediate 5 (690.5 mg, 2.041 mmol, 1 equiv) and 2-(5,5-dimethyl-1,3,2- 20 dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (460.9 mg, 2.041 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added XPhos Pd G3 (259.1 mg, 0.306 mmol, 0.15 equiv) and Cs2CO3 (1329.8 mg, 4.082 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined 25 organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash 303 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in intermediate 6 (576 mg, 62.55%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 549. 5 Step 6: Preparation of tert-butyl 4-(5-acetyl-3-{[4-(difluoromethyl)-5-{6-methoxyimidazo[1,2-a]pyridin-7- yl}pyridin-2-yl](methyl)amino}-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 7). To a stirred mixture of intermediate 6 (400.1 mg, 0.729 mmol, 1 equiv) and 7-chloro-6- 10 methoxyimidazo[1,2-a]pyridine (133.2 mg, 0.729 mmol, 1 equiv) in and 1,4-ioxane (10 mL) and H2O (2 mL) was added XPhos Pd G3 (92.6 mg, 0.109 mmol, 0.15 equiv) and K3PO4 (309.6 mg, 1.458 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (60 mL), extracted with EtOAc (3 x100 mL). The combined organic layers were washed 15 with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 25 min; detector, UV 254 nm. This resulted in intermediate 7 (280 mg, 58.99%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 651. 20 A mixture of intermediate 7 (258.2 mg, 0.396 mmol, 1 equiv) in TFA (1 mL) and DCM (10 mL) was 25 stirred at room temperature for 2h. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in Water (0.1% TFA), 10% to 50% gradient in 15 min; detector, UV 254 nm. This resulted in intermediate 8 (200 mg, 91.61%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 551. 30 304 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 To a stirred mixture of intermediate 2 (50.0 mg, 0.159 mmol, 1 equiv) and 1-(3-{[4-(difluoromethyl)-5- {6-methoxyimidazo[1,2-a]pyridin-7-yl}pyridin-2-yl](methyl)amino}-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-5-yl)ethanone (87.3 mg, 0.159 mmol, 1 equiv) in DMSO (2 mL) and AcOH (0.1 mL) was added STAB (67.2 mg, 0.318 mmol, 2 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2h. Desired product could be detected by LCMS. The mixture was purified 10 by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: MeOH--HPLC; Flow rate: 60 mL/min; Gradient (B%): 21% B to 31% B in10min; Wave Length: 254nm/220 nm; RT1(min): 10.57) to afford compound 160 (20.8 mg, 15.43%) as a white solid. LCMS (ESI) m/z: [M+H]+ = 850.35.1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.18 (t, J = 7.9 Hz, 1H), 7.01 (dd, J = 8.1, 1.3 Hz, 1H), 15 6.96 – 6.50 (m, 3H), 4.28 (s, 2H), 4.14 – 4.00 (m, 1H), 3.84 – 3.67 (m, 6H), 3.59 – 3.48 (m, 1H), 3.42 (s, 3H), 3.09 – 2.92 (m, 4H), 2.91 – 2.84 (m, 1H), 2.82 – 2.69 (m, 3H), 2.66 – 2.59 (m, 2H), 2.27 (d, J = 6.9 Hz, 2H), 2.20 – 1.98 (m, 10H), 1.93 – 1.78 (m, 4H), 1.66 (s, 1H), 1.39 – 1.26 (m, 2H). Preparation of 5-chloro-4-(difluoromethyl)-N-methylpyridin-2-amine (Intermediate A). 20 Step 1: Preparation of 2,5-dichloro-4-(difluoromethyl)pyridine (Intermediate 2). 25 A mixture of 2,5-dichloropyridine-4-carbaldehyde (5 g, 28.409 mmol, 1 equiv) in DCM (20 mL) was added DAST (9.16 g, 56.818 mmol, 2 equiv) dropwise at 0°C. The resulting mixture was stirred for 1h at 0°C. Desired product could be detected by LCMS. The reaction was quenched with ice water (50 mL) at 0°C. The aqueous layer was extracted with CH2Cl2 (3 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in intermediate 2 (4.2 g, 74.67%) as a 30 white oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 198. 305 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 2: Preparation of 5-chloro-4-(difluoromethyl)-N-methylpyridin-2-amine (Intermediate A). 5 To a stirred mixture of intermediate 2 (4 g, 20.203 mmol, 1 equiv) and methanamine, hydrochloride (2.73 g, 40.406 mmol, 2 equiv) in DMSO (20 mL) was added DIEA (5.22 g, 40.406 mmol, 2 equiv). The resulting mixture was stirred at 120°C for 1h. Desired product could be detected by LCMS. The mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (3 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel 10 column chromatography, eluted with PE / EA (5:1) to afford intermediate A (2.6 g, 66.82%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 193. Preparation of 1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-2-methylphenyl]piperidine-4-carbaldehyde (Intermediate 15 Step 1: Preparation of 1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-2-methylphenyl]piperidine-4-carbaldehyde (Intermediate B). 20 A mixture of 1-{3-[4-(hydroxymethyl)piperidin-1-yl]-2-methylphenyl}-1,3-diazinane-2,4-dione (50.0mg, 0.158 mmol, 1 equiv) and IBX (88.2 mg, 0.316 mmol, 2 equiv) in DMSO (2 mL) was stirred at room temperature for 2h. Desired product could be detected by LCMS. The crude product mixture of Intermediate B was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 316. 25 The following compounds in TABLE 18 were prepared using standard chemical manipulations and procedures that are the same or similar to those used for the preparation of Compound 160 in Example 22. 306 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 TABLE 18 307 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 308 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 309 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 310 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 23. Preparation of 1-(3-(3-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(6-methoxyimidazo[1,2- a]pyridin-7-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1- yl)piperidin-1-yl)prop-1-yn-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 213). 5 311 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred solution of 3-iodo-2-methylaniline (1 g, 4.291 mmol, 1 equiv) in toluene (10 mL) was added 3-butenoic acid (1.11 g, 12.873 mmol, 3 equiv). The resulting mixture was stirred at 110°C for 5 overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford intermediate 2 (650 mg, 49.65%) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ =306. Step 2: 1-(3-iodo-2-methylphenyl)-1,3-diazinane-2,4-dione (Intermediate 3). 10 To a stirred solution of intermediate 2 (650 mg, 2.131 mmol, 1 equiv) in AcOH (10 mL) was added urea (640 mg, 10.652 mmol, 5 equiv). The resulting mixture was stirred at 120°C for overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford intermediate 3 (698 mg, 99.36%) as a yellow solid. LCMS (ESI) m/z [M+H]+ =331. 15 Step 3: Preparation of 1-(3-(3-hydroxyprop-1-yn-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 4). To a stirred solution of intermediate 3 (200 mg, 0.606 mmol, 1 equiv) and trimethyl(prop-2-yn-1- yloxy)silane (116.54 mg, 0.909 mmol, 1.5 equiv) in DMF (2 mL) was added Pd(PPh3)2Cl2 (85.05 mg, 20 0.121 mmol, 0.2 equiv) and CuI (11.54 mg, 0.061 mmol, 0.1 equiv), Cs2CO3 (592.17 mg, 1.818 mmol, 3 equiv). The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL), extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the 25 following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in intermediate 4 (120 mg, 76.69%) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 259. 312 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 4: Preparation of 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)propiolaldehyde (Intermediate 5). To a stirred solution of intermediate 4 (60 mg, 0.232 mmol, 1 equiv) in DMSO (1 mL) was added 5 IBX (130.10 mg, 0.464 mmol, 2 equiv). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. Na2S2O3 (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the 10 following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in intermediate 5 (43 mg, 72.23%) as a white solid. LCMS (ESI) m/z [M+H]+ = 257. 15 To a stirred solution of intermediate 3 (40 mg, 0.156 mmol, 1 equiv) and 1-{3-[7-(difluoromethyl)-6-{6- methoxyimidazo[1,2-a]pyridin-7-yl}-3,4-dihydro-2H-quinolin-1-yl]-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3- 20 c]pyridin-5-yl}ethanone (107.83 mg, 0.187 mmol, 1.2 equiv) in DMSO (2 mL) was added STAB (99.25 mg, 0.468 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 9%B to 20%B in10min; Wave Length: 254 nm/220 nm; RT1(min): 9.13) to afford 25 compound 213 (35.5 mg, 27.87%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.30 (s, 1H), 8.16 (s, FA salt, 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.34 – 7.21 (m, 3H), 6.99 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.53 (t, J = 55.2, 4.6 Hz, 1H), 4.22 (d, J = 9.1 Hz, 2H), 4.09 – 3.99 (m, 1H), 3.85 – 3.74 (m, 2H), 3.71 (s, 4H), 3.65 (s, 2H), 3.64 – 3.57 (m, 2H), 3.57 – 3.47 (m, 1H), 3.01 – 2.94 (m, 2H), 2.91 – 2.82 (m, 4H), 2.81 – 2.73 (m, 1H), 2.76 – 2.62 (m, 1H), 2.47 – 2.39 (m, 2H), 2.30 (s, 3H), 30 2.11 – 2.01 (m, 4H), 2.01 – 1.95 (m, 3H), 1.94 – 1.87 (m, 2H). LCMS (ESI) m/z [M+H]+ = 816.40. 313 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 24. Preparation of 1-(3-((4-(5-acetyl-3-((3-(difluoromethyl)-4-(6-methoxyimidazo[1,2- a]pyridin-7-yl)phenyl)(methyl)amino)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)methyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 204). 5 Step 1: Preparation of 1-(3-ethenyl-2-methylphenyl)-1,3-diazinane-2,4-dione (Intermediate 2). To a stirred solution of intermediate 1 (300 mg, 0.909 mmol, 1 equiv) and 2-ethenyl-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (209.95 mg, 1.364 mmol, 1.5 equiv) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Pd(dppf)Cl2 (66.49 mg, 0.091 mmol, 0.1 equiv) and Cs2CO3 (888.26 mg, 2.727 mmol, 3 equiv) at room 10 temperature. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 60% gradient in 15 min; detector, UV 254 nm. This resulted in intermediate 2 (120 mg, 57.35%) as a white solid. LCMS (ESI) m/z: [M+H]+ = 231. 15 Step 2: Preparation of 3-(2,4-dioxo-1,3-diazinan-1-yl)-2-methylbenzaldehyde (Intermediate 3). To a stirred solution of intermediate 2 (115 mg, 0.499 mmol, 1 equiv) and 2,6-lutidine (160.55 mg, 1.497 mmol, 3 equiv) in 1,4-dioxane (2 mL) and H2O (2 mL) was added NaIO4 (427.28 mg, 1.996 mmol, 4 equiv) 20 and Potassium osmate(VI) dihydrate (5.52 mg, 0.015 mmol, 0.03 equiv) at 0oC. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were dried over anhydrous 314 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in intermediate 3 (120 mg, crude) as a dark grey solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 233. 5 To a stirred solution of intermediate 4 (50 mg, 0.091 mmol, 1 equiv) and intermediate 3 (63.38 mg, 10 0.273 mmol, 3 equiv) in DMF (1 mL) was added AcOH (0.55 mg, 0.009 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added STAB (38.56 mg, 0.182 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for additional 2h. The mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile 15 Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 2%B to 28%B in 10 min; Wave Length: 254 nm/220 nm; RT1(min): 6.29) to afford compound 204 (14.8 mg, 21.24%) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.40 (s, 1H), 7.96 (s, 1H), 7.64 (d, J = 3.3 Hz, 1H), 7.44 – 7.34 (m, 2H), 7.32 – 7.27 (m, 2H), 7.25 – 7.17 (m, 1H), 7.08 – 7.03 (m, 1H), 7.01 – 6.92 (m, 1H), 6.67 (t, J = 54.9 Hz, 1H), 4.23 – 4.13 (m, 3H), 3.82 – 3.68 (m, 7H), 3.54 – 3.44 (m, 2H), 3.31 – 3.29 (m, 3H), 2.90 – 2.84 (m, 2H), 2.83 – 20 2.63 (m, 4H), 2.53 – 2.51 (m, 2H), 2.25 – 2.20 (m, 3H), 2.19 – 2.07 (m, 4H), 2.04 – 1.96 (m, 3H). LCMS (ESI) m/z: [M+H]+ = 766.45. 315 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 25. Preparation of 5-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(6-methoxyimidazo[1,2-a]pyridin- 7-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)- N-(2,6-dioxopiperidin-3-yl)-N-methylpicolinamide (Compound 229). 5 Step 1: Preparation of 3-(benzyl(methyl)amino)piperidine-2,6-dione (Intermediate 2). To a stirred solution of 3-bromopiperidine-2,6-dione (700 mg, 3.646 mmol, 1 equiv) in DMF (10 mL) was added dimethylbenzylamine (591.51 mg, 4.375 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (60 mL). The resulting mixture was 10 was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography, MeCN in Water (0.1% FA), 0% to 50% gradient in 30 min; detector, UV 254 nm). Pure fractions were evaporated to dryness to afford intermediate 2 (520 mg, 61.41%) as a blue solid. LCMS (ESI) m/z [M+H]+ =233. 15 316 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 2: Preparation of 3-(methylamino)piperidine-2,6-dione (Intermediate 3). To a stirred solution of intermediate 2 (510 mg, 2.196 mmol, 1 equiv) in EtOH (6 mL) was added Pd/C (52 mg). The resulting mixture was stirred at room temperature for 2h under 30 psi of hydrogen pressure. 5 The resulting mixture was filtered, the filter cake was washed with EtOH (3 x 50 mL). After filtration, the filtrate was concentrated under reduced pressure to afford intermediate 3 (270 mg, crude) as a blue oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ =143. 10 Step 3: Preparation of 5-bromo-N-(2,6-dioxopiperidin-3-yl)-N-methylpicolinamide (Intermediate 4). To a stirred solution of intermediate 3 (250 mg, 1.759 mmol, 1 equiv) and 5-bromopyridine-2- carboxylic acid (355.25 mg, 1.759 mmol, 1 equiv) in DMA (3 mL) was added HATU (1003.03 mg, 2.638 mmol, 1.50 equiv) and DIEA (681.88 mg, 5.277 mmol, 3.00 equiv). The resulting mixture was stirred at 15 room temperature for 2h. The mixture was purified by flash C18-flash chromatography, MeCN in Water (0.1% TFA), 0% to 50% gradient in 30 min; detector, UV 254 nm. Pure fractions were evaporated to dryness to afford intermediate 4 (201 mg, 35.04%) as an off-white solid. LCMS (ESI) m/z [M+H]+ =326/328. 20 317 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred solution of intermediate 4 (40.79 mg, 0.125 mmol, 1.2 equiv) and 1-(3-(7-(difluoromethyl)- 6-(6-methoxyimidazo[1,2-a]pyridin-7-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (60 mg, 0.104 mmol, 1 equiv) in DMF (1 mL) was added Pd- PEPPSI-IPentCl 2-methylpyridine (10.15 mg, 0.010 mmol, 0.1 equiv) and Cs2CO3 (67.92 mg, 0.208 5 mmol, 2 equiv). The resulting mixture was stirred at 100oC for 1h under nitrogen atmosphere. Without any additional work-up, the resulting mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 16%B to 25%B in10min; Wave Length: 254nm/220 nm; RT1(min): 8.73) to afford compound 229 (20.0 mg, 23.38 %) as a light yellow solid.1H NMR (400 MHz, 10 DMSO-d6) δ 10.90 – 10.78 (m, 1H), 8.36 – 8.26 (m, 2H), 7.88 (s, 1H), 7.60 – 7.48 (m, 2H), 7.48 – 7.39 (m, 1H), 7.28 (s, 1H), 6.98 (s, 1H), 6.86 – 6.78 (m, 1H), 6.68 – 6.34 (m, 1H), 5.51 – 5.03 (m, 1H), 4.45 – 4.31 (m, 1H), 4.28 – 4.19 (m, 2H), 4.11 – 3.98 (m, 2H), 3.88 – 3.63 (m, 5H), 3.64 – 3.53 (m, 2H), 3.16 – 2.98 (m, 4H), 2.95 – 2.89 (m, 1H), 2.87 – 2.70 (m, 5H), 2.61 – 2.55 (m, 1H), 2.44 – 2.35 (m, 1H), 2.24 – 1.99 (m, 6H), 1.99 – 1.82 (m, 4H). LCMS (ESI) m/z [M+H]+ =821.45. 15 Example 26. Preparation of 3-(5-(4-(5-acetyl-3-(7-fluoro-6-(6-methoxyimidazo[1,2-a]pyridin-7-yl)-4- methyl-3,4-dihydroquinoxalin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 201). 20 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Step 1: 2-((5-chloro-4-fluoro-2-nitrophenyl)(methyl)amino)ethan-1-ol (Intermediate 2). To a stirred mixture of 1-chloro-2,5-difluoro-4-nitrobenzene (2 g, 10.334 mmol, 1 5 equiv) and methylethanolamine (776.22 mg, 10.334 mmol, 1 equiv) in DMF (25 mL) was added K2CO3 (2.86 g, 20.668 mmol, 2 equiv). The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with saturated brine (200 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by flash C18-flash chromatography, 10 elution gradient 0 to 100% MeCN in water (containing 0.05% TFA). Pure fractions were evaporated to dryness to afford intermediate 2 (2.2 g, 79.39%) as a red oil.LCMS (ESI) m/z [M+H+ =249.04 Step 2: 2-((5-chloro-4-fluoro-2-nitrophenyl)(methyl)amino)ethyl methanesulfonate(Intermediate 3). To a stirred solution of intermediate 2 (2.1 g, 8.446 mmol, 1 equiv), MsCl (1.45 g, 12.669 mmol, 1.5 15 equiv) and TEA (2.56 g, 25.338 mmol, 3 equiv) in DCM (25 mL) was added DMAP (103.18 mg, 0.845 mmol, 0.1 equiv). The resulting mixture was stirred for 1h at room temperature. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (120 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford intermediate 3 (2.9 g, crude )as a red oil that was used directly without further 20 purification. LCMS (ESI) m/z: [M+H]+ = 327.01. Step 3: 7-chloro-6-fluoro-1-methyl-1,2,3,4-tetrahydroquinoxaline (Intermediate 4). To a stirred mixture of intermediate 3 (2.9 g, 8.876 mmol, 1 equiv) and Fe (34.19 mg, 0.610 mmol, 10 equiv) in H2O (4 mL) and EtOH (36 mL) was added con.HCl (1 mL, 0.006 mmol). The resulting mixture was 25 stirred for 2h at 90°C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford intermediate 4 (498 mg, 56.3%purity) as a black 30 solid. LCMS (ESI) m/z [M+H+ =201.05. 319 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a solution of intermediate 4 (1 g, 2.623 mmol, 1 equiv) and 7-chloro-6-fluoro-1-methyl-3,4-dihydro- 5 2H-quinoxaline (526.2 mg, 2.623 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added XPhos Pd G3 (222.0 mg, 0.262 mmol, 0.1 equiv) and XPhos (250.0 mg, 0.525 mmol, 0.2 equiv) and t-BuONa (504.1 mg, 5.246 mmol, 2 equiv) under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water 10 (0.1% TFA), 45% to 80% gradient in 25 min; detector, UV 254 nm) to afford intermediate 5 (837 mg, 63.82%) as a brown solid. LCMS (ESI) m/z: [M+H]+ = 501. 15 To a solution of intermediate 5 (827.1 mg, 1.651 mmol, 1 equiv) in EA (10 mL) was added PtO2 (374.8 mg, 1.651 mmol, 1 equiv) at room temperature. The resulting mixture was stirred at 20°C for for 5h under 30 psi of hydrogen pressure. The mixture solution was filtered through a Celite pad and concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography with the 20 following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 80% gradient in 25 min; detector, UV 254 nm) to afford intermediate 6 (625 mg, 75.11%) as a light yellow solid. LCMS (ESI) m/z [M+H]+ =505. 320 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a solution of intermediate 6 (500 mg, 0.990 mmol, 1 equiv) and DIEA (255.9 mg, 1.980 mmol, 2 equiv) 5 in DCM (10 mL) was added Ac2O (59 mg, 0.99 mmol, 1 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 80% gradient in 25 min; detector, UV 254 nm) to afford intermediate 7 (357 mg, 65.91%) as a brown solid. 10 LCMS (ESI) m/z: [M+H]+ = 547. Step 7: Preparation of tert-butyl 4-(5-acetyl-3-(7-fluoro-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-3,4-dihydroquinoxalin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1- carboxylate (Intermediate 8). 15 To a stirred solution of intermediate 7 (300 mg, 0.548 mmol, 1 equiv) and bis(pinacolato)diboron (278.5 mg, 1.096 mmol, 2 equiv) in 1,4-dioxane (1 mL) was added Pd-170 (36.9 mg, 0.055 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was 20 concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford intermediate 8 (200 mg, 65.54%) as an off-white solid. LCMS (ESI) m/z: [M+H]+ = 639. Step 8: Preparation of tert-butyl 4-(5-acetyl-3-(7-fluoro-6-(6-methoxyimidazo[1,2-a]pyridin-7-yl)-4-methyl- 25 3,4-dihydroquinoxalin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (Intermediate 9). 321 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a solution of intermediate 8 (168.3 mg, 0.263 mmol, 1 equiv) and 7-chloro-6-methoxyimidazo[1,2- a]pyridine (48.0 mg, 0.263 mmol, 1 equiv) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Pd(dtbpf)Cl2 (17.1 mg, 0.026 mmol, 0.1 equiv) and K3PO4 (111.6 mg, 0.526 mmol, 2 equiv) under nitrogen atmosphere. 5 The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The mixture was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 80% gradient in 25 min; detector, UV 254 nm) to afford intermediate 9 (95 mg, 55.10%) as a brown solid. LCMS (ESI) m/z: [M+H]+ = 659. 10 Step 9: Preparation of 1-(3-(7-fluoro-6-(6-methoxyimidazo[1,2-a]pyridin-7-yl)-4-methyl-3,4- dihydroquinoxalin-1(2H)-yl)-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1- one (Intermediate 10). To a stirred solution of intermediate 9 (90 mg, 0.137 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 15 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 70% gradient in 20 min; detector, UV 254 and 220 nm. This resulted in intermediate 10 (75 mg, 98.10%) as an off-white solid. LCMS (ESI) m/z: [M+H]+ = 559. 20 Step 10: Preparation of 3-(5-(4-(5-acetyl-3-(7-fluoro-6-(6-methoxyimidazo[1,2-a]pyridin-7-yl)-4-methyl-3,4- dihydroquinoxalin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 201). 322 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 To a stirred solution of 10 (40 mg, 0.072 mmol, 1 equiv) and 3-(5-bromo-1-oxo-3H-isoindol-2- yl)piperidine-2,6-dione (23.1 mg, 0.072 mmol, 1 equiv) in DMF (2 mL) was added Cs2CO3 (46.6 mg, 0.144 mmol, 2 equiv) and Pd-PEPPSI-IPentCl 2-methylpyridine (7 mg, 0.0072 mmol, 0.1 equiv) under nitrogen 5 atmosphere. The resulting mixture was stirred at 100oC for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): isocratic 17%B to 28%B in 10min; Wave Length: 254nm/220 nm; RT1(min): 8.22) to afford compound 201 (11 mg, 10 19.18%) as a yellow solid.1H NMR (300 MHz, DMSO) δ 10.80 (s, 1H), 8.27 (s, 1H), 7.85 (s, 1H), 7.62 – 7.46 (m, 2H), 7.37 (s, 1H), 7.14 – 7.07 (m, 2H), 6.55 (d, J = 7.3 Hz, 1H), 6.22 (d, J = 12.8 Hz, 1H), 5.06 – 4.97 (m, 1H), 4.45 – 4.30 (m, 2H), 4.29 – 4.22 (m, 3H), 4.04 (d, J = 13.1 Hz, 2H), 3.78 – 3.69 (m, 7H), 3.32 – 3.27 (m, 2H), 3.12 – 3.04 (m, 2H), 2.92– 2.82 (m, 6H), 2.67 – 2.56 (m, 1H), 2.43 – 2.26 (m, 1H), 2.11 – 1.97 (m, 8H). LCMS (ESI) m/z [M+H]+ = 801.45. 15 Example 27. HeLa IF Degradation Assay Procedure: On day 0, HeLa cells were seeded in 30 μL phenol-free RPMI media supplemented with 10% FBS into each well of 384-well cell culture plates. The seeding density was 5000 cells/well. On day one, cells were treated with 90 nL DMSO or 90 nL of 3-fold serially DMSO-diluted compounds (10 points in 20 duplicates with 30 μM as final top dose). Subsequently plates were incubated for 24 hours in a standard tissue culture incubator. After the 24 hours incubation, medium was removed and cells were fixed with a solution of 4% paraformaldehyde for 20 minutes at room temperature. Subsequently, cells were washed three times with PBS-0.1% Tween20 and permeabilized with a 0.1%Triton X-100 solution for 20 minutes at room temperature. Cells were then washed three times with 25 PBS-0.1% Tween20 and incubated with blocking buffer (5% goat serum PBS-0.1% Tween20) for 1 hour at room temperature. Cells were washed three times with PBS-0.1% Tween20. Subsequently cells were incubated with primary antibody appropriately diluted in blocking buffer. Cells were incubated in primary antibody (either CREBBP or EP300 specific antibody) over night at 4℃. Cells were washed three times with PBS-0.1% Tween20. Cells were then incubated in secondary antibody conjugated with Alexa 488 30 fluorophore appropriately diluted in PBS-0.1% Tween20 for 1 hour at room temperature. A DAPI stain solution (0.1ug/ml) was added to stain the cell nuclei for 5 minutes at room temperature. Cells were washed three times with PBS-0.1% Tween20 and finally 80ul of PBS-only were added to the well. Cells were imaged with a high content imager at 20X magnification and fluorescence was quantified with the imager analyses software. 323 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Results: The Inhibition% was calculated using the following formula: %Inhibition = 100 x (1-fluorescence intensity / fluorescence intensity DMSO). The data was fit to a four parameter, non-linear curve fit to calculate DC50 (μM) values using Graphpad PRISM. DC50 and Dmax values are shown in Table 19. 5 TABLE 19. Degradation Results 324 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 325 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 326 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 327 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 328 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 Example 28: Example: U2OS IF Degradation Assay Procedure: A set of two CRISPR knock-in stable U2OS polyclonal cell lines, each with a HiBiT tag fused 5 to either CREBBP or EP300 were purchased from Promega. On day 0, cells were seeded in 30 μL phenol-free RPMI media supplemented with 10% FBS into each well of 384-well cell culture plates. The seeding density was 5000 cells/well. On day one, cells were treated with 90 nL DMSO or 90 nL of 3-fold serially DMSO-diluted compounds (10 points in duplicates with 30 μM as final top dose). Subsequently plates were incubated for 24 hours in a standard tissue culture incubator. After the 24 hours incubation, 10 medium was removed and cells were fixed with a solution of 4% paraformaldehyde for 20 minutes at room temperature. Subsequently, cells were washed three times with PBS-0.1% Tween20 and permeabilized with a 0.1%Triton X-100 solution for 20 minutes at room temperature. Cells were then washed three times with 15 PBS-0.1% Tween20 and incubated with blocking buffer (5% goat serum PBS-0.1% Tween20) for 1 hour at room temperature. Cells were washed three times with PBS-0.1% Tween20. Subsequently cells were incubated with primary antibody appropriately diluted in blocking buffer. Cells were incubated in primary antibody over night at 4℃. U2OS CREBBP HiBiT line was stained with a CREBBP specific primary antibody and U2OS EP300 HiBiT line was stained with a EP300 specific primary antibody. Cells were 20 washed three times with PBS-0.1% Tween20. Cells were then incubated in secondary antibody conjugated with Alexa 488 fluorophore appropriately diluted in PBS-0.1% Tween20 for 1 hour at room temperature. A DAPI stain solution (0.1ug/ml) was added to stain the cell nuclei for 5 minutes at room temperature. Cells were washed three times with PBS-0.1% Tween20 and finally 80ul of PBS-only were added to the well. Cells were imaged with a high content imager at 20X magnification and fluorescence 25 was quantified with the imager analyses software. Results: The Inhibition% was calculated using the following formula: %Inhibition = 100 x (1-fluorescence intensity / fluorescence intensity DMSO). The data was fit to a four parameter, non-linear curve fit to calculate DC50 (μM) values using Graphpad PRISM. DC50 and Dmax values are shown in Table 20. 30 TABLE 20. Degradation Results 329 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 330 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 331 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 332 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 333 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 334 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 ENUMERATED EMBODIMENTS E1. A compound having the structure of Formula I: A-L-B Formula I, wherein A is an EP300 binding moiety has the structure of Formula III: 5 Formula III wherein R1 is halo, C1-4 alkyl, wherein any C1-4 alkyl is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I,—C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—10 N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)— Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)— Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, or —N(Ra)—S(O)2—N(Ra)2; and R2 is C1-4alkyl, C2-4alkenyl, C2-4alkynyl, -C(O)—N(Rh)2, —S(O)—N(Rh)2, —S(O)2—N(Rh)2, — C(O)—Rh, —C(O)—O—Rh, —S(O)—Rh, or —S(O)2—Rh, wherein any C1-4 alkyl, C2-4 alkenyl, or C2-415 alkynyl is optionally substituted with one or more substituent groups independently selected from —F, — Cl, —Br, —I,—C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, — O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, — N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2— Ra, —N(Ra)—S(O)—N(Ra)2, or —N(Ra)—S(O)2—N(Ra)2; 20 each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; X1 is NRN, CH2, or O; and 25 RN is C1-C3 alkyl or H; B is a degradation moiety; and 335 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 L is a linker between the EP300 binding moiety and the degradation moiety. E2. The compound of embodiment 1, wherein R1 is C1-C4 alkyl optionally substituted with one or more F groups. 5 E3. The compound of embodiment 2, wherein R1 is difluroromethyl. E4. The compound of embodiment 1, wherein R2 has the structure: . 10 E5. The compound of embodiment 1, wherein X1 is CH2. E6. The compound of any one of embodiments 1 to 5, wherein the EP300 binding moiety has the structure: 15 . E7. The compound of any one of embodiments 1 to 6, wherein the degradation moiety is a ubiquitin ligase binding moiety. E8. The compound of embodiment 7, wherein the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel- Lindau (VHL) ligands, or derivatives or analogs thereof. 336 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 E9. The compound of any one of embodiments 1-8, wherein the degradation moiety comprises the structure of Formula AY: , Formula AY wherein each of RA1, RA2, RA3, and RA4 is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2- C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; or RA1 and RA2, RA2 and RA3, and/or RA3 and RA4, together with the carbon atoms to which each is attached, combine to form optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl; RA5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each of RA6 and RA7 is, independently, H or optionally substituted C1-C6 alkyl; or RA6 and RA7, together with the carbon atom to which each is bound, form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl; RA8 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; where one of RA1, RA2, RA3, and RA4 is A2, or a pharmaceutically acceptable salt thereof. E10. The compound of embodiment 9, wherein each RA1, RA2, RA3, and RA4 is, independently, A2, H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, hydroxyl, optionally substituted amino; or RA1 and RA2, RA2 and RA3, or RA3 and RA4, together with the carbon atoms to which each is attached, combine to form optionally substituted C2-C9 heterocyclyl. E11. The compound of embodiment 9, wherein RA5is H. E12. The compound of any one of embodiments 9 to 11, wherein Y1 is . E13. The compound of embodiment 12, wherein Y1 is . 337 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 E14. The compound of any one of embodiments 9 to 13, wherein the structure of Formula AY has the structure of Formula AY1: , Formula AY1 or a pharmaceutically acceptable salt thereof. E15. The compound of any one of embodiments 9 to 13, wherein the structure of Formula AY has the structure of Formula AY2: , Formula AY2 or a pharmaceutically acceptable salt thereof. E16. The compound of any one of embodiments 9 to 13, wherein the structure of Formula AY has the structure of Formula AY3: , Formula AY3 or a pharmaceutically acceptable salt thereof. E17. The compound of any one of embodiments 9 to 13, wherein the structure of Formula AY has the structure of Formula AY4: , Formula AY4 or a pharmaceutically acceptable salt thereof. 338 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 E18. The compound of any one of embodiments 9 to 17, wherein the structure of Formula AY is derivative or an analog thereof. E19. The compound of any one of embodiment 1-18, wherein L has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D)-(B Formula or a pharmaceutically acceptable salt thereof, wherein 5 A1 is a bond between the linker and the EP300 binding moiety; A2 is a bond between the degradation moiety and the linker; each of B1, B2, B3, and B4 is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C10 arylene, optionally substituted C6-C10 aryl C1-4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C3-C10 cycloalkylene, optionally substituted C2-C8 heterocyclylene, 10 optionally substituted C2-C8 heteroarylene, optionally substituted C6–12 arylene, O, S, S(O)2, or NRN; each RN is, independently, H, optionally substituted C1–C4 alkylene, optionally substituted C2–C4 alkenylene, optionally substituted C2–C4 alkynylene, optionally substituted C2–C6 heterocyclylene, optionally substituted C2–C6 heteroarylene, or optionally substituted C1–C7 heteroalkylene; each of C1 and C2 is, independently, carbonylene, thiocarbonylene, sulphonylene, or 15 phosphorylene; each of f, g, h, i, j, and k is, independently, 0 or 1; and D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C8 heterocyclylene, optionally substituted C2–C8 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or 20 optionally substituted C1–C10 heteroalkylene. E20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof, wherein each of B1, B2, B3, and B4 is, independently, optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2–C8 heteroarylene, or O. 25 E21. The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein B1 or B2 is optionally substituted C2-C8 heterocyclylene. 339 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 E22. The compound of embodiment 21, or a pharmaceutically acceptable salt thereof, wherein B1 or B2 of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, 5 E24. The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein . 10 E25. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein f is 0. E26. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein f is 1. 15 E27. The compound of any one of embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, wherein g is 0. E28. The compound of any one of embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, 20 wherein g is 1. E29. The compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, wherein h is 0. 25 E30. The compound of any one of embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, wherein h is 1. E31. The compound of any one of embodiments 1 to 30, or a pharmaceutically acceptable salt thereof, wherein i is 0. 30 E32. The compound of any one of embodiments 1 to 30, or a pharmaceutically acceptable salt thereof, wherein i is 1. E33. The compound of any one of embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, 35 wherein j is 0. 340 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 E34. The compound of any one of embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, wherein j is 1. E35. The compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, 5 wherein k is 0. E36. The compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein k is 1. 10 E37. The compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C8 heterocyclylene, optionally substituted C2–C8 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene. 15 E38. The compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C2-C8 heterocyclylene. E39. The compound of embodiment 38, wherein D is . 20 E40. The compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C2–C8 heteroarylene. E41. The compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, 25 wherein D is optionally substituted C1-C10 alkylene. E42. The compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C1-C10 heteroalkylene. 30 E43. The compound of any one of embodiments 1 to 42, or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of: 341 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 5 343 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 . E44. The compound of any one of embodiments 19 to 43, or a pharmaceutically acceptable salt 5 thereof, wherein the shortest chain of atoms connecting two valencies of the linker is 2 to 10 atoms long. E45. The compound of any one of embodiments 19 to 44, or a pharmaceutically acceptable salt thereof, wherein the shortest chain of atoms connecting two valencies of the linker is 6 atoms long. 10 E46. The compound of any one of embodiments 1 to 45, wherein the compound is any one of compounds 1 to 30 of Table 1A, or a pharmaceutically acceptable salt thereof. E47. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 46 and a pharmaceutically acceptable excipient. 15 E48. A method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of embodiments 1 to 46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 47. 20 E49. The method of embodiment 48, wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myeloma, skin, endometrial, esophageal, cervical, gastric, lymphoma, leukemia, esophogeal, stomach, lung cancer, or non-small cell lung cancer. 25 E50. The method of embodiment 48 or 49, wherein the cancer is metastatic. E51. The method of any one of embodiments 48 to 50, wherein the subject or cancer has a CBP loss of function mutation. 30 E52. The method of any one of embodiments 48 to 51, wherein the cancer is prostate cancer. 344 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 E53. The method of embodiment 52, wherein the cancer is castration-resistant prostate cancer (CRPC). E54. The method of embodiment 52, wherein the cancer is castration-sensitive prostate cancer. 5 E55. The method of embodiment 52, wherein the cancer is AR+ prostate cancer. E56. The method of any one of embodiments 48 to 51, wherein the cancer is lymphoma. 10 E57. The method of embodiment 56, wherein the lymphoma is Diffuse large B cell lymphoma (DLBCL). E58. The method of any one of embodiments 48 to 57, wherein the method further comprises administering to the subject an anticancer therapy. 15 E59. The method of embodiment 58, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof. OTHER EMBODIMENTS All publications, patents, and patent applications mentioned in this specification are incorporated 20 herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term. While the invention has been described in connection with specific embodiments thereof, it will be 25 understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. 30 Other embodiments are in the claims. 345

Claims

PATENT ATTORNEY DOCKET NO.: 51121-103WO2 What is claimed is: CLAIMS 1. A compound having the structure of Formula I: A-L-B Formula I, wherein A is an EP300 binding moiety has the structure of Formula III: Formula III wherein R1 is halo, C1-C4 alkyl, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; and R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; X1 is NRN, CH2, or O; and RN is C1-C3 alkyl or H; B is a degradation moiety; and L is a linker between the EP300 binding moiety and the degradation moiety. 2. The compound of claim 1, wherein R1 is C1-C4 alkyl optionally substituted with one or more F groups. 3. The compound of claim 2, wherein R1 is difluroromethyl. 346 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 4. The compound of claim 1, wherein R2 has the structure: . 5. The compound of claim 1, wherein X1 is CH2. 6. The compound of any one of claims 1 to 5, wherein the EP300 binding moiety has the structure: . 7. A compound having the structure of Formula I: A-L-B Formula I, wherein A is an EP300 binding moiety has the structure of Formula IIIa: Formula IIIa wherein X1’ is N or CR6; X2’ is N, or CR5; 347 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 R1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; and R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; R3 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, or optionally substituted C1-C4 alkyl C2-C9 heteroaryl, wherein each C1-C4 alkyl, C1-C4 alkoxy, C3-C10 carbocyclyl, C2-C9 heterocyclyl, C6-C10 aryl, or C2-C9 heteroaryl, C1-4 alkyl C2-C9 heterocyclyl, or C1-4 alkyl C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from O, oxo, halo, amino, hydroxyl, C1-C4 alkoxy, C1-C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl that is optionally substituted with one or more groups independently selected from C1-C3 alkyl, C3-C10 carbocyclyl, or halo; R4 is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo, or R5 and R4 of Formula (IIIa) taken together with the atoms to which they are attached form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups of Re; R5 is H, C1-C3 alkyl, or C1-C3 alkoxy, or R5 and R4 of Formula (IIIa) taken together with the atoms to which they are attached form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups of Re; R6 is H, halo, C1-C3 alkyl, or C1-C3 alkoxy; each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; each Re is, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, 348 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, C3-C12 carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-12 heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, in which the carbocyclyl and C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, ORg, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl; each Rg is, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and C1- C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg are taken together with the nitrogen to which they are attached to form a heterocyclyl (e.g. C3-C12 heterocyclyl) that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and each Rh is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; B is a degradation moiety; and L is a linker between the EP300 binding moiety and the degradation moiety. 8. The compound of claim 7, wherein the EP300 binding moiety has the structure of Formula IIIb: Formula IIIb wherein X3 is O, NRN2’ or CR7; RN2’ is C1-C3 alkyl or H; R1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, 349 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 N(Ra)C(O)—ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; and R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; R7 is H, halo, or C1-C3 alkyl; R3 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, or optionally substituted C1-C4 alkyl C2-C9 heteroaryl, wherein each C1-C4 alkyl, C1-C4 alkoxy, C3-C10 carbocyclyl, C2-C9 heterocyclyl, C6-C10 aryl, or C2-C9 heteroaryl, C1-C4 alkyl C2-C9 heterocyclyl, or C1-C4 alkyl C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C4 alkoxy, C1-C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl that is optionally substituted with one or more groups independently selected from C1-C3 alkyl, C3-C10 carbocyclyl, or halo; each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; each Rh is, independently, hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, or C2-5cycloalkyl, wherein each C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo. 9. The compound of claim 8, wherein R2 has the structure: . 10. The compound of claim 8, wherein R1 is H, halo, C1-C3 alkoxy, or C1-C4 alkyl optionally substituted with one or more substituent groups independently selected from F. 11. The compound of claim 8, wherein X3 is CH2, NCH3, or O. 350 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 12. The compound of any one of claims 8 to 11, wherein the EP300 binding moiety has the structure: . 13. The compound of claim 7, wherein the EP300 binding moiety has the structure of Formula IIIc: Formula IIIc wherein X1’ is N or CR6, wherein R6 is H, halo, C1-C3 alkyl, or C1-C3 alkoxy; X2’ is N, or CR5, wherein R5 is H, C1-C3 alkyl, or C1-C3 alkoxy; R1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; and R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, 351 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; R3 is optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, or optionally substituted C1-C4 alkyl C2-C9 heteroaryl, wherein each C1-C4 alkyl, C1-4 alkoxy, C3-C10 carbocyclyl, C2-C9 heterocyclyl, C6-C10 aryl, or C2-C9 heteroaryl, C1-C4 alkyl C2-C9 heterocyclyl, or C1-C4 alkyl C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C4 alkoxy, C1-C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl that is optionally substituted with one or more groups independently selected from C1-C3 alkyl, C3-C10 carbocyclyl, or halo; R4 is hydrogen or methyl; each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and each Rh is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo. 14. The compound of claim 13, wherein R2 has the structure: . 15. The compound of claim 13, wherein R1 is H, halo, C1-C3 alkoxy, or C1-C4 alkyl optionally substituted with one or more substituent groups independently selected from F. 16. The compound of claim 13, wherein X1 is CH, C1-C3 alkoxy, or N. 17. The compound of claim 13, wherein X2 is CH or N. 352 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 18. The compound of any one of claims 13 to 17, wherein the EP300 binding moiety has the structure: , 19. The compound of any one of claims 7 to 18, wherein R3 is optionally substituted C2-C9 heteroaryl, wherein the C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from halo, C1-C4 alkoxy, C1-C3 alkyl, C3-C10 carbocyclyl, or C2-C9 heterocyclyl, that is optionally substituted with one or more groups independently selected from halo, C1-C3 alkyl or C3-C10 carbocyclyl. 20. The compound of any one of claims 7 to 19, wherein R3 is: , , , , , , , 353 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 . The compound of any one of claims 7 to 20, wherein R3 is: The compound of any one of claims 7 to 20, wherein R3 is: . The compound of any one of claims 7 to 20, wherein R3 is: 24. The compound of any one of claims 7 to 20, wherein R3 is: . 25. The compound of any one of claims 7 to 20, wherein R3 is: . 354 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 26. The compound of any one of claims 7 to 19, wherein R3 is optionally substituted C1-C4 alkyl C2-C9 heterocyclyl, wherein the C1-C4 alkyl C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from oxo, and C1-C3 alkyl. 27. The compound of any one of claims 7 to 19 or 26, wherein R3 is: 28. The compound of claim 7, wherein the EP300 binding moiety has the structure of Formula IIID: wherein X1 is NRN, CH2, or O; RN is C1-C3 alkyl or H; R1’ is H, halo, C1-C4 alkyl, or C1-C4 alkoxy, wherein any C1-C4 alkyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; and R2 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted with one or more substituent groups independently selected from F, Cl, Br, I, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, or N(Ra)S(O)2N(Ra)2; each Ra is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein each C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and each Rh is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with 355 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo. 29. The compound of claim 28, wherein R1 is C1-C4 alkyl optionally substituted with one or more F groups. 30. The compound of claim 29, wherein R1 is difluroromethyl. 31. The compound of claim 28, wherein R2 has the structure: . 32. The compound of claim 28, wherein X1 is CH2. 33. The compound of any one of claims 28 to 32, wherein the EP300 binding moiety has the structure: . 34. The compound of any one of claims 1 to 33, wherein the degradation moiety is a ubiquitin ligase binding moiety. 35. The compound of claim 34, wherein the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel- Lindau (VHL) ligands, or derivatives or analogs thereof. 356 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 36. The compound of any one of claims 1 to 35, wherein the degradation moiety comprises the structure of Formula Y: Formula Y, wherein A2 is a bond between the degradation moiety and the linker; v1 is 0, 1, 2, 3, 4, or 5; u1 is 1, 2, or 3; RA5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each RJ1 is, independently, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; JA is absent, O, optionally substituted amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; and J is absent, optionally substituted C3-C10 carbocyclylene, optionally substituted C6-C10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene, or a pharmaceutically acceptable salt thereof. 37. The compound of claim 30, wherein T1 is a bond. 38. The compound of any one of claims 30-31, wherein T2 is . 39. The compound of any one of claims 30-32, wherein RA5 is H. 40. The compound of any one of claims 30-33, wherein JA is absent. 41. The compound of any one of claims 30-33, wherein J is absent. 357 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 42. The compound of any one of claims 30-35, wherein the structure of Formula Y is . 43. The compound of any one of claims 30-33, wherein J is optionally substituted C2-C9 heteroarylene or optionally substituted C6-C10 arylene. 44. The compound of any one of claims 30-33 or 37, wherein the structure of Formula Y is 45. The compound of any one of claims 30-33 or 37, wherein the structure of Formula Y is The compound of any one of claims 30, 32-34, or 40, wherein the structure of Formula Y is . The compound of claim 30, wherein T1 is . 49. The compound of claim 42, wherein J is optionally substituted C6-C10 arylene. 358 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 50. The compound of any one of claims 30, 32-34, or 42-43 wherein the structure of Formula Y is 51. The compound of any one of claims 30, 32-34, or 42-43, wherein the structure of Formula Y is , or . 52. The compound of any one of claims 1-29, wherein the degradation moiety comprises the structure of Formula AY: , Formula AY wherein each of RA1, RA2, RA3, and RA4 is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2- C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; or RA1 and RA2, RA2 and RA3, and/or RA3 and RA4, together with the carbon atoms to which each is attached, combine to form optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl; RA5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 359 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 each of RA6 and RA7 is, independently, H or optionally substituted C1-C6 alkyl; or RA6 and RA7, together with the carbon atom to which each is bound, form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl; RA8 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; where one of RA1, RA2, RA3, and RA4 is A2, or a pharmaceutically acceptable salt thereof. 53. The compound of claim 46, wherein each RA1, RA2, RA3, and RA4 is, independently, A2, H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, hydroxyl, optionally substituted amino; or RA1 and RA2, RA2 and RA3, or RA3 and RA4, together with the carbon atoms to which each is attached, combine to form optionally substituted C2-C9 heterocyclyl. 54. The compound of claim 46, wherein RA5 is H. 55. The compound of any one of claims 46 to 48, wherein Y1 is . 56. The compound of any one of claims 46 to 49, wherein the structure of Formula AY has the structure of Formula AY1: , Formula AY1 or a pharmaceutically acceptable salt thereof. 57. The compound of any one of claims 46 to 49, wherein the structure of Formula AY has the structure of Formula AY2: , Formula AY2 or a pharmaceutically acceptable salt thereof. 360 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 58. The compound of any one of claims 46 to 49, wherein the structure of Formula AY has the structure of Formula AY3: , Formula AY3 or a pharmaceutically acceptable salt thereof. 59. The compound of any one of claims 46 to 49, wherein the structure of Formula AY has the structure of Formula AY4: , Formula AY4 or a pharmaceutically acceptable salt thereof. 60. The compound of any one of claims 46 to 53, wherein the structure of Formula AY is , 361 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 61. The compound of any one of claims 46 to 53, wherein the structure of Formula AY is The compound of any one of claims 46 to 53, wherein the structure of Formula AY is derivative or an analog thereof. 63. The compound of any one of claims 46 to 53, wherein the structure of Formula AY is . one of claims 46 to 53, wherein the structure of Formula AY has the structure of Formula AY5: Formula AY5, or a pharmaceutically acceptable salt thereof. 65. The compound of any one of claims 46 to 53, wherein the structure of Formula AY has the structure of Formula AY6: Formula AY6, 362 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 or a pharmaceutically acceptable salt thereof. 66. The compound of any one of claims 46-53, wherein the structure of Formula AY is . 67. The compound of any one of claim 1-66, wherein L has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D)-(B Formula or a pharmaceutically acceptable salt thereof, wherein A1 is a bond between the linker and the EP300 binding moiety; A2 is a bond between the degradation moiety and the linker; each of B1, B2, B3, and B4 is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C10 arylene, optionally substituted C6-C10 aryl C1-4 alkylene, optionally substituted C2-C8 heterocyclyl C1-4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C3-C10 cycloalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2-C8 heteroarylene, optionally substituted C6–12 arylene, O, S, S(O)2, or NRN; each RN is, independently, H, optionally substituted C1–C4 alkylene, optionally substituted C2–C4 alkenylene, optionally substituted C2–C4 alkynylene, optionally substituted C2–C6 heterocyclylene, optionally substituted C2–C6 heteroarylene, or optionally substituted C1–C7 heteroalkylene; each of C1 and C2 is, independently, carbonylene, thiocarbonylene, sulphonylene, or phosphorylene; each of f, g, h, i, j, and k is, independently, 0 or 1; and D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C9 heterocyclylene (e.g. C2-C8 heterocyclylene), optionally substituted C2–C9 heteroarylene (e.g. C2-C8 heteroarylene), optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene. 68. The compound of claim 67, or a pharmaceutically acceptable salt thereof, wherein each of B1, B2, B3, and B4 is, independently, optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2–C8 heteroarylene, optionally substituted C2-C8 heterocyclyl C1-C4 alkylene, or O. 69. The compound of claim 68, or a pharmaceutically acceptable salt thereof, wherein B1 or B2 is optionally substituted C2-C8 heterocyclylene or optionally substituted C3-C10 cycloalkylene. 363 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 70. The compound of claim 69, or a pharmaceutically acceptable salt thereof, wherein B1 or B2 is 71. The compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein . 72. The compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein . 73. The compound of any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof, wherein f is 0. 74. The compound of any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof, wherein f is 1. 75. The compound of any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, wherein g is 0. 76. The compound of any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, wherein g is 1. 77. The compound of any one of claims 1 to 76, or a pharmaceutically acceptable salt thereof, wherein h is 0. 78. The compound of any one of claims 1 to 76, or a pharmaceutically acceptable salt thereof, wherein h is 1. The compound of any one of claims 1 to 78, or a pharmaceutically acceptable salt thereof, wherein i is 0. 80. The compound of any one of claims 1 to 78, or a pharmaceutically acceptable salt thereof, wherein i is 1. 81. The compound of any one of claims 1 to 80, or a pharmaceutically acceptable salt thereof, wherein j is 0. 364 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 82. The compound of any one of claims 1 to 80, or a pharmaceutically acceptable salt thereof, wherein j is 1. 83. The compound of any one of claims 1 to 82, or a pharmaceutically acceptable salt thereof, wherein k is 0. 84. The compound of any one of claims 1 to 82, or a pharmaceutically acceptable salt thereof, wherein k is 1. 85. The compound of any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C9 heterocyclylene, optionally substituted C2–C9 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene. 86. The compound of any one of claims 1 to 85, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C2-C9 heterocyclylene. 88. The compound of any one of claims 1 to 85, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C2–C9 heteroarylene. 89. The compound of any one of claims 1 to 85, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C6–C12 arylene. 90. The compound of any one of claims 1 to 85, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C1-C10 alkylene. 91. The compound of any one of claims 1 to 85, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C1-C10 heteroalkylene. 365 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 92. The compound of any one of claims 1 to 91, or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of: , PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 367 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 368 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 369 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 370 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 371 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 372 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 374 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 375 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 376 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 , 377 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 378 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 93. The compound of any one of claims 68 to 92, or a pharmaceutically acceptable salt thereof, wherein the shortest chain of atoms connecting two valencies of the linker is 2 to 10 atoms long. 94. The compound of any one of claims 68 to 92, or a pharmaceutically acceptable salt thereof, wherein the shortest chain of atoms connecting two valencies of the linker is 6 atoms long. 95. The compound of any one of claims 1 to 94, wherein the compound is any one of compounds 1- 30 of Table 1A, Compounds 31-46 of Table 1B, Compounds 49-58 of Table 1B, Compounds 60-61 of Table 1B, Compounds 63-64 of Table 1B, Compounds 66-70 of Table 1B, Compounds 72-234 of Table 1B, or a pharmaceutically acceptable salt thereof. 96. A pharmaceutical composition comprising a compound of any one of claims 1 to 95 and a pharmaceutically acceptable excipient. 97. A method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 95, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 96. 98. The method of claim 97, wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myeloma, skin, endometrial, esophageal, cervical, gastric, lymphoma, leukemia, esophogeal, stomach, lung cancer, or non-small cell lung cancer. 99. The method of claim 97 or 98, wherein the cancer is metastatic. 100. The method of any one of claims 97 to 99, wherein the subject or cancer has a CBP loss of function mutation. 101. The method of any one of claims 97 to 100, wherein the cancer is prostate cancer. 102. The method of claim 101, wherein the cancer is castration-resistant prostate cancer (CRPC). 103. The method of claim 101, wherein the cancer is castration-sensitive prostate cancer. 104. The method of claim 101, wherein the cancer is AR+ prostate cancer. 105. The method of any one of claims 97 to 100, wherein the cancer is lymphoma. 106. The method of claim 105, wherein the lymphoma is Diffuse large B cell lymphoma (DLBCL), 379 PATENT ATTORNEY DOCKET NO.: 51121-103WO2 107. The method of any one of claims 97 to 106, wherein the method further comprises administering to the subject an anticancer therapy. 108. The method of claim 107, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof. 380
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