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WO2024220946A1 - Compounds and uses thereof - Google Patents

Compounds and uses thereof Download PDF

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Publication number
WO2024220946A1
WO2024220946A1 PCT/US2024/025593 US2024025593W WO2024220946A1 WO 2024220946 A1 WO2024220946 A1 WO 2024220946A1 US 2024025593 W US2024025593 W US 2024025593W WO 2024220946 A1 WO2024220946 A1 WO 2024220946A1
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Prior art keywords
optionally substituted
alkyl
carbocyclyl
heterocyclyl
halo
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/US2024/025593
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French (fr)
Inventor
Shawn E.r. SCHILLER
Wesley Francis Austin
Md Imran HOSSAIN
David S. HUANG
Melek Nihan UCISIK
Solymar NEGRETTI EMMANUELLI
Francois BRUCELLE
Paige Justine MONSEN
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Foghorn Therapeutics Inc
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Foghorn Therapeutics Inc
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Publication of WO2024220946A1 publication Critical patent/WO2024220946A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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

Definitions

  • CBP-binging protein is a transcriptional co-activator that maintains gene expression programs through lysine acetylation and acts as a protein scaffold that helps recruit and construct the complexes that are necessary for transcription or chromatin remodeling.
  • CBP is involved in cell differentiation, apoptosis, and the cell cycle.
  • the present invention is related to useful compositions and methods for the treatment of CBP-related disorders, such as cancer and infection.
  • SUMMARY CREB-binding protein is an intracellular protein that regulates the expression of genes and is critical for establishing and activating enhancer-mediated transcription. CBP is overexpressed in multiple cancer cell lines.
  • agents that reduce the levels and/or activity of CBP may provide new methods for the treatment of disease and disorders, such as cancer and infection.
  • the inventors have found that depleting CBP results in the downregulation/depletion of MYC in those cells.
  • agents that degrade CBP e.g., compounds
  • the present disclosure features compounds and methods useful for treating CBP-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 a CBP binding moiety; B is a degradation moiety; and L has the structure of Formula II: A 1 –(F)–(E) m –C-A 2 , Formula II wherein A 1 is a bond between the linker and A; A 2 is a bond between B and the linker; m is, independently, 0 or 1; C is, independently, absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; E is, independently, absent, O, S, NR N , optionally substituted C 1 –C 10 alkylene, optionally substituted C 2 - C 10 alkenylene, optionally substituted C 2– C 10 alkynylene, optionally substituted C 2 -C 10 polyethylene glycol, or optionally substituted C 1 –C 10 heteroalkylene wherein any C 1 –C 10 alkylene, C 2 -C 10
  • a 1 is a bond between the linker and A.
  • a 2 is a bond between B and the linker.
  • m is 0.
  • E is absent.
  • m is 1.
  • E is optionally substituted C1–10 alkylene.
  • E is methylene or ethylene.
  • F is optionally substituted C 2 -C 9 heteroarylene.
  • F is the structure: , wherein X7 and X8 are each independently C or N; and R15 and R16 combine with the atoms to which they are attached to form an optionally substituted 3-12 membered heteroaryl, wherein the heteroaryl is optionally substituted with A 1 and/or one or more of the following groups: halogen or C 1 –C 6 alkyl.
  • F is optionally substituted C 2 -C 10 heterocyclylene.
  • C is absent.
  • C is carbonyl.
  • the CBP binding moiety has the structure of Formula III: Formula III wherein X 1a is, independently, C or N; X 2a is, independently, C or N; R 1a and R 1b , independently,combine with the atoms to which they are attached to form an optionally substituted C 3 -C 10 carbocycle, an optionally substituted C 5 -C 10 aryl, an optionally substituted C 3 -C 9 heteroaryl, or optionally substituted C 3 -C 9 heterocycle, wherein the carbocycle, aryl, heteroaryl or heterocycle is optionally substituted with A 1 and/or one or more of the following groups: halogen, C 1 –C 6 alkyl, C 5 -C 10 aryl, C 2 -C 9 heteroaryl, C 2 -C 9 heterocycle, C 3 -C 10 carbocycle, C(O)N(R 1e ) 2 , S(O)N(R 1e ) 2 , S(O) 2 N(R
  • R 1c is, independently, A 1 , NR 2a R 3a , C 6 -C 20 aryl, C 2 -C 9 heterocyle, C 1 -C 20 heteroaryl, ( C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), (C 1 -C 20 heteroaryl)-(C 6 -C 20 aryl), and (C 1 -C 20 heteroaryl)(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl) and (C 1 -C 20 heteroaryl)-(C 1 - C 20 heteroaryl) is independently optionally substituted with A 1 and/or one or more substituent groups independently selected from R 1h , oxo, F, Cl, Br, I, C 1 -C 9 alkyl, C 1 -C 9 heteroalkyl, CHF 2 ,
  • the CBP binding moiety of Formula III has the structure: . In some embodiments, the CBP binding moiety of Formula III has the structure: . In some embodiments, the CBP binding moiety of Formula III has the structure: . In some embodiments, the CBP binding moiety of Formula III has the structure:
  • the CBP binding moiety of Formula III has the structure:
  • the CBP binding moiety of Formula (III) has the structure:
  • the CBP binding moiety of Formula (III) has the structure:
  • the CBP binding moiety of Formula (III) has the structure:
  • the CBP binding moiety of Formula (III) has the structure of Formula (III- A):
  • R 8 is, independently, C 1 -C 12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C 1 -12alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 8 is optionally substituted with one or more groups R O ;
  • R 9 is, independently, C 1 -C 4 alkyl, C 2 –C 6 heteroaryl, C 2 -C 9 heterocycle, C(O)N(R h2 ) 2 , S(O)N(R h2 ) 2 , S(O) 2 , C(O)R h2 , C(O)OR h2 , S(O)R h2 , or
  • R 8 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R 8 is optionally substituted with one or more groups R b2 . In some embodiments, .
  • R 9 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
  • R 9 has the structure: .
  • the CBP binding moiety has the structure:
  • the CBP binding moiety has the structure:
  • R 10 has the structure:
  • X3 is CH2 and X4 is CH.
  • R 10 has the structure: .
  • the CBP binding moiety has the structure:
  • the CBP binding moiety of Formula (III) has the structure of Formula (III- Formula III-B wherein R 1 is, independently, 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 C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 1 is optionally substituted with A 1 and/or one or more groups R b ;
  • R 2 is, independently, C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -20 aryl)(C 1 -C 20 heteroaryl), (C 1 - C 20 heteroaryl)(C 6 -C 20 aryl), and (C 1 -C 20 hetero
  • R 1 is C 1 -C 12 alkyl or 3-12 membered heterocycle. In some embodiments, R 1 is Methyl. In some embodiments, R 1 is 3-12 membered heterocycle, e.g., , . In some embodiments, R b is H. In some embodiments, R 2 is C 6 -C 20 aryl that is optionally substituted with one or more substituent groups independently selected from R c . In some embodiments, R 2 comprises A 1 . In some embodiments, . In some embodiments, . In some embodiments, R c is C 1 –C 6 alkyl that is optionally substituted with one or more groups independently selected from halo. In some embodiments, R c is CHF 2 .
  • R 3 is a C 1 -C 12 alkyl or 3-12 membered heterocycle that is optionally substituted with one or more groups R e .
  • R 2 and R 3 of Formula (III-B) taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e .
  • R 2 and R 3 of Formula (III-B) taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R e ; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring.
  • R e is H.
  • R 4 is C(O)R h .
  • R 4 is acetyl, e.g., .
  • R h is methyl.
  • the CBP binding moiety has the structure: .
  • the CBP binding moiety of Formula (III) has the structure of Formula (III- C): wherein: X1 is C or N; X2 is C or N; R 5 is, independently, C 1 –C 12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C 1 -C 12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 5 is optionally substituted with one or more groups R k1k ; R 6 is, independently, C 1 -4alkyl, C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), (C 1 - C 20 heteroaryl)-(C 6 -C 20 aryl), and (C 1 -C 20 heteroaryl)(C 1 -C 20 heteroaryl), C(O)N(R h1 ) 2 , S(O)N(R h1 )
  • the CBP binding moiety has the structure of Formula IV: Formula IVIV wherein: R 11 is, independently, C 1 -C 12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C 1 -C 12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 11 is optionally substituted with one or more groups R M R M ; R 12 is, independently, C 1 -C 4 alkyl, C(O)N(R h3 ) 2 , S(O)N(R h3 ) 2 , S(O)N(R h3 ) 2 , C(O)R h3 , C(O)OR h3 , S(O)R h3 , or S(O)R h3 , wherein any C 1 -C 4 alkyl is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O
  • the CBP binding moiety of Formula IV has the structure: I , In some embodiments, R 13 C 1 -C 20 heteroaryl, e.g., . In some embodiments, the CBP binding moiety of Formula IV has the structure:
  • the degradation moiety (B) is a ubiquitin ligase binding moiety.
  • the degradation moiety (B) 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 (B) comprises the structure of Formula V: Formula V, wherein R B1a is, independently, H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B2a is, independently, H, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3a is, independently, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B4a is, independently, H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B5a is, independently,
  • the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-A): Formula V-A, wherein R B1a is, independently, H, A 2 , C(O)A 2 , optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B2a is, independently, H, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3a is, independently, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B4a is, independently, H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10
  • the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-B): Formula V-B, wherein R B1a is, independently, H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl; R B2a is, independently, H, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3a is, independently, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B4a is, independently, H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10
  • each R B6 is, independently, halogen, optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, hydroxy, thiol;
  • R B9 is, independently, H, or optionally substituted C 1 –C 6 alkyl;
  • R B10 is, independently, H, or optionally substituted C 1 –C 6 alkyl, and v2 is 0, 1, 2, 3, or 4.
  • each R B6 is, independently, halogen, optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 - C6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, hydroxy, thiol;
  • R B11 is optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl;
  • R B9 is, independently, H, or optionally substituted C 1 –C 6 alkyl;
  • R B10 is, independently, H, or optionally
  • each R B6 is, independently, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 - C6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; each of R B7 and R B8 is, independently, H, halogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 6 -C 10 aryl; and R B9 and R B10 are, independently, H, or optionally substituted C 1 –C 6 alkyl.
  • each R B6 is, independently, halogen, optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 - C6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; each of R B7 and R B8 is, independently, H, halogen, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 6 -C 10 aryl; and R B9 and R B10 are, independently, H, or optionally substituted C 1 –C 6 alkyl.
  • R B6a is .
  • R B6a is .
  • the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-C): Formula V-C-C, wherein R B1 is, independently, H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl; R B3 is, independently, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 –C 6 alkyl, C 3 -C 10 carbocyclyl, or optionally substituted C 1 –C 6 alkyl wherein the C 1 –C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 carbocyclyl, C 6 -C 10 ary
  • R B9 is H. In some embodiments, R B9 is optionally substituted C 1 –C 6 alkyl. In some embodiments, R B9 is methyl. In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B1 is A 2 . In some embodiments, R B1 is C(O)A 2 . In some embodiments, R B3 is optionally substituted C 1 –C 6 alkyl. In some embodiments, R B6 is optionally substituted C 2 -C 9 heteroaryl.
  • R B6 is halogen or optionally substituted C2-C6 alkynyl. In some embodiments, R B6 is optionally substituted C 1 –C 6 heteroalkyl. In some embodiments, optionally substituted C 1 –C 6 heteroalkyl is methoxy. In some embodiments, the structure of Formula V-C is thereof.
  • the degradation moiety of Formula (V) comprises the structure of Formula V-D: Formula V-DD, wherein R B1 is, independently, H, A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B2 is, independently, H, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3 is, independently, A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B4 is, independently, H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B5 is, independently, H, optionally substituted C 1 –CDD, wherein
  • R B1 is H. In some embodiments, R B1 is A 2 . In some embodiments, R B2 is H. In some embodiments, R B3 is optionally substituted C 1 –C 6 alkyl or optionally substituted C 1 –C 6 heteroalkyl wherein any C 1 –C 6 alkyl, and C 1 –C 6 heteroalkyl is optionally substituted with one or more groups independently selected from oxo, halo, NO 2 , N(R f3 ) 2 , CN, C(O)N(R f3 ) 2 , S(O)N(R f3 ) 2 , S(O) 2 N(R f3 ) 2 , O)R f3 , C(R f3 O)R f3 , R f3 C(O)R f3 , C(O)N(R f3 ) 2 , N(R f3 )R f3 C(O)R f3 ,
  • R B3 is , or . In some embodiments, . In some embodiments, R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B6 is H. In some embodiments, R B7 is H, or optionally substituted C 1 -6 alkyl. In some embodiments, R B7 is methyl. In some embodiments, R B8 is H. In some embodiments, R B9 is H, or optionally substituted C 1 -6 alkyl. In some embodiments, R B9 is H. In some embodiments, R B9 is methyl. In some embodiments, R B10 is H, or optionally substituted C 1 -6 alkyl. In some embodiments, R B10 is H.
  • R B10 is methyl. analog thereof.
  • the degradation moiety has the structure: .
  • the degradation moiety has the structure: .
  • the degradation moiety comprises the structure of Formula V-E:
  • R C1 is, independently, optionally substituted C 1 –C 6 alkyl
  • R C2 is, independently, A 2 , or optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 6 -C 10 aryl, or optionally substituted C 2 -C 9 heteroaryl, that is substituted with A 2 and/or one or more groups R J
  • R C3 is, independently, H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl
  • R C4 is, independently, H, H,
  • R C2 is optionally substituted C 2 -C 9 heteroaryl that is substituted with A 2 .
  • R C3 is H.
  • R C4 is H.
  • v2 is 0.
  • each of R C5 and R C6 is, independently, H or methyl.
  • each of R C8 and R C9 is, independently, H or methyl.
  • the degradation moiety has the structure: or analog thereof.
  • the degradation moiety of Formula (V) comprises the structure of Formula V-FF: Formula V-FF, wherein R B1 is, independently, H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl; R B3 is, independently, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B4 is, independently, H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B5 is, independently, H, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl or ary
  • R B4 is H. In some embodiments, R B5 is H. In some embodiments, R B1 is A 2 . In some embodiments, R B1 is C(O)A 2 . In some embodiments, R B3 is optionally substituted C 1 –C 6 alkyl. In some embodiments, the degradation moiety has the structure of Formula V-G: derivative or analog thereof. In some embodiments, the compound is any one of compounds in Table 1. Table 1. Compounds of the invention
  • the disclosure features a pharmaceutical composition including any of the foregoing compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.
  • the invention features a method of decreasing the levels and/or activity of a 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 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 AR, i.e.
  • the cell is a cancer cell.
  • the invention features a method of treating a CBP-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 CBP-related disorder is cancer.
  • the invention features a method of inhibiting CBP, 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 CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, 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 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, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric 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 sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesen
  • 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, 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 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 cancer is gastric cancer. In some embodiments, the breast cancer is found to be ER positive i.e. the cancer cells contain estrogen receptors. In some embodiments, the breast cancer is found to be ER negative i.e. cancer cells do not contain estrogen receptors.
  • ER positive i.e. the cancer cells contain estrogen receptors. 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.
  • the prostate cancer is CRPC i.e. castration-sensitive prostate cancer.
  • the disclosure features a method of treating a CBP-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 pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the CBP-related disorder is cancer.
  • the CBP-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, 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 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, neuroblast
  • Additional cancers which may be treated using the disclosed compounds according to the present invention include, for 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 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
  • 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®, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, demci
  • 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, 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 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, neuroblast
  • Additional cancers which may be treated using the disclosed compounds according to the present invention include, for 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 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
  • 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 cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve
  • 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, 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 embodiments of any of the foregoing methods, the cancer has or has been determined to have CBP mutations. In some embodiments of any of the foregoing methods, the CBP 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 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. In another aspect, the disclosure provides a method of treating a disorder related to CBP (e.g., cancer or viral infections) in a subject in need thereof.
  • a disorder related to CBP 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 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
  • a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretrovirus
  • the disorder is Coffin Siris, Neurofibromatosis (e.g., NF-1, NF-2, or Schwannomatosis), or Multiple Meningioma.
  • the disclosure provides a method of treating gastric cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • the disclosure provides a method of treating inflammatory and/or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.
  • the inflammatory and/or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, refractory, moderate- to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post- polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 ⁇ 109/L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile id
  • the inflammatory and/or autoimmune disorder is non-infectious non- anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.
  • the method further comprises administering to the subject a JAK inhibitor.
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.
  • the disclosure provides a method of treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway, the method including administering to the subject an effective amount of a compound of the present disclosure.
  • the member of the JAK-STAT pathway is a janus kinase (JAK).
  • the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT).
  • the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.
  • the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, refractory, moderate-to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 ⁇ 109/L, polycythemia vera, steroid- refractory acute graft-versus-host disease, chronic
  • the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is non-infectious non-anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.
  • the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.
  • the disclosure provides a method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • the disclosure provides a method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • the disclosure provides a method of suppressing a memory CD8 + T cell response in a subject in a subject having or at risk of developing an inflammatory response, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.
  • An aspect of the present invention relates to a method of treating a disorder related to CBP such as inflammation and/or autoimmune disorders in a subject in need thereof.
  • the compound is administered in an 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 T cell (e.g., CD8 + memory T cells) activity, (b) reduced inflammation, (c) reduced thrombopoiesis, (d) reduced B cell proliferation, (e) increased survival of subject, and (f) increased progression free survival of a subject.
  • treating an inflammatory disorder and/or autoimmune disorder can result in a reduction in T cell (e.g., CD8 + memory T cells) activity.
  • T cell e.g., CD8 + memory T cells
  • T cell activity 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.
  • treating an inflammatory disorder and/or autoimmune disorder can result in a reduction in inflammation.
  • inflammation 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.
  • treating an inflammatory disorder and/or autoimmune disorder can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition, or a downstream affect such as CBP degradation).
  • inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF- ⁇ , IL-6, IL- 11, IL-13, IL-25, IL-27, and/or IL-31, which in turn can affect the immune system response.
  • cytokines that interact with JAK1, JAK3, and/or TYK2 include IL-10, IL-22, type 1 IFNs ( ⁇ / ⁇ ), IL-2, IL-4, IL- 7, IL-9, IL-15, and IL-21.
  • the disclosure provides a method for treating a viral infection in a subject in 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)), 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), Papillomavirid
  • the invention features a method of treating melanoma, 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 reducing tumor growth of melanoma, 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, 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, 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 CBP and/or EP300 in a melanoma, 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, 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 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 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 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 the percent of reduction of the level of EP300.
  • the effective amount of the compound that reduces the level of CBP 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 EP300.
  • the effective amount of the compound that reduces the level 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%, 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%, 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 days, 6 days, 7 days, 14 days, 28 days, or more).
  • 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%, 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 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%, 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 (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).
  • the subject has cancer.
  • the cancer expresses CBP and/or EP300 protein and/or the cell or subject has been identified as expressing CBP and/or EP300.
  • the cancer expresses CBP protein and/or the cell or subject has been identified as expressing CBP.
  • the cancer expresses EP300 protein and/or the cell or subject has been identified as expressing EP300.
  • 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 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.
  • 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 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 (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 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, 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 CBP and/or EP300 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 cell with an anticancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation.
  • an 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 inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor.
  • an anticancer therapy is a chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparagine- specific enzyme, bisphosphon
  • 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 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 amount
  • the cancer is resistant to one or more chemotherapeutic or cytotoxic 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, 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 pembroli
  • 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.
  • 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 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(RN1) 2 , wherein each RN1 is, independently, H, OH, NO 2 , N(RN2) 2 , SO 2 ORN2, SO 2 RN2, 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.
  • each RN1 is, independently, H, OH, NO 2 , N(RN2) 2 , SO 2 ORN2, SO 2 RN2, SORN2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g.,
  • 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 ).
  • 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.
  • arylalkyl represents an alkyl group substituted with an aryl group.
  • Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C 1 -C6 alkyl C6-C10 aryl, C 1 -C10 alkyl C6-C10 aryl, or C 1 -C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl.
  • the alkyl and the aryl each are further substituted with 1, 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.
  • 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 groups and unsaturated carbocyclyl radicals.
  • a carbocyclylene is a divalent carbocyclyl group.
  • cycloalkyl refers to a saturated, non-aromatic, and monovalent mono- di-, or tricyclic radical of 3 to 10, preferably 3 to 6 carbon atoms.
  • the cycloalkyl group may be fully saturated or contain 1 or more double or triple bonds, provided that no ring is aromatic.
  • radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.
  • cycloalkoxy refers to cycloalkyl-O- groups (e.g., cyclopropoxy and cyclobutoxy).
  • 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 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.
  • 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 can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyl groups.
  • 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, 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.
  • heteroarylalkyl represents an alkyl group substituted with a heteroaryl group.
  • Unsubstituted heteroarylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C 1 -C6 alkyl C2-C9 heteroaryl, C 1 -C10 alkyl C2-C9 heteroaryl, or C 1 -C20 alkyl C2- C9 heteroaryl).
  • the alkyl and the heteroaryl each are further substituted with 1, 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.
  • 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 aromatic.
  • 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 heteroocyclyl 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.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted.
  • 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 thioalkoxy), heteroaryl (e.g., substituted and unsubstituted thiazole, substituted and unsubstituted pyridine, substituted and unsubstituted benzothiazole, substituted and unsubstituted furan, substituted and unsubstituted
  • alkyl e.g., unsubstituted and substituted
  • 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, 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. 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 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 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 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,” 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 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 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, 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.
  • 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 ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.
  • 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 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.
  • CBP refers to the Creb-binding protein in a human cell.
  • CBP-related disorder refers to a disorder that is caused or affected by the level of activity of CBP.
  • CBP loss of function mutation refers to a mutation in CBP that leads to the protein having diminished activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity).
  • Exemplary CBP loss of function mutations include, but are not limited to, a homozygous CBP mutation and chromosomal translocations.
  • CBP loss of function disorder refers to a disorder (e.g., cancer) that exhibits a reduction in CBP activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP 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 “ad in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen 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.
  • 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, 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.
  • 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 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, 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, 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
  • 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 CBP (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 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 CBP 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 CBP.
  • a given agent that reduces the level and/or activity of CBP 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 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.
  • a “therapeutically effective amount” of an agent that reduces the level and/or activity of CBP of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control.
  • a therapeutically effective amount of an agent that reduces the level and/or activity of CBP 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 protein (e.g., CBP). 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 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 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
  • a level of a protein may be expressed in mass/vol (e.g., g/dL, mg/mL, ⁇ g/mL, ng/mL) or percentage relative to total protein in a sample.
  • decreasing the activity of CBP is meant decreasing the level of an activity related to CBP, or a related downstream effect.
  • the activity level of a CBP may be measured using any method known in the art, e.g., HiBit assay.
  • pharmaceutical composition represents a composition containing a 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 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 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, 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, 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), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C,
  • 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 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 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.
  • the compounds are prepared or used as pharmaceutically 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, 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, pe
  • 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.
  • 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.
  • 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 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 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 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 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 described herein may retain or improve upon the biological activity of the original material.
  • the term “degrader” refers to a small molecule compound including a degradation moiety, wherein the compound interacts with a protein (e.g., CBP) 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., CBP
  • degradation moiety refers to a moiety whose binding results in degradation of a protein, e.g., CBP. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., CBP.
  • Figures 1 and 2 are a series of graphs illustrating the dose dependent depletion of CBP and EP300 levels in osteosarcoma cell line in the presence of a CBP-selective degrader as described in Example 536.
  • Figure 3 is a graph illustrating the effect on cell growth of four bladder cancer cell lines (UM-UC-3, ScaBER, 647V and 639V) in the presence of a CBP degrader as described in Example 537.
  • Figure 4 is a graph illustrating the effect on cell growth of two gastric cancer cell lines (IM95 and AGS) as described in Example 538.
  • Figure 5 is a graph illustrating the effect on cell growth of two colorectal cancer cell lines (HT29 and RKO) as described in Example 539.
  • Figure 6 is a series of graphs illustrating the results of the WB evaluation of the percent of remaining CBP and EP300 protein level (normalized to vehicle) after treatment with our CBP selective degrader @ 20mg/kg and 50mg/kg at 2H, 6H and 24H post last dose as described in Example 540.
  • Figure 7 is a volcano plot illustrating all proteins identified in the proteome database, for the treated (with compound 6) and untreated groups taken at a 6H timepoint post treatment. Purple dots represent all the bromodomain proteins identified in this analysis.
  • FIG. 8 is a graph illustrating the Platelet count on Day 14: Dose-Response Platelet Decrease with GNE- 781, Absence of Thrombocytopenia with exemplified compound 132 as described in Example 542.
  • DETAILED DESCRIPTION OF THE INVENTION The present disclosure features compositions and methods useful for the treatment of CBP- related disorders (e.g., cancer and infection).
  • compositions and methods useful for inhibition of the level and/or activity of CBP 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.
  • 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 CBP, or a related downstream effect, or reduce the level of CBP in a cell or subject.
  • Exemplary compounds described herein have the structure according to Formula I.
  • A-L-B Formula I wherein A is a CBP binding moiety; B is a degradation moiety; and L has the structure of Formula II: A 1 –(F)-(E)m–C-A 2 , Formula II wherein A 1 is a bond between the linker and A; A 2 is a bond between B and the linker; m is, independently, 0 or 1; C is, independently, absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl;
  • Figure 4 is a graph illustrating the effect on cell growth of two gastric cancer cell lines (IM95 and AGS) as described in Example 538.
  • Figure 5 is a graph illustrating the effect on cell growth of two colorectal cancer cell lines (HT29 and RKO) as described in Example 539.
  • Figure 6 is a series of graphs illustrating the results of the WB evaluation of the percent of remaining CBP and EP300 protein level (normalized to vehicle) after treatment with our CBP selective degrader @ 20mg/kg and 50mg/kg at 2H, 6H and 24H post last dose as described in Example 540.
  • Figure 7 is a volcano plot illustrating all proteins identified in the proteome database, for the treated (with compound 6) and untreated groups taken at a 6H timepoint post treatment. Purple dots represent all the bromodomain proteins identified in this analysis.
  • FIG. 8 is a graph illustrating the Platelet count on Day 14: Dose-Response Platelet Decrease with GNE- 781, Absence of Thrombocytopenia with exemplified compound 132 as described in Example 542.
  • Figure 9A is a graph illustrating tumor volume in response to dosing of FHT-76118 (Compound 142) and FHT-77559 over time.
  • Figure 9B is a graph illustrating the body weight in response to dosing of FHT-76118 (Compound 142) and FHT-77559 over time.
  • Figure 9C is a graph illustrating PK/PD effect of FHT-77559 over CBP 3 mg/kg, 1 mg/kg, 0.3 mg/kg, and 0.1 mg/kg.
  • Figure 9D is a graph illustrating the PK/PD effect of FHT-77559 over c-MYC 3 mg/kg, 1 mg/kg, 0.3 mg/kg, and 0.1 mg/kg.
  • Figure 10A is a graph illustrating the tumor volume over time in response to dosing of FHT-76118 (compound 142) and FHT-77559.
  • Figure 10B is a graph illustrating the body weight change over time in response to dosing of FHT-76118 (compound 142) and FHT-77559.
  • Figure 10C is a graph illustrating the PK/PD effect of FHT-76118 (Compound 142) and FHT-77559 over CBP.
  • Figure 10D is a graph illustrating the PK/PD effect of FHT-76118 (Compound 142) and FHT-77559 over c- MYC.
  • Figure 11A is a graph illustrating the tumor volume over time in response to dosing of FHT-76118 (compound 142) and FHT-77559.
  • Figure 11B is a graph illustrating the body weight change over time in response to dosing of FHT-76118 (compound 142) and FHT-77559.
  • Figure 11C is a graph illustrating the PK/PD effect of FHT-76118 (Compound 142) and FHT-77559 over CBP.
  • A-L-B Formula I wherein A is a CBP binding moiety; B is a degradation moiety; and L has the structure of Formula II: A 1 –(F)-(E)m–C-A 2 , Formula II wherein A 1 is a bond between the linker and A; A 2 is a bond between B and the linker; m is, independently, 0 or 1; C is, independently, absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; E is, independently, absent ,O, S, NR N , optionally substituted C1–10 alkylene, optionally substituted C2–10 alkenylene, optionally substituted C2–10 alkynylene, optionally substituted C 2 -C 10 polyethylene glycol, or optional
  • PKs CBP and Janus Kinase (JAK) Pathway Protein kinases (PKs) regulate diverse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer.
  • Cytokines, low-molecular weight polypeptides or glycoproteins, regulate many pathways involved in the E is, independently, absent ,O, S, NR N , optionally substituted C1–10 alkylene, optionally substituted C2–10 alkenylene, optionally substituted C2–10 alkynylene, optionally substituted C 2 -C 10 polyethylene glycol, or optionally substituted C1–10 heteroalkylene; each R N is, independently, H, optionally substituted C1–4 alkyl, optionally substituted C2–4 alkenyl, optionally substituted C2–4 alkynyl, optionally substituted C2–6 heterocyclyl, optionally substituted C6–12 aryl, or optionally substituted C1–7 heteroalkyl; F is, independently, optionally substituted C 3 -C 10 carbocyclylene, optionally substituted C2–10 heterocyclylene, optionally substituted C 6 -C 10 arylene, or optionally substituted C 2
  • PKs CBP and Janus Kinase (JAK) Pathway Protein kinases
  • PKs Pathway Protein kinases
  • Cytokines low-molecular weight polypeptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and can modulate both pro-inflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens.
  • JAKs Janus kinase family
  • JAK2 Janus kinase- 1
  • JAK2 JAK3
  • TYK2 protein-tyrosine kinase 2
  • STAT6 protein-tyrosine kinase 6
  • JAK2- catalyzed phosphorylation allows CBP to bind with higher affinity to acetylated histone peptides such as H3 and increases the number of acetylated histone markers that CBP recognizes. This may indicate a mechanism that could contribute to initiation of transcriptional programs in memory CD8+ T cells. Further, it was observed that CBP is essential for conventional effector and memory CD8+ T-cell formation.
  • JAK inhibitors e.g., JAK2 inhibitors
  • the JAK-STAT pathway plays a role in transduction of cytokines and growth factor signals in inflammatory and autoimmune diseases.
  • Globally approved JAK inhibitors include abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, and upadacitinib.
  • JAK inhibitors include AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, and ritlecitinib.
  • the present disclosure provides a method of treating inflammatory and/or autoimmune disorders, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering to the subject a JAK inhibitor.
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.
  • the JAK inhibitor is AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib.
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib.
  • Filgotinib, oclacitinib, and upadacitinib are JAK1 inhibitors.
  • Filgotinib e.g., Jyseleca, Europe
  • Upadacitinib e.g., Rinvoq
  • moderate-to-severe rheumatoid arthritis psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, and refractory, moderate-to-severe atopic dermatitis.
  • the JAK inhibitor is a JAK1 inhibitor.
  • the JAK inhibitor is filgotinib, oclacitinib, or upadacitinib.
  • the JAK inhibitor is filgotinib or upadacitinib.
  • the inflammatory and/or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, and refractory, moderate-to-severe atopic dermatitis.
  • Fedratinib and pacritinib are JAK2 inhibitors.
  • Fedratinib e.g., Inrebic
  • Pacritinib (e.g., Vonjo) is approved for use in intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 ⁇ 10 9 /L.
  • Pacritinib acts as an inhibitor of both JAK2 and FLT3 that could be used to overcome resistance in existing acute myeloid leukaemia (AML) treatments. Pacritinib was tested in glioblastoma multiforme in combination with temozolomide.
  • the JAK inhibitor is a JAK2 inhibitor.
  • the JAK2 inhibitor is fedratinib or pacritinib.
  • the disorder is intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis or intermediate- or high-risk primary or secondary (post- polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 ⁇ 10 9 /L.
  • Abrocitinib, baricitinib, and ruxolitinib are JAK1/2 inhibitors.
  • Abrocitinib e.g., Cibinqo
  • Baricitinib (e.g., Olumiant) is approved for use in moderate-to-severe rheumatoid arthritis.
  • Ruxolitinib (e.g., Jakafi) is approved for use in intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease. Baricitinib was authorized for emergency use for treatment of COVID-19 in combination with remdesivir.
  • Baricitinib was shown to improve symptoms of systemic lupus erythematosus and decrease inflammation/pruritus in atopic dermatitis when used with topical corticosteroids. Baricitinib is being studied in Aicardi goutieres syndrome and primary sjogren's syndrome. The combination of ruxolitinib and ERBB1/2/4 inhibitors also displayed synergistic anticancer activity against lung, breast, and ovarian cancer cells.
  • the JAK inhibitor is a JAK1/2 inhibitor.
  • the JAK1/2 inhibitor is abrocitinib, baricitinib, or ruxolitinib.
  • the inflammatory and/or autoimmune disorder is refractory, moderate-to-severe atopic dermatitis, moderate-to-severe rheumatoid arthritis, intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post- essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, or chronic graft-versus-host disease.
  • the inflammatory and/or autoimmune disorder is a result of a COVID-19 infection in the lung.
  • the inflammatory and/or autoimmune disorder is systemic lupus erythematosus, inflammation/pruritus in atopic dermatitis, Aicardi goutieres syndrome or primary sjogren's syndrome.
  • Tofacitinib is a JAK1/2/3 inhibitor.
  • Tofacitinib (e.g., Xeljanz) is approved for use in active psoriatic arthritis, moderate-to severe-rheumatoid arthritis, moderate-to-severe active ulcerative colitis, particular course juvenile idiopathic arthritis, and active ankylosing spondylitis. Trials are underway to study tofacitinib in COVID-19 related lung problems.
  • the JAK inhibitor is a JAK1/2/3 inhibitor.
  • the JAK1/2/3 inhibitor is tofacitinib.
  • the inflammatory and/or autoimmune disorder is active psoriatic arthritis, moderate-to severe-rheumatoid arthritis, moderate-to-severe active ulcerative colitis, particular course juvenile idiopathic arthritis, and active ankylosing spondylitis.
  • the inflammatory and/or autoimmune disorder is a result of a COVID-19 infection in the lung.
  • the inflammatory and/or autoimmune disorder is toxic epidermal necrolysis.
  • Delgocitinib is a non-selective JAK inhibitor that is approved for use in atopic dermatitis in Japan. Delgocitinib was tested and showed improvement in psoriasis and chronic hand eczema.
  • the JAK inhibitor is delgocitinib.
  • the inflammatory and/or autoimmune disorder is atopic dermatitis.
  • the inflammatory and/or autoimmune disorder is psoriasis or chromic hand eczema.
  • Peficitinib is a pan-JAK inhibitor approved for use in rheumatoid arthritis in Japan.
  • the pan-JAK inhibitor is peficitinib.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis.
  • Brepocitinib is being evaluated in active non-infectious non-anterior uveitis, dermatomyositis, and cicatricial alopecia.
  • Cerdulatinib is being evaluated for relapsed/refractory peripheral T-cell lymphoma, chronic lymphcytic leukemia, small lymphocytic lymphoma, B-cell non-hodgkin lymphoma, follicular lymphoma, T- cell lymphoma and vitiligo.
  • Decernotinib is a JAK3 inhibitor being evaluated for rheumatoid arthritis.
  • Deucravacitinib is being evaluated in pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pstulosis, crohn’s disease, ulcerative colitis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, and systemic lupus erythematosus, among others.
  • Gandotinib is a JAK2 inhibitor being evaluated for myeloproliferative disorders including myelofibrosis, graft-versus host disease, and rheumatoid arthritis.
  • Itacitinib is a JAK1 inhibitor being evaluated for acute graft-versus-host disease.
  • Momelotinib is being evaluated for primary myelofibrosis, polycythemia vera myelofibrosis, post- essential thrombocytopenia myelofibrosis, and non-small cell lung cancer, among others.
  • Nezulcitinib is being evaluated in COVID-19 related lung problems.
  • Ritlecitinib is a JAK3 inhibitor being evaluated for nonsegmental vitiligo, cutaneous T-cell lymphoma, cicatricial alopecia, and alopecia areata.
  • the JAK inhibitor is brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, icacitinib, momelotinib, nezulcitinib,or ritlecitinib.
  • the present disclosure provides a method of treating inflammatory and/or autoimmune disorders, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • a compound as described herein is administered as a replacement therapy for treating a disease associated with JAK activity.
  • the disease associated with JAK activity is an inflammatory and/or autoimmune disorder.
  • the inflammatory and/or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, refractory, moderate- to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post- polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 ⁇ 109/L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile id
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, crohn’s disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis.
  • the inflammatory and/or autoimmune disorder is non-infectious non- anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.
  • the present disclosure provides a method of treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, crohn’s disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating inflammatory and/or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.
  • the method further comprises administering to the subject a JAK inhibitor.
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.
  • the present disclosure provides a method of treating a disease, disorder, or medical condition mediated by JAK activity, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the disease, disorder, or medical condition mediated by JAK activity is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.
  • the present disclosure provides a method of treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the member of the JAK-STAT pathway is a janus kinase (JAK).
  • the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT).
  • the treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.
  • the present disclosure provides a method of inducing immune tolerance in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of suppressing a memory CD8+ T cell response in a subject in a subject having or at risk of developing an inflammatory response, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.
  • the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is a skin disorder. In some embodiments, the skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease or pancreatic cancer. In some embodiments, the cancer is lymphoma, leukemia, or multiple myeloma.
  • the myeloproliferative disorder is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).
  • the myeloproliferative disorder is myelofibrosis.
  • the myeloproliferative disorder is primary myelofibrosis (PMF).
  • the myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV MF). In some embodiments, the myeloproliferative disorder is post- essential thrombocythemia myelofibrosis (Post-ET MF).
  • 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 CBP, e.g., by inhibiting the activity or level of the CBP in a cell within a mammal.
  • An aspect of the present invention relates to methods of treating disorders related to CBP such as cancer in a subject in need thereof.
  • the compound is administered in an 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 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 organs distant from the primary tumor site. For example, after treatment, the number of metastatic 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.
  • 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 50x).
  • An aspect of the present invention relates to methods of treating disorders related to CBP such as inflammation and/or autoimmune disorders in a subject in need thereof.
  • the compound is administered in an 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 T cell (e.g., CD8 + memory T cells) activity, (b) reduced inflammation, (c) reduced thrombopoiesis, (d) reduced B cell proliferation, (e) increased survival of subject, and (f) increased progression free survival of a subject.
  • Treating inflammatory disorders and/or autoimmune disorders can result in a reduction in T cell (e.g., CD8 + memory T cells) activity.
  • T cell activity 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.
  • T cell activity may be measured by any reproducible means of measurement.
  • Treating inflammatory disorders and/or autoimmune disorders can result in a reduction in inflammation.
  • inflammation 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.
  • T cell activity may be measured by any reproducible means of measurement.
  • Treating inflammatory disorders and/or autoimmune disorders can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition, or a downstream affect such as CBP degradation).
  • each cytokine receptor is paired with a JAK pair.
  • the JAK pair When the JAK pair is cross-linked by its cytokine, the JAKs phosphorylate each other and also phosphorylate the cytokine receptor, which creates a STAT binding site for a STAT to then also become phosphorylated.
  • inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF- ⁇ , IL-6, IL-11, IL-13, IL-25, IL-27, and/or IL-31, which in turn can affect the immune system response.
  • cytokines that interact with JAK1, JAK3, and/or TYK2 include IL-10, IL-22, type 1 IFNs ( ⁇ / ⁇ ), IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.Treating cancer, inflammatory disorders, and/or autoimmune disorders 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 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.
  • Treating cancer, inflammatory disorders, and/or autoimmune disorders 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 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.
  • a method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer, inflammatory disorders, and/or autoimmune disorders or symptoms associated therewith, or in combination with other types of therapies to treat cancer, inflammatory disorders, and/or autoimmune disorders.
  • the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, 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).
  • chemotherapeutic agents e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer.
  • alkylating agents include alkylating 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
  • leucovorin LV
  • irenotecan oxaliplatin
  • capecitabine paclitaxel
  • doxetaxel Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl 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 topotecan); bryostatin; callystatin; CC-1065 (including
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic 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-norle
  • chemotherapeutic agents can be used in a cocktail to be administered in combination with the first 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); 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® (panit
  • 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 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 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; 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 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 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 JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib.
  • the first and second therapeutic agents are administered simultaneously or sequentially, in either order.
  • the first therapeutic agent may be 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 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 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 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.
  • compositions for nasal administration may 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 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 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 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.
  • 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 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).
  • kits including (a) a pharmaceutical composition including an agent that reduces the level and/or activity of CBP 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 CBP 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 CBP 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.
  • tert-Butyl 3-amino-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate A solution of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (20 g, 89 mmol) in EtOH (200 mL) was treated with hydrazine hydrate (80%) (6.7 g, 130 mmol) at 0°C. The reaction mixture was stirred for 2 h at 80°C. The reaction mixture was concentrated under reduced pressure, diluted with water (1.5 L) and extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L x 2), dried over anhydrous Na2SO4.
  • Step 2 tert Butyl 3bromo 1467tetrahydro5Hpyrazolo[4,3-c]pyridine-5-carboxylate
  • CuBr2 (15.5 g, 69 mmol) was added to a stirred solution of tert-Butyl 3-amino-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (15 g, 63 mmol) in ACN (100 mL).3-methylbutyl nitrite (11.1 mL, 63 mmol) was then added dropwise at 0°C. The reaction mixture was stirred for an additional 3 h at 60°C. The mixture was allowed to cool down to room temperature.
  • tert-Butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-5-carboxylate Cs2CO3 (32.4 g, 99.3 mmol) was added to a stirred solution of tert-Butyl 3-bromo-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (10 g, 33.1 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (8.95 g, 49.6 mmol) in DMF (100 mL).
  • the reaction mixture was stirred for 3.5 h at 80°C.
  • the resulting mixture was then diluted with water (700 mL) and extracted with EtOAc (700 mL x 2).
  • the organic layers were combined and washed with brine (1 L x 3), dried over anhydrous Na2SO4, and filtered.
  • the filtrate was concentrated under reduced pressure.
  • the second eluting isomer was collected and concentrated under reduced pressure.
  • Ac2O (596 mg, 5.8 mmol) was added in portions at 0°C to a stirred mixture of 6-Bromo-7-(difluoromethyl)- 1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4- tetrahydroquinoline (2.5 g, 5.3 mmol) and TEA (1.6 g, 15.9 mmol) in DCM (25.0 mL).
  • tert-Butyl 3-amino-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate Hydrazine hydrate (50-60% in water) (105 mL, 1.35 mol) was added to a solution of tert-butyl 3-cyano-4- oxopiperidine-1-carboxylate (10 g, 0.45 mol) in EtOH (600 mL). The resulting mixture was stirred for 2 h at 80°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was diluted with water (1.5 L) and extracted with DCM (1 L x 3).
  • the reaction mixture was then diluted with EtOAc (1 L) and washed with sat. NH4Cl (aq.) (600 mL x 4), 1 M HCl (600 mL x 3), and brine (600 mL x 2).
  • the organic phases were combined and dried over anhydrous Na2SO4 and removed the solvents under reduced pressure.
  • the crude was dried under a high vacuum for overnight to obtain the reddish solid.
  • Methyl tert-butyl ether (MTBE) was added portion-wise to the crude and stirred to make a slurry.
  • NBS (3.73 g, 21.0 mmol) was added to a stirred solution of 1-(3-(6-(difluoromethyl)-2,3-dihydro-4H- benzo[b][1,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1-one (9.07 g, 21.0 mmol) in MeCN (100 mL) in 3 portions at 0 °C.
  • tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate LiHMDS (792 mg, 4.73 mmol) was added dropwise at -78°C to a stirred solution of tert-butyl 6-oxo-2- azaspiro[33]heptane-2-carboxylate (500 mg 236 mmol) in THF (5 mL). The mixture was stirred for 0.5 h and then 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.69 g, 4.73 mmol) was added into the mixture.
  • tert-Butyl 9-(((trifluoromethyl)sulfonyl)oxy)-3-azaspiro[5.5]undec-8-ene-3-carboxylate Lithium bis(trimethylsilyl)amide (0.06 mL, 0.56 mmol) was added dropwise at -78°C to a stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (100 mg, 0.37 mmol) in THF (3 mL).
  • Ethyl [(5-bromo-2-formylpyridin-3-yl)carbamoyl]formate Ethyl chloroglyoxylate (441 mg, 3.23 mmol) was added in portions at 0 o C to a stirred solution of 3-amino- 5-bromopyridine-2-carbaldehyde (500 mg, 2.49 mmol) and pyridine (590 mg, 7.46 mmol) in DCM (6 mL). The resulting mixture was stirred for 1h at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with DCM (60 mL), washed with water (60 mL x 2) and saturated brine (60 mL x 3), dried over anhydrous Na2SO4.
  • Ethyl [(5-bromo-2-formylphenyl)carbamoyl]formate (512 mg, 3.75 mmol) was added dropwise at 0 o C to a stirred mixture of 2-amino-4- bromobenzaldehyde (500 mg, 2.50 mmol) and pyridine (593 mg, 7.50 mmol) in DCM (5 mL). The resulting mixture was stirred for an additional 1 h at room temperature. The reaction was quenched with water (100 mL). The mixture was extracted with DCM (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4.
  • Step 1.1-Chloro-2-(difluoromethyl)-5-fluoro-4-nitrobenzene DAST (19.8 g, 122.8 mmol) was added to a stirred solution of 2-chloro-4-fluoro-5-nitrobenzaldehyde (5.0 g, 24.6 mmol) in DCM (50 mL) at 0 °C. The resulting mixture was stirred for 16 h at rt. The reaction was quenched by the addition of sat. NH4HCO3 (aq.) (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (100 mL x 3).
  • N-(6-chloro-5-(difluoromethyl)pyridin-3-yl)-1,1-diphenylmethanimine t-BuONa (9.3 g, 96.5 mmol), XantPhos (8.6 g, 14.8 mmol) and Pd2(dba)3 (6.8 g, 7.4 mmol) was added to a stirred mixture of 5-bromo-2-chloro-3-(difluoromethyl)pyridine (18.0 g, 74.2 mmol) and diphenylmethanimine (13.5 g, 74.2 mmol) in toluene (200 mL) under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere.
  • Step 3.6-Chloro-5-(difluoromethyl)pyridin-3-amine 1M HCl (200 mL, 200 mmol) was added dropwise to a stirred solution of N-(6-chloro-5- (difluoromethyl)pyridin-3-yl)-1,1-diphenylmethanimine (34.2 g, 99.8 mmol) in THF (200 mL) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was diluted with water (200 mL), then extracted with EtOAc (500 mL x 2).
  • Ethyl (E)-3-(3-amino-6-chloro-5-(difluoromethyl)pyridin-2-yl)acrylate K 2 CO 3 (19.0 g, 137.5 mmol) and Pd(dppf)Cl 2 (3.4 g, 4.6 mmol) was added to a stirred mixture of 2-bromo- 6-chloro-5-(difluoromethyl)pyridin-3-amine (11.8 g, 45.8 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)prop-2-enoate (8.8 mg, 0.039 mmol) in dioxane (100 mL) and H2O (20 mL) under nitrogen atmosphere.
  • Step 8.6-Chloro-7-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine BH3-THF (70.93 mL, 70.94 mmol) was added dropwise to a stirred solution of 6-chloro-7-(difluoromethyl)- 3,4-dihydro-1,5-naphthyridin-2(1H)-one (5.5 g, 23.6 mmol) in THF (50 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched by the addition of MeOH (100 mL) at 0 °C.
  • Oxolane-3-carbonyl chloride (5 g, 37.16 mmol) was added dropwise at 0 0 C to a stirred solution of 1- (pyrazin-2-yl)methanamine (4.06 g, 37.16 mmol), and TEA (7.52 g, 74.32 mmol) in DCM (60 mL). The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was concentrated under vacuum.
  • Step 2.3-(Oxolan-3-yl)imidazo[1,5-a]pyrazine POCl3 (3.40 g, 22.20 mmol) was added dropwise at 0 °C to a stirred solution of N-(pyrazin-2- ylmethyl)oxolane-3-carboxamide (4.6 g, 22.20 mmol), and DMF (1.62 g, 22.20 mmol) in MeCN (60 mL). The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4HCO3 (aq.) (350 ml) at room temperature.
  • Step 3.1-Bromo-3-(oxolan-3-yl)imidazo[1,5-a]pyrazine NBS (2.35 g, 13.21 mmol) was added to a stirred solution of 3-(oxolan-3-yl)imidazo[1,5-a]pyrazine (2.5 g, 13.21 mmol) in ACN (25 mL). The mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (2.1 g) as an orange solid.
  • reverse FCC columnumn, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm
  • Step 5.6-Bromo-7-(difluoromethyl)-1-[3-(oxolan-3-yl)imidazo[1,5-a]pyrazin-1-yl]-3,4-dihydro-2H- quinoline A solution of NBS (1.10 g, 6.18 mmol) in HFIP (10 mL) was added dropwise at -10 °C to a stirred solution of 7-(difluoromethyl)-1-[3-(oxolan-3-yl)imidazo[1,5-a]pyrazin-1-yl]-3,4-dihydro-2H-quinoline (2.08 g, 5.62 mmol) in HFIP (20 mL).
  • Ac2O 115.12 mg, 1.128 mmol
  • 6-bromo-7- (difluoromethyl)-1-[3-(oxolan-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl]-3,4-dihydro-2H-quinoline (426 mg, 0.940 mmol) and TEA (285 mg, 2.82 mmol) in DCM (6 mL).
  • 2-methyl- (2.93 g, 27.49 mmol) was added dropwise at 0°C to a stirred solution of 1- (pyrazin-2-yl)methanamine (3 g, 27.49 mmol) and TEA (5.56 g, 54.98 mmol) in DCM (30 mL).
  • the resulting mixture was stirred at 0 °C for an additional 1 h.
  • the resulting mixture was diluted with water (100 mL).
  • the resulting mixture was extracted with CH2Cl2 (300 mL x 3).
  • Step 2.3-Isopropylimidazo[1,5-a]pyrazine POCl3 (2.08 mL, 22.32 mmol) was added dropwise at 0°C to a stirred solution of 2-methyl-N-(pyrazin-2- ylmethyl)propanamide (4 g, 22.32 mmol) and DMF (1.73 mL, 22.32 mmol) in ACN (40 mL). The resulting mixture was stirred for 1 h at 80 °C. The reaction was quenched with water/ice at 0 °C. The resulting mixture was basified to pH 8 with saturated Na2CO3 (aq.) and extracted with CH2Cl2 (300 mL x 3).
  • Step 4.7-(Difluoromethyl)-1- ⁇ 3-isopropylimidazo[1,5-a]pyrazin-1-yl ⁇ -3,4-dihydro-2H-quinoline XPhos Pd G3 (141 mg, 0.167 mmol) and t-BuONa (472 mg, 4.998 mmol) were added to a stirred solution of 1-bromo-3-isopropylimidazo[1,5-a]pyrazine (400 mg, 1.67 mmol) and 7-(difluoromethyl)-1,2,3,4- tetrahydroquinoline (305 mg, 1.67 mmol) in dioxane (5 mL).
  • Step 7.1- ⁇ 1-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-isopropyl-5H,6H,8H- imidazo[1,5-a]pyrazin-7-yl ⁇ ethenone TEA (112.24 mg, 1.110 mmol) was added dropwise at room temperature to a stirred solution of 6-bromo- 7-(difluoromethyl)-1- ⁇ 3-isopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl ⁇ -3,4-dihydro-2H-quinoline (158 mg, 0.370 mmol) and acetic anhydride (37.8 mg, 0.370 mmol) in DCM (3 mL).
  • Step 1.7-Chloro-6-(difluoromethyl)-4- ⁇ 3-isopropylimidazo[1,5-a]pyrazin-1-yl ⁇ -2,3-dihydro-1,4- benzoxazine XPhos Pd G3 (94.6 mg, 0.112 mmol) was added to a stirred solution of 1-bromo-3-isopropylimidazo[1,5- a]pyrazine (268 mg, 1.118 mmol), K3PO4 (712 mg, 3.35 mmol) and 7-chloro-6-(difluoromethyl)-3,4-dihydro- 2H-1,4-benzoxazine (245.5 mg, 1.118 mmol) in dioxane (3.5 mL).
  • Ac2O (40.0 mg, 0.392 mmol) was added to a solution of 7-chloro-6-(difluoromethyl)-4- ⁇ 3-isopropyl- 5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl ⁇ -2,3-dihydro-1,4-benzoxazine (150 mg, 0.392 mmol) and TEA (119 mg, 1.176 mmol) in DCM (1 mL).
  • N-(4-Chlorophenyl)-3-isopropyl-N-methylimidazo[1,5-a]pyrazin-1-amine Cs2CO3 (2.24 g, 6.87 mmol) and XPhos Pd G3 (193.90 mg, 0.229 mmol) was added to a stirred solution of 1-bromo-3-isopropylimidazo[1,5-a]pyrazine (550 mg, 2.29 mmol), 4-chlor-N-methylanilin (324 mg, 2.29 mmol) in dioxane (10 mL) The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere.
  • N-(4-Chlorophenyl)-3-isopropyl-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-amine (Cp*RhCl2) 2 (116 mg, 0.146 mmol) was added to a stirred solution of N-(4-chlorophenyl)-3-isopropyl-N- methylimidazo[1,5-a]pyrazin-1-amine (440 mg, 1.46 mmol) in HCOOH (5 mL) and TEA (7 mL). The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was diluted with water (50 mL).
  • Ac2O (176 mg, 1.72 mmol) was added to a stirred solution of N-(4-chlorophenyl)-3-isopropyl-N-methyl- 5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-amine (350 mg, 1.148 mmol) and TEA (349 mg, 3.44 mmol) in DCM (5 mL).
  • the resulting mixture was stirred for 1 h at room temperature.
  • the resulting mixture was concentrated under reduced pressure.
  • Ac2O (35.7 uL, 0.378 mmol) was added to a stirred solution of 4-(1-(6-chloro-7-(difluoromethyl)-3,4- dihydroquinolin-1(2H)-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)morpholine (80 mg, 0.189 mmol) and TEA (78.7 uL, 0.567 mmol) in DCM (3 mL).
  • Step 3.1-Bromo-3-cyclopropylimidazo[1,5-a]pyrazine NBS (2.80 g, 15.70 mmol) was added dropwise at 0°C to a stirred solution of N-(pyrazin-2- ylmethyl)cyclopropanecarboxamide (2.5 g, 15.70 mmol) in ACN (25 mL).
  • the resulting mixture was stirred for 1 h at room temperature.
  • the reaction was quenched by the addition of sat. sodium hyposulfite (aq.) (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4.
  • XPhos Pd G3 (284 mg, 0.336 mmol) was added to a stirred mixture of 1-bromo-3-cyclopropylimidazo[1,5- a]pyrazine (800 mg, 3.360 mmol), 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (616 mg, 3.360 mmol) and t-BuONa (969 mg, 10.08 mmol) in toluene (8 mL).
  • TEA TEA
  • Step 1.7-Chloro-4- ⁇ 3-cyclopropylimidazo[1,5-a]pyrazin-1-yl ⁇ -6-(difluoromethyl)-2,3-dihydro-1,4- benzoxazine t-BuONa 350.1 mg, 3.64 mmol
  • XPhos Pd G3 154.2 mg, 0.182 mmol
  • 7-chloro-6-(difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine 400 mg, 1.82 mmol
  • 1-bromo-3- cyclopropylimidazo[1,5-a]pyrazine 520.4 mg, 2.18 mmol
  • Step 2.7-Chloro-4- ⁇ 3-cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl ⁇ -6-(difluoromethyl)-2,3- dihydro-1,4-benzoxazine A solution of 7-chloro-4- ⁇ 3-cyclopropylimidazo[1,5-a]pyrazin-1-yl ⁇ -6-(difluoromethyl)-2,3-dihydro-1,4- benzoxazine (600 mg, 1.59 mmol) and PtO 2 (72.3 mg, 0.318 mmol) in MeOH (10 mL) was stirred for 3 h at room temperature under hydrogen atmosphere.
  • Step 2.3-(Oxetan-3-yl)imidazo[1,5-a]pyrazine Burgess reagent (3.95 g, 8.28 mmol) was added at 0 °C to a stirred solution of N-(pyrazin-2- ylmethyl)oxetane-3-carboxamide (1.60 g, 8.28 mmol) in DCM (10 mL). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (648 mg) as a yellow solid.
  • Step 4.7-(Difluoromethyl)-1-(3-(oxetan-3-yl)imidazo[1,5-a]pyrazin-1-yl)-1,2,3,4-tetrahydroquinoline t-BuONa 453.9 mg, 4.72 mmol
  • XPhos Pd G3 133.3 mg, 0.158 mmol
  • 1-bromo-3-(oxetan-3-yl)imidazo[1,5-a]pyrazine 400 mg, 1.57 mmol
  • 7-(difluoromethyl)-1,2,3,4- tetrahydroquinoline (288.4 mg, 1.57 mmol) in toluene (5 mL).
  • Ac2O 55.8 mg, 0.546 mmol
  • 6-bromo-7-(difluoromethyl)-1-(3-(oxetan-3- yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-1,2,3,4-tetrahydroquinoline 120 mg, 0.273 mmol
  • TEA 82.9 mg, 0.819 mmol
  • Step 2.3-Cyclobutylimidazo[1,5-a]pyrazine POCl3 (3.61 g, 23.53 mmol) was added dropwise at 0°C to a stirred mixture of N-(pyrazin-2- ylmethyl)cyclobutanecarboxamide (4.5 g, 23.53 mmol), and DMF (1.72 g, 23.5 mmol) in ACN (50 mL). The resulting mixture was stirred at 80°C for 1 h. The reaction was quenched by the addition of water (200 mL) at 0 °C. The resulting mixture was neutralized to pH 7 with saturated Na2CO3 (aq.).
  • Step 4.1- ⁇ 3-Cyclobutylimidazo[1,5-a]pyrazin-1-yl ⁇ -7-(difluoromethyl)-3,4-dihydro-2H-quinoline XPhos Pd G3 (0.34 g, 0.397 mmol) was added to a stirred mixture of 1-bromo-3-cyclobutylimidazo[1,5- a]pyrazine (1 g, 3.97 mmol), 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (0.73 g, 3.97 mmol) and t- BuONa (1.14 g, 11.90 mmol) in toluene (10 mL).
  • Step 5.6-Bromo-1- ⁇ 3-cyclobutylimidazo[1,5-a]pyrazin-1-yl ⁇ -7-(difluoromethyl)-3,4-dihydro-2H- quinoline NBS (276.2 mg, 1.55 mmol) was added in portions at 0°C to a stirred mixture of 1- ⁇ 3-cyclobutylimidazo[1,5- a]pyrazin-1-yl ⁇ -7-(difluoromethyl)-3,4-dihydro-2H-quinoline (500 mg, 1.41 mmol) in 1,1,1,3,3,3- hexafluoropropan-2-ol (5 mL). The resulting mixture was stirred for 2 h at -15 °C.
  • the resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 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 reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (119 mg) as a Brown yellow solid.
  • Step 4.5-[6-Chloro-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-N,1-dimethylpyrrolo[3,2- b]pyridine-3-carboxamide HATU 145.6 mg, 0.383 mmol was added to a stirred mixture of 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro- 2H-quinolin-1-yl]-1-methylpyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.255 mmol), methanamine hydrochloride (20.7 mg, 0.306 mmol) and DIEA (66 mg, 0.510 mmol) in DMF (1 mL).
  • H2O (37.3 mg, 0.890 mmol) was added to a stirred solution of methyl 5-[6-bromo-7-(difluoromethyl)- 3,4-dihydro-2H-quinolin-1-yl]-1-methylpyrrolo[2,3-c]pyridine-3-carboxylate (80 mg, 0.178 mmol) in THF (2 mL) and H2O (1 mL). The resulting mixture was stirred at room temperature for 2 h.
  • Step 2.2 3-Dimethyl 6-bromo-4-methylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate K2CO3 (535 mg, 3.87 mmol) was added to a stirred solution of 1-amino-3-bromo-5-methylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (500 mg, 1.29 mmol) and dimethyl acetylenedicarboxylate (275 mg, 1.94 mmol) in DMF (10 mL). The resulting mixture was stirred for 2 h at room temperature.
  • Step 3.6-Bromo-4-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid A solution of 2,3-dimethyl 6-bromo-4-methylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate (380 mg, 1.17 mmol) in sulfuric acid (8 mL) was stirred for 2 h at 120°C. The resulting mixture was diluted with water (50 mL) and neutralized to pH 5 with K2CO3. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Ethyl [(5-bromo-3-fluoro-2-formylphenyl)carbamoyl]formate Ethyl chloroglyoxylate (407 mg, 2.98 mmol) was added dropwise at 0°C to a stirred solution of 2-amino-4- bromo-6-fluorobenzaldehyde (500 mg, 2.29 mmol) and pyridine (544 mg, 6.88 mmol) in DCM (10 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with H2O (100 mL) and extracted with CH2Cl2 (100 mL x 3).
  • Methyl 7-fluoroquinoline-4-carboxylate Pd(dppf)Cl2CH2Cl2 (1.44 g, 1.77 mmol) was added to a solution of 4-bromo-7-fluoroquinoline (2 g, 8.85 mmol) and TEA (2.69 g, 26.54 mmol) in MeOH (60 mL). The resulting mixture was stirred for overnight at 100°C under 20 atm with carbon monoxide atmosphere. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (200 mL x 3) The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Methyl 2- ⁇ [6-(benzyloxy)-5-fluoro-3-nitropyridin-2-yl]oxy ⁇ acetate Methyl 2-hydroxyacetate (947 mg, 10.52 mmol) was added to a stirred mixture of 2-(benzyloxy)-3,6-difluoro- 5-nitropyridine (1.4 g, 5.26 mmol) and K2CO3 (1.45 g, 10.52 mmol) in DMF (20 mL). The resulting mixture was stirred for 1h at room temperature. The resulting mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL x 3).
  • Step 3.6-(Benzyloxy)-7-fluoro-1H,3H-pyrido[2,3-b][1,4]oxazin-2-one Fe (1.25 g, 22.30 mmol) was added to a stirred solution of methyl 2- ⁇ [6-(benzyloxy)-5-fluoro-3-nitropyridin- 2-yl]oxy ⁇ acetate (1.5 g, 4.46 mmol) in EtOH (10 mL), AcOH (2 mL) and H2O (8 mL). The resulting mixture was stirred for 1h at 80°C. After the reaction was completed, filtered while hot and concentrated under reduced pressure to give crude product.
  • Ac2O (263 mg, 2.58 mmol) was added to a stirred solution of 6-(benzyloxy)-7-fluoro-1-(1-(tetrahydro-2H- pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (800 mg, 1.72 mmol) and Et3N (869 mg, 8.59 mmol)
  • Step 4 tert-Butyl 4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-bromo-2,3- dihydroquinoxaline-1-carboxylate NBS (332.6 mg, 1.87 mmol) was added in portions to a stirred solution of tert-butyl 4-[5-acetyl-1-(oxan-4- yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydroquinoxaline-1-carboxylate (750 mg, 1.56 mmol) in MeCN (10 mL).
  • Ac2O (1.56 mL, 16.51 mmol) was added to a stirred solution of 6-chloro-7-(difluoromethyl)-1-(1-(tetrahydro- 2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (3.5 g, 8.26 mmol) and TEA (3.44 mL, 24.77 mmol)
  • Step 6 1-(3- ⁇ 7-Chloro-2H,3H-pyrido[4,3-b][1,4]oxazin-4-yl ⁇ -1-(oxan-4-yl)-4H,6H,7H-pyrazolo [4,3- c]pyridin-5-yl)ethanone
  • Ac2O 75 mg, 0.735 mmol
  • 3- ⁇ 7-chloro-2H,3H-pyrido[4,3- b][1,4]oxazin-4-yl ⁇ -1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c]pyridine (251 mg, 0.668 mmol) and Et3N (338 mg, 3.34 mmol) in DCM (3 mL).
  • ethyl 2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetate (2.03 g, 3.48 mmol) in THF (10 mL) and H2O (10
  • the reaction mixture was stirred for 2 h at room temperature.
  • the crude product was purified by Prep-HPLC (Column: Xselect Peptide CSH C18 19*150mm 5 ⁇ m, 1; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 52% B in 7 min, 52% B; Wave Length: 254/220 nm; RT1(min): 6.25) affording the title compound (16.5 mg, 0.017 mmol) as a white solid.
  • Example 115 (2S,4R)-1-((S)-2-(2-(6-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2- azaspiro[3.3]heptan-2-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide Step 1.
  • the reaction mixture was stirred for 2 h at room temperature.
  • the reaction mixture was directly purified by Prep-HPLC (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: 18% B to 37% B in 8 min, 37% B; Wave Length: 254/220 nm; RT1(min): 9.15) affording the title compound (11.8 mg, 0.012 mmol) as a white solid.
  • Dimethyl (1-diazo-2-oxopropyl)phosphonate (50.3 mg, 0.26 mmol) was added dropwise at 0 °C to a stirred solution of 1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7- (difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (100 mg, 0.22 mmol) and K2CO3 (9
  • the reaction mixture was stirred for 1 h at room temperature.
  • the crude product was purified by Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5 ⁇ m, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min; Wave Length: 220 nm; RT1(min): 7.27) affording the title compound (26.6 mg, 0.28 mmol) as a white solid.
  • the reaction mixture was stirred at room temperature for 1 h.
  • the reaction mixture was purified directly by Prep-HPLC (Column: Xselect Peptide CSH C1819*150mm 5 ⁇ m, 1; Mobile Phase A: Water (0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 38% B in 8 min, 38% B; Wave Length: 254/220 nm; RT1(min): 10.73) affording the title compound (24.7 mg, 0.025 mmol) as an orange solid.
  • Example 130 (2S,4R)-1-((S)-2-((5-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrimidin-2- yl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide Step 1.1-(3-(7-(Difluoromethyl)-6-(2-fluoropyrimidin-5-yl)-3,4-dihydroquinolin-1(2H)-yl)-1- (tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-
  • the reaction mixture was stirred for overnight at 100°C.
  • the crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 8.47) affording the title compound (18.7 mg, 0.020 mmol) as a white solid.
  • Example 537 U2OS HiBiT Degradation Assay Procedure: A set of two CRISPR knock-in stable U2OS polyclonal cell lines, each with a HiBiT tag fused to either CREBBP or EP300 were purchased from Promega. On day 0, 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.
  • the cells were aspirated from the media, washed with sterile 1XPBS and treated with Trypsin. Cell were resuspended in media and the cells were counted with Cell Counter. On day 1, cells were treated with 12uL DMSO or 36uL of 3-fold serially DMSO-diluted compound 1 (10 points in duplicates with 1uM as final top dose). Subsequently plates were incubated over 168 hours in a standard culture incubator (Corning 3764) and equilibrated at room temperature for 15 minutes. Luciferase activity was measured by adding 40 uL of CellTiter-Glo reagent, and reading the luminesce using an Envision reader.
  • Example 528 CTG Assay on gastric cancer cell lines Procedure: A set of gastric cancer cell lines (IM95, AGS) in 1640 medium with 10%FBS, 1% Penicillin- Streptomycin at 37°C, 5% CO 2 . On day 0, the cells were aspirated from the media, washed with sterile 1XPBS and treated with Trypsin. Cell were resuspended in media and the cells were counted with Cell Counter. On day 1, cells were treated with 12uL DMSO or 36uL of 3-fold serially DMSO-diluted compound 6 (10 points in duplicates with 1uM as final top dose).
  • the GI50 for AGS was 0.04 mM, while the GI50 for IM95 was greater than 10 mM.
  • Treatment of the cell lines with CBP degraders can result in dose-dependent reduction in cell proliferation of EP300mut gastric cancer cell lines as compared to EP300/CBPwt gastric cancer cell lines ( Figure 4).
  • Example 539 CTG Assay on colorectal cancer cell lines Procedure: A set of colorectal cancer cell lines (HT29, and RKO) in 1640 medium with 10%FBS, 1% Penicillin-Streptomycin at 37°C, 5% CO 2 . On day 0, the cells were aspirated from the media, washed with sterile 1XPBS and treated with Trypsin.
  • Example 540 CBP Selective PD in CBP/EP300 Wild type Cell Line MM1S Method for Tumor Inoculation
  • MM.1S human multiple myeloma tumor cells (1 x 10 7 ) in 100 ⁇ L RPMI 1640 with 10% FBS and Matrigel mixture (1:1 ratio) for the tumor development.
  • the treatment started when the mean tumor size reached about 254 mm 3 .Mice were randomized into each group and treated according to study design.
  • Tumor Measurements The measurement of tumor size was conducted once a week with a caliper and recorded.
  • Vehicle Vehicle for compound 132 5% DMSO, 10% solutol, 85% 20% HP- ⁇ -CD in water.
  • Samples Collection At the end of study, plasma was collected at 0.5h, 2h, 4h, 6h, 12h and 24h post last dose. The tumors were collected at 2h, 6h and 24h, which were cut into 2 pieces, one piece for WB analysis, one piece snap frozen for backup. Liver, spleen, kidney, lung and muscle (right flank near tumor site) were collected at 2h, snap freeze and store the samples at -80 o C.
  • Example 541 Global Proteomics in U2OS Osteosarcoma Cell Lines Shows Selectivity for CBP After treatment with compound 6, media was aspirated and cells were twice washed with PBS. Cells were then dissociated from the culture plate using cold PBS with 1mM EDTA, pelleted, and washed twice with cold PBS. Cells were then snap frozen in liquid nitrogen and stored at -80 0 C until lysis. After thawing on ice, cells were then lysed in 100ul 8M Urea, 50mM NaCl with 1x protease inhibitor cocktail.
  • Lysates were then sonicated using ten 1 second pulses and centrifuged at 17,000g for 5 min at 4 0 C. The supernatant lysate was then quantified using a BCA assay (Pierce), 150 ug were taken from each sample and the volume was normalized to 100ul in lysis buffer. Samples were then reduced with 15 mM DTT for 1 hr at room temperature under shaking, alkylated with 20 mM iodoacetamide for 20 minutes in the dark at room temperature under shaking, and methanol-chloroform precipitated.
  • Resulting protein pellets were then resuspended in 100ul of 200 mM 3-[4-(2- Hydroxyethyl)piperazin-1-yl]propane-1-sulfonic acid (EPPS) pH 8.0 and digested overnight with 2ug trypsin/lys-C (Promega). Peptides were then quantified using a fluorometric peptide assay (Pierce).50 mg of peptide was brought to 100 ul in 200 mM EPPS pH 8.0, 25% acetonitrile (ACN). Peptides were then labeled with 5 ul from a 20 ug/ul stock of TMTpro 18-plex labels (Thermo Fisher) in ACN.
  • the sample was fractionated into a 96 well plate by high pH reverse-phase HPLC with a mobile phase A of 5% ACN, 10 mM ammonium bicarbonate pH 8.0 and a mobile phase B of 90% ACN, 10 mM ammonium bicarbonate pH 8.0. Fractions were then combined into 24 fractions to maximize elution coverage. Combined fractions were dried in a speedvac and resuspended in 5% ACN, 5% formic acid.12 fractions were chosen to run on one hour gradients each. Mass spectrometric data were collected on an Oribtrap Lumas couple to an EASY nanoLC-1200 (ThermoFisher) or Vanquish Neo liquid chromatography system.
  • peptides were loaded on a 75 ⁇ m capillary column packed in-house with Sepax GP-C18 resin (1.8 ⁇ m, 150 ⁇ , Sepax) to a final length of 35 cm.
  • Peptides for total protein analysis were separated using a 60 minute linear gradient from 14% to 40% acetonitrile in 0.1% formic acid.
  • CID collisional-induced dissociation
  • NCE normalized collision energy
  • NCE normalized collision energy
  • NCE isolation window
  • AGC target of 1e4 A real-time search
  • Online spectral identification was accomplished via a custom software client that monitors spectral acquisition though a vendor supplied instrument application programming interface and assigns peptide sequences through a probabilistic model, in real-time (Orbitrap Lumos).
  • the RTS client utilized a peptide database composed of in-silico predicated organism specific tryptic peptides.
  • Mass spectra were processed using Proteome Discoverer (ThermoFisher). Database searching included all entries from the Human Reference Proteome (2018-12) as well as a curated list of contaminants. A maximum of two missed cleavages was allowed and the minimum peptide length was set to 7 amino acids. Searches used a 20 ppm precursor ion tolerance for total protein level analysis. Product ion parameters were set to a tolerance of 1.0005, a fragment bin offset of 0.4, and theoretical fragment ions set to 1.
  • TMTpro tag labeling on peptide N-termini and lysine residues (+304.2071 Da) and carbamidomethylation of cysteine residues (+57.0215 Da) were set as a static modification, while oxidation of methionine residues (+15.9949 Da) was set as a variable modification.
  • Peptide-spectrum matches (PSMs) were set to a false discovery rate of 2. For TMT reporter ion quantifications, the summed signal to noise ratio for each TMT channel was extracted and the most confident centroid to the expected mass of the TMT reporter ion was found, with an integration tolerance of 0.001 Daltons.
  • Example 542 Selective CBP Degradation Does Not Show Thrombocytopenia in Mice at Pharmacologically Relevant Doses
  • the plasma samples were collected at 0.25h, 2h, 6h, 12h (pre-last dose), 12.25h (0.25h post last dose) and 24h (12h post last dose) post penultimate dose for PK analysis.
  • the CBC and BC samples were collected at 12.25h (0.25h post last dose) and 24h (12h post last dose).
  • Results Others have reported significant, but reversible, thrombocytopenia for dual CBP/EP300 bromodomain inhibitors (Katavolos et al., Toxicol Pathol, 2020).
  • Dual bromodomain inhibitors were known to decrease platelet counts in vivo and display adverse events related to platelets in the clinic. The observation of decreased platelet counts recapitulated in mice with dual bromodomain inhibitor GNE-781 to a similar degree as reported. Surprisingly, our EP300 degraders show a slight increase in platelets at relevant doses (Figure 8). Regarding the safety profile, animals tolerated well with the treatment of compound 132 during the study period. Additionally, no clinical abnormalities were observed in any of the animals treated.
  • Example 543 U2OS IF Degradation Assay Procedure: A set of two CRISPR knock-in stable U2OS polyclonal cell lines, each with a HiBiT tag fused to either CREBBP or EP300 were purchased from Promega.
  • 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, 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 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.
  • R 1 is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 carbocycle, or C 2 -C 12 heterocycle, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 carbocycle, and C 2 -C 12 heterocycle of R 1 is optionally substituted with A 1 and/or one or more groups R b ;
  • R 2 is C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), (C 1 -C 20 heteroaryl)(C6- C 20 aryl), and (C 1 -C 20 heteroaryl)(C 1 -C 20 heteroaryl), wherein each
  • R 1 is C 1 –C 12 alkyl, C 2 –C 12 alkenyl, C 2 –C 12 alkynyl, C 3 –C 12 carbocycle, or C 3 –C 12 heterocycle, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 carbocycle, and C 3 -C 12 heterocycle is optionally substituted with A 1 and/or one or more groups R b ;
  • R 2 is C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), (C 1 -C 20 heteroaryl)(C6- C 20 aryl), or (C 1 -C 20 heteroaryl)(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6
  • R 4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
  • R 4 has the structure: .
  • E11 The compound of any one of embodiments 2 to 10, wherein the CBP binding moiety has the structure: . E12.
  • R 8 is C 1 -C 12 alkyl, C 3 -C 12 carbocycle, or C 3 -C 12 heterocycle, wherein each C 1 -C 12 alkyl, C 3 -C 12 carbocycle, and C 3 -C 12 heterocycle is optionally substituted with one or more groups R o ;
  • R 9 is C 1 -C 4 alkyl, C(O)N(R h2 ) 2 , S(O)N(R h2 ) 2 , S(O) 2 , C(O)R h2 , C(O)OR h2 , S(O) 2 R h2 , C 2 –C 6 heteroaryl, or C 2 -C 9 heterocycle wherein any C 1 -C 4 alkyl, C 2 –C 6 heteroaryl, or C 2 -C 9 heterocycle is optionally substituted one or more substituent groups independently selected from F, Cl, Br
  • R 9 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
  • R 9 has the structure: .
  • E17 The compound of embodiment 12, wherein the CBP binding moiety has the structure: . E18.
  • R 10 has the structure: , wherein X3 is NR N2 , CH2, or O; X4 is N, CH; X5 is N, CH; X6 is NR N2 , CH2, or O; R 14 is CHF2, CHCl2, CH3, Cl, F, or H, and each R N2 is independently, C1-C3 alkyl or H. E19.
  • R 10 has the structure: . E21.
  • the compound of embodiment 12, wherein the CBP binding moiety has the structure: . E22.
  • R 1 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C 3 -C 12 carbocycle, or C2-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C 3 -C 12 carbocycle, and C2-C12 heterocycle of R 1 is optionally substituted with A 1 and/or one or more groups R b ;
  • R 2 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- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroary
  • R 1 is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 carbocycle, or C 3 -C 12 heterocycle, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 carbocycle, and C 3 -C 12 heterocycle is optionally substituted with A 1 and/or one or more groups R b ;
  • R 2 is C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), (C 1 -C 20 heteroaryl)(C6- C 20 aryl), or (C 1 -C 20 heteroaryl)(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (
  • R 4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
  • R 4 has the structure: .
  • E32 The compound of any one of embodiments 22 to 31, wherein the CBP binding moiety has the structure: . E33.
  • the compound of embodiment 1, wherein the CBP binding moiety has the structure: Formula III-C wherein: X1 is C or N; X2 is C or N; R 5 is C 1 -C 12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C 1 - C12alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 5 is optionally substituted with one or more groups R k1k ; R 6 is C 1 -4alkyl, C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), (C 1 -C 20 heteroaryl)- (C 6 -C 20 aryl), and (C 1 -C 20 heteroaryl)(C 1 -C 20 heteroaryl), C(O)N(R h1 ) 2 , S(O)N(R h1 ) 2 , S(O)
  • R 11 is C 1 -C 12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C 1 - C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 11 is optionally substituted with one or more groups R M ;
  • R 12 is C 1 –C 4 alkyl, C(O)N(R h3 ) 2 , S(O)N(R h3 ) 2 , S(O)N(R h3 ) 2 , C(O)R h3 , C(O)OR h3 , S(O)R h3 , or S(O)R h3 , wherein any C 1 -C 4 alkyl is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(R h3
  • R 1c is A 1 , NR 2a R 3a , C 6 -C 20 aryl, C 2 -C 9 heterocyle, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 - C 20 heteroaryl), (C 1 -C 20 heteroaryl)-(C 6 -C 20 aryl), and (C 1 -C 20 heteroaryl)(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl) and (C 1 -C 20 heteroaryl)-(C 1 -C 20 heteroaryl) is independently optionally substituted with A 1 and/or one or more substituent groups independently selected from R 1h , oxo, F, Cl, Br, I, C 1 -C 9 alkyl, C 1 -C 9 heteroalkyl, CHF 2 , CF 3
  • R 10 has the structure: or , wherein X3 is NR N2 , CH2, or O; X4 is N, CH; X5 is N, CH; X6 is NR N2 , CH2, or O; R 14 is CHF 2 , CHCl2, CH3, Cl, F, or H, and each R N2 is independently, C 1 -C 3 alkyl or H.
  • X3 is NR N2 , CH2, or O
  • X4 is N, CH
  • X5 is N, CH
  • X6 is NR N2 , CH2, or O
  • R 14 is CHF 2 , CHCl2, CH3, Cl, F, or H
  • each R N2 is independently, C 1 -C 3 alkyl or H.
  • R 1 is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 carbocycle, or C 2 -C 12 heterocycle, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 carbocycle, and C 2 -C 12 heterocycle of R 1 is optionally substituted with A 1 and/or one or more groups R b ;
  • R 2 is C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), (C 1 -C 20 heteroaryl)(C6- C 20 aryl), and (C 1 -C 20 heteroaryl)(
  • R 1 is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 carbocycle, or C 3 -C 12 heterocycle, wherein each C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 carbocycle, and C 3 -C 12 heterocycle is optionally substituted with A 1 and/or one or more groups R b ;
  • R 2 is C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), (C 1 -C 20 heteroaryl)(C 6 - C 20 aryl), or (C 1 -C 20 heteroaryl)(C 1 -C 20 heteroaryl), wherein each C 6 -C 20 aryl, C 1 -C 20 heteroaryl, wherein each C 6 -C
  • R 4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.
  • R 4 has the structure: .
  • E66 The compound of embodiment 35, wherein the CBP binding moiety has the structure: Formula III-C wherein: X1 is C or N; X2 is C or N; R 5 is C 1 -C 12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C 1 - C12alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 5 is optionally substituted with one or more groups R k1k ; R 6 is C 1 -4alkyl, C 6 -C 20 aryl, C 1 -C 20 heteroaryl, (C 6 -C 20 aryl)(C 1 -C 20 heteroaryl), (C 1 -C 20 heteroaryl)- (C 6 -C 20 aryl), and (C 1 -C 20 heteroaryl)(C 1 -C 20 heteroaryl), C(O)N(R h1 ) 2 , S(O)N(R h1 ) 2 , S
  • R 11 is C 1 -C 12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C 1 - C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R 11 is optionally substituted with one or more groups R M ;
  • R 12 is C 1 –C 4 alkyl, C(O)N(R h3 ) 2 , S(O)N(R h3 ) 2 , S(O)N(R h3 ) 2 , C(O)R h3 , C(O)OR h3 , S(O)R h3 , or S(O)R h3 , wherein any C 1 -C 4 alkyl is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(R h3 ) 2
  • E79 The compound of any one of embodiments 1 to 79, wherein the degradation moiety is a ubiquitin ligase binding moiety.
  • E80 The compound of embodiment 12, 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.
  • IAP Inhibitors of Apoptosis
  • MDM2 mouse double minute 2 homolog
  • VHL von Hippel-Lindau
  • the compound of any one of embodiments 1 to 80, wherein the degradation moiety comprises the structure of Formula IV: Formula IV, wherein R B1 is H, A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B2 is H, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3 is A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 –C 6 alkyl C 3 -C 10 carbocyclyl, or optionally substituted C 1 –C 6 alkyl C 6 -C 10 aryl; R B4 is H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbo
  • R B1 is H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl
  • R B3 is A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 –C 6 alkyl, C 3 -C 10 carbocyclyl, or optionally substituted C 1 –C 6 alkyl wherein the C 1 –C 6 alkyl, C 1 –C 6 heteroalkyl, C 3 -C 10 carbocyclyl, C 6 -C 10 aryl, C 1 –C 6 alkyl, C 3 -
  • the compound of embodiment 93, wherein the structure of Formula V-D is E95.
  • the compound of embodiment 93, wherein the degradation moiety has the structure: Attorney Docket No.51121-086WO3 PATENT . E96.
  • the compound of embodiment 93, wherein the degradation moiety has the structure: . E97.
  • R C1 is optionally substituted C 1 -C 6 alkyl
  • R C2 is A 2 , or optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, wherein each C1-C6 alkyl, C3-10 carbocyclyl, C1-C6 heteroalkyl, C6-C10 aryl, or C2-C9 heteroaryl is optionally substituted with A 2 and/or one or more groups R J ;
  • R C3 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl;
  • R C4 is H, optionally substituted C1
  • the compound of embodiment 97, wherein the linker-degradation moiety has the structure: E99.
  • E100 The compound of any one of embodiments 1 to 80, wherein the degradation moiety has the structure of Formula V-F: or a derivative or analog thereof.
  • E101 The compound of any one of embodiments 1 to 80, wherein the degradation moiety comprises the structure of Formula V: Formula V, wherein R B1a is H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B2a is H, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3a is A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B4a is H, optionally substituted C 1 –C 6 alkyl
  • the compound of embodiment 129, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-A): Formula V-A, wherein R B1a is H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B2a is H, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3a is A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B4a is H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl;
  • E103 The compound of embodiment 129, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-B): Formula V-B, wherein R B1a is H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B2a is H, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3a is A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B4a is H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 ary
  • each R B6 is, independently, halogen, optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, hydroxy, thiol;
  • R B9 is, independently, H, or optionally substituted C 1 –C 6 alkyl;
  • R B10 is, independently, H, or optionally substituted C 1 –C 6 alkyl, and v2 is 0, 1, 2, 3, or 4.
  • R B6a is . wherein each R B6 is, independently, halogen, optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 - C6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, hydroxy, thiol; R B11 is optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl; R B9 is, independently, H, or optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 - C
  • each R B6 is, independently, halogen, optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 - C6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; each of R B7 and R B8 is, independently, H, halogen, optionally substituted C 1 –C 6 alkyl, or optionally substituted C 6 -C 10 aryl; and R B9 and R B10 are, independently, H, or optionally substituted C 1 –C 6 alkyl.
  • the compound of embodiment 129, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula V-C: Formula V-C, R B1 is H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3 is A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 –C 6 alkyl, C 3 -C 10 carbocyclyl, or optionally substituted C 1 –C 6 alkyl wherein the C 1 –C 6 alkyl, C 1 –C 6 heteroalkyl, C 3 -C 10 carbocyclyl, C 6
  • R C1 is optionally substituted C 1 –C 6 alkyl
  • R C2 is A 2 , or optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, wherein each C 1 –C 6 alkyl, C3-10 carbocyclyl, C 1 –C 6 heteroalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl is optionally substituted with A 2 and/or one or more groups R J ;
  • R C3 is H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6
  • the compound of embodiment 125, wherein the linker-degradation moiety has the structure: E127.
  • the compound of embodiment 125, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula V-F: Formula V-F, wherein R B1 is H, A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, or optionally substituted C 1 –C 6 heteroalkyl; R B3 is A 2 , C(O)A 2 , optionally substituted C 1 –C 6 alkyl, optionally substituted C 1 –C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B4 is H, optionally substituted C 1 –C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl; R B5 is H, optionally substituted C 1 –C
  • E128 The compound of embodiment 127, wherein the degradation moiety has the structure of Formula V-F: or a derivative or analog thereof.
  • E129. The compound of any one of embodiments 1 to 128, wherein L has the structure of Formula II: A 1 –(F)–(E)m–C-A 2 , Formula II wherein A 1 is a bond between the linker and A; A 2 is a bond between B and the linker; m is 0 or 1; C is absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; E is absent, optionally substituted C1–10 alkylene; and F is optionally substituted C2–10 heterocyclylene or optionally substituted C 2 -C 9 heteroarylene.
  • the compound of embodiment 129, wherein m is 0. E131.
  • E132. The compound of any one of embodiments 1 to 129, wherein E is methylene or ethylene.
  • E133. The compound of any one of embodiments 1 to 129, wherein E is methylene, ethylene, , E134.
  • C is carbonyl.
  • E135. The compound of any one of embodiments 1 to 129, wherein C is absent.
  • E136. The compound of any one of embodiments 1 to 129, wherein F is optionally substituted C2–10 heterocyclylene.
  • E137. The compound of any one of embodiments 1 to 129, wherein F is: E139.
  • E146 The compound of any one of embodiments 1 to 143, wherein the compound is any one of compounds 1 to 536, or a pharmaceutically acceptable salt thereof.
  • E147. The compound of any one of embodiments 1 to 143, wherein the compound is any one of compounds 1A to 28A of Table 2, or a pharmaceutically acceptable salt thereof.
  • E148. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 147 and a pharmaceutically acceptable excipient.
  • E149 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 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.
  • the method of embodiment 149 wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophogeal, stomach, or lung cancer.
  • E151. The method of embodiment 150, wherein the cancer is gastric cancer.
  • E152. A method of treating gastric 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 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.
  • E153 A method of treating gastric 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 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.
  • any one of embodiments 149 to 152, wherein the cancer is metastatic.
  • E154. The method of any one of embodiments 149 to 153, wherein the subject or cancer has a EP300 loss of function mutation.
  • E155. The method of any one of embodiments 149 to 154, wherein the method further comprises administering to the subject an anticancer therapy.
  • E156. The method of embodiment 155, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof.
  • a method of treating inflammatory and/or autoimmune disorders in a subject in need thereof including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. E158.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.
  • the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’
  • the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.
  • a method of treating a disease, disorder, or medical condition mediated by member of the JAK- STAT pathway including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.
  • E162. The method of embodiment 161, wherein the member of the JAK-STAT pathway is a janus kinase (JAK).
  • JAK-STAT pathway is a signal transducer and activator of transcription (STAT).
  • the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.
  • E165 A method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.
  • E166 A method for inhibiting an inflammatory or autoimmune response in a subject in need thereof, including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.
  • E167 A method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.
  • a method of suppressing a memory CD8 + T cell response in a subject in a subject having or at risk of developing an inflammatory response including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.
  • E168. A method of treating an infection 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 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.
  • E169. The method of embodiment 109, wherein the infection is Herpesvirus K*. E170.
  • a method of treating rubinstein taybi syndrome in a subject in need thereof including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148.

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Abstract

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

Description

COMPOUNDS AND USES THEREOF BACKGROUND OF THE INVENTION CREB-binging protein (CBP) is a transcriptional co-activator that maintains gene expression programs through lysine acetylation and acts as a protein scaffold that helps recruit and construct the complexes that are necessary for transcription or chromatin remodeling. CBP is involved in cell differentiation, apoptosis, and the cell cycle. The present invention is related to useful compositions and methods for the treatment of CBP-related disorders, such as cancer and infection. SUMMARY CREB-binding protein is an intracellular protein that regulates the expression of genes and is critical for establishing and activating enhancer-mediated transcription. CBP is overexpressed in multiple cancer cell lines. Accordingly, agents that reduce the levels and/or activity of CBP may provide new methods for the treatment of disease and disorders, such as cancer and infection. The inventors have found that depleting CBP results in the downregulation/depletion of MYC in those cells. Thus, agents that degrade CBP (e.g., compounds) are useful in the treatment of disorders (e.g., cancers or infections) related to CBP and/or MYC. The present disclosure features compounds and methods useful for treating CBP-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 a CBP binding moiety; B is a degradation moiety; and L has the structure of Formula II: A1–(F)–(E)m–C-A2, Formula II wherein A1 is a bond between the linker and A; A2 is a bond between B and the linker; m is, independently, 0 or 1; C is, independently, absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; E is, independently, absent, O, S, NRN, optionally substituted C1–C10 alkylene, optionally substituted C2- C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene wherein any C1–C10 alkylene, C2-C10 alkenylene, C2-C10 alkynylene, C2-C10 polyethylene glycol, or C1–C10 heteroalkylene 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, C(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)2, 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 RN is, independently, H, optionally substituted C1–C4 alkyl, optionally substituted C2–C4 alkenyl, optionally substituted C2–C4 alkynyl, optionally substituted C2–C6 heterocyclyl, optionally substituted C6–C12 aryl, or optionally substituted C1–C7 heteroalkyl wherein any C1–C4 alkyl, C2–C4 alkenyl, C2–C4 alkynyl, C2–C6 heterocyclyl, C6–C12 aryl, or C1–C7 heteroalkyl 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, C(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)2, 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; F is, independently, optionally substituted C3-C10 carbocyclylene, optionally substituted C2-C10 heterocyclylene, optionally substituted C6-C10 arylene, or optionally substituted C2-C9 heteroarylene, wherein any C3-C10 carbocyclylene, C2-C10 heterocyclylene, C6-C10 arylene, or C2-C9 heteroarylene 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, C(O)Rf, S(O)2Rf, C(O)ORf, 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, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, C(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)2, 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; each Rg is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, 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 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; or a pharmaceutically acceptable salt thereof.In some embodiments, the linker has the structure of Formula II: A1–(F)–(E)m–C-A2. Formula II In some embodiments, A1 is a bond between the linker and A. In some embodiments, A2 is a bond between B and the linker. In some embodiments, m is 0. In some embodiments, E is absent. In some embodiments, m is 1. In some embodiments, E is optionally substituted C1–10 alkylene. In some embodiments, E is methylene or ethylene.
Figure imgf000005_0001
In some embodiments, F is optionally substituted C2-C9 heteroarylene. In some embodiments, F is the structure:
Figure imgf000005_0002
, wherein X7 and X8 are each independently C or N; and R15 and R16 combine with the atoms to which they are attached to form an optionally substituted 3-12 membered heteroaryl, wherein the heteroaryl is optionally substituted with A1 and/or one or more of the following groups: halogen or C1–C6 alkyl.
Figure imgf000005_0003
I
Figure imgf000006_0001
, In some embodiments, F is optionally substituted C2-C10 heterocyclylene.
Figure imgf000006_0002
In some embodiments, C is absent. In some embodiments, C is carbonyl. In some embodiments, the CBP binding moiety has the structure of Formula III:
Figure imgf000006_0003
Formula III wherein X1a is, independently, C or N; X2a is, independently, C or N; R1a and R1b , independently,combine with the atoms to which they are attached to form an optionally substituted C3-C10 carbocycle, an optionally substituted C5-C10 aryl, an optionally substituted C3-C9 heteroaryl, or optionally substituted C3-C9 heterocycle, wherein the carbocycle, aryl, heteroaryl or heterocycle is optionally substituted with A1 and/or one or more of the following groups: halogen, C1–C6 alkyl, C5-C10 aryl, C2-C9 heteroaryl, C2-C9 heterocycle, C3-C10 carbocycle, C(O)N(R1e)2, S(O)N(R1e)2, S(O)2N(R1e)2, OR1e, C(O)R1e, C(O)OR1e, S(O)R1e, S(O)2R1e, SR1e, OC(O)R1e, OC(O)OR1e, OC(O)N(R1e)2, N(R1e)C(O)N(R1e)2, N(R1e)C(O)OR1e, N(R1e)C(O)R1e, N(R1e)S(O)R1e, N(R1e)S(O)2R1e, N(R1e)S(O)N(R1e)2, or N(R1e)S(O)N(R1e)2; wherein any C1–C6 alkyl, C5-C10 aryl, C2-C9 heteroaryl, C2-C9 heterocycle, C3-C10 carbocycle is optionally substituted A1 and/or one or more substituent groups independently selected from halogen, C1–C6 alkyl, C2-C9 heteroaryl, C3-C12 carbocycle, C2-C9 heterocycle, C(O)N(R1e)2, S(O)N(R1e)2, S(O)2N(R1e)2, C(O)R1e, C(O)OR1e, S(O)R1e, or S(O)2R1e. R1c is, independently, A1, NR2aR3a, C6-C20 aryl, C2-C9 heterocyle, 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-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 R1h, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(R1f)2, CN, C(O)N(R1f)2, S(O)N(R1f)2, S(O)2N(R1f)2, OR1f, SR1f, OC(O)R1f, OC(O)OR1f, C(O)R1f, C(O)OR1f, S(O)R1f, S(O)2R1f, OC(O)N(R1f)2, N(R1f)C(O)OR1f, N(R1f)C(O)N(R1f)2, N(R1a1)C(O)R1f, N(R1f)S(O)R1f, N(R1f)S(O)2R1f, N(R1f)S(O)N(R1f)2, and N(R1f)S(O)2N(R1f)2; R1d is, independently, C1-C12 alkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1d is optionally substituted with one or more groups R1g; each R1e 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; R2a is, independently, H, C1-C12 alkyl, C5-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-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 R1k, oxo, F, Cl, Br, I, NO2,N(R1j)2, CN, C(O)N(R1j)2, S(O)N(R1j)2, S(O)2N(R1j)2, OR1j, SR1j, OC(O)R1j, OC(O)OR1j, C(O)R1j, C(O)OR1j, S(O)R1j, S(O)2R1j, OC(O)N(R1j)2, N(R1j)C(O)OR1j, N(R1j)C(O)N(R1j)2, N(R1j)C(O)R1j, N(R1j)S(O)R1j, N(R1j)S(O)2R1j, N(R1j)S(O)N(R1j)2, and N(Ra)S(O)2N(R1j)2; R3a is, independently, 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-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3a is optionally substituted with A1 and/or one or more groups R1k; or R2a and R3a of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups R1k; each R1f is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C9 carbocyclyl, and C2-C9 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 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 independently selected from oxo and halo; or two R1f are taken together with the nitrogen to which they are attached to form a 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; each R1g is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C9 carbocyclyl, C2-C9 heterocyclyl, C5-C9 aryl, C1-C20 heteroaryl, F, Cl, Br, I, NO2, N(R1L)2, CN, C(O)N(R1L)2, S(O)N(R1L)2, S(O)2N(Rc)2, OR1L, SR1L, OC(O)OR1L, OC(O)OR1L, C(O)R1L, C(O)OR1L, S(O)R1L, S(O)2R1L, OC(O)N(R1L)2, N(R1L)C(O)OR1L, N(R1L)C(O)N(R1L)2, N(R1L)C(O)R1L, N(R1LS(O)R1L, N(R1L)S(O)2R1L, N(R1L)S(O)N(R1L)2, or N(R1L)S(O)2N(R1L)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(R1L)2, CN, C(O)N(R1L)2, S(O)N(R1L)2, S(O)2N(R1L)2, OR1L, SR1L, OC(O)R1L, C(O)R1L, S(O)R1L,S(O)2R1L, C(O)N(R1L)2, N(R1L)C(O)R1L, N(R1L)S(O)R1L, N(R1L)S(O)2R1L and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each R1h is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R1M)2, CN, C(O)N(R1M)2, S(O)N(R1M)2, S(O)2N(R1M)2, OR1M, SR1M, OC(O)R1M, C(O)R1M, C(O)OR1M, S(O)R1M, S(O)R1M, C(O)N(R1M)2, N(R1M)C(O)R1M, N(R1M)S(O)R1M, N(R1M)S(O)2R1M, 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(R1M)2, OR1M, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each R1j is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or 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 independently selected from oxo and halo; or two R1j are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; each R1k is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R1N)2, CN, CHF2, CF3, C(O)N(R1N)2, S(O)N(R1N)2, S(O)2N(R1N)2, OR1N, SR1N, OC(O)R1N, C(O)R1N, C(O)OR1N, S(O)R1N, S(O)2R1Nd, C(O)N(R1N)2, N(R1N)C(O)R1N, N(R1N)S(O)R1N, N(R1N)S(O)2R1N, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(R1N)2, OR1N, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each R1M is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynylC6alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd2 are taken together with the nitrogen to which they are attached to form a 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; each R1N is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C 6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R1N are taken together with the nitrogen to which they are attached to form a 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 one and only one of R1a, R1b, R1c, or R1d comprises A1. In some embodiments, the CBP binding moiety of Formula III has the structure:
Figure imgf000009_0001
. In some embodiments, the CBP binding moiety of Formula III has the structure:
Figure imgf000009_0002
. In some embodiments, the CBP binding moiety of Formula III has the structure:
Figure imgf000009_0003
. In some embodiments, the CBP binding moiety of Formula III has the structure:
Figure imgf000009_0004
. In some embodiments, the CBP binding moiety of Formula III has the structure:
Figure imgf000010_0001
In some embodiments, the CBP binding moiety of Formula III has the structure:
Figure imgf000011_0001
Figure imgf000012_0001
In some embodiments, the CBP binding moiety of Formula (III) has the structure:
Figure imgf000012_0002
Figure imgf000013_0001
.
Figure imgf000014_0001
In some embodiments, the CBP binding moiety of Formula (III) has the structure:
Figure imgf000015_0001
, In some embodiments, the CBP binding moiety of Formula (III) has the structure:
Figure imgf000015_0002
In some embodiments, the CBP binding moiety of Formula (III) has the structure of Formula (III- A):
Figure imgf000016_0001
Formula III-AA R8 is, independently, C1-C12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-12alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R8 is optionally substituted with one or more groups RO; R9 is, independently, C1-C4alkyl, C2–C6 heteroaryl, C2-C9 heterocycle, C(O)N(Rh2)2, S(O)N(Rh2)2, S(O)2, C(O)Rh2, C(O)ORh2, S(O)Rh2, or S(O)2Rh2, wherein any C1-C4alkyl, C2C-6 heteroaryl, or C2-C9 heterocycle is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh2)2, S(O)N(Rh2)2, N(Rh2)C(O)ORh2, N(Rh2)C(O)N(Rh2)2, N(Rh2)C(O)Rh2, N(Rh2)2, N(Rh2)S(O)2Rh2, N(Rh2)S(O)N(Rh2)2, and N(Rh2)S(O)2N(Rh2)2; R10 is, independently, C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1- 20 heteroaryl)(C6-C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1- C20 heteroaryl, (C6-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 RPP, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Ra2)2, CN, C(O)N(Ra2)2, S(O)N(Ra2)2, S(O)2N(Ra2)2, N(Ra2)C(O)ORa2)C(O)N(Ra2)C(O)N(Ra2)S(O)2Ra2, N(Ra2)S(O)N(Ra2)2, and N(Ra2)S(O)2N(Ra2)2; each Ra2 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6alkenyl, C2–C6 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 independently selected from oxo and halo; or two Ra2 are taken together with the nitrogen to which they are attached to form a 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; each RO is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RP)2, CN, C(O)N(RP)2, S(O)N(RP)2, S(O)2N(Rc)2, C(O)ORP, OCOC(O)RP, C(O)ORP, S(O)RP, S(O)2RP, OCRP(O)2, N(RP)2, N(RP)RPC(O)RPN(RP)2, RPN(RP)2, N(RPS(O)RP, N(RPS(O)RPPN(RPRPRP)2, or N(RP)S(O)2N(RP)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(RP)2, CN, C(O)N(RP)2, S(O)RP, S(O)2N(RP)S(O)RP, N(RP)S(O)2RP and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RPRP is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd2)2, CN, C(O)N(Rd2)2, S(O)N(Rd2)2, S(O)2N(Rd2)2, ORd2, SRd2, C(O)Rd2, S(O)Rd2, C(O)N(Rd2)2, N(Rd2)C(O)Rd2, N(Rd2)S(O)Rd2, N(Rd2)S(O)2Rd2, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, N(Rd2)2, ORd2, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl; each Rd2 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6C alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd2 are taken together with the nitrogen to which they are attached to form a 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; each Rh2 is, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, 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, C1-3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and wherein R10 comprises A1. In some embodiments, R8 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R8 is optionally substituted with one or more groups Rb2. In some embodiments,
Figure imgf000017_0001
. In some embodiments, R9 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. In some embodiments, R9 has the structure:
Figure imgf000017_0002
. In some embodiments, the CBP binding moiety has the structure:
Figure imgf000017_0003
In some embodiments, the CBP binding moiety has the structure:
Figure imgf000018_0001
In some embodiments, R10 has the structure:
Figure imgf000018_0002
In some embodiments, X3 is CH2 and X4 is CH. In some embodiments, R10 has the structure:
Figure imgf000019_0001
. In some embodiments, the CBP binding moiety has the structure:
Figure imgf000019_0002
In some embodiments, the CBP binding moiety of Formula (III) has the structure of Formula (III-
Figure imgf000019_0003
Formula III-B wherein R1 is, independently, C1-C12 alkyl, C2-C12alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1 is optionally substituted with A1 and/or one or more groups Rb; R2 is, independently, C6-C20 aryl, C1-C20 heteroaryl, (C6-20 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-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, N(Ra)C(O)ORa)C(O)N(Ra)2, N(Ra)2, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is, independently, C1–C12alkyl, C2–C12alkenyl, C2–C12alkynyl, 3-12 membered carbocycle, or 3- 12 membered heterocycle, wherein each C1-C12alkyl, C2-C12alkenyl, C2-C12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; R4 is, independently, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with A1 and/or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)N(Rh)2, N(Rh)S(O)2Rh, N(Rh)S(ON(Rh)2, and N(Rh)S(O)N(Rh)2; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or 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 independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; each Rb is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, N(Rc)C(O)Rc)C(O)N(Rc, S(O)Rc, S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(Rc)S(O)2N(Rc)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, C(O)N(Rc)2, N(Rc)C(O)2N(Rc) S(O)Rc, N(Rc)S(O)2Rc and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, C(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, N(Rd)S(O))Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6a lkyl; each Rd is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a 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; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, OC(OC(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OCRf1(O)2, Rf1 N(Rf1)2, N(Rf1)Rf1C(O)Rf1N(Rf11)2, N(Rf1)S(O)Rf1, N(Rf1)Rf1S(O)2Rf1, N(Rf1)Rf1S(O)Rf1 N(Rf1)2, or N(Rf1)Rf1S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1Rf1)2, CN, C(O)N(Rf1)2,S(O)N(Rf1)2, S(O)Rf1, SRf1, OC(O)Rf1, N(Rf1)Rf1S(O)Rf1, N(Rf1S(O)2Rf1, carbocycle, and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, O)Rg1, C(Rg1O)Rg1, Rg1C(O)Rg1, C(O)N(Rg1)2, N(Rg1)Rg1C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)Rg1S(O)2Rg1, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1Rg1)2, ORg1Rg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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 A1 and/or 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; wherein and only one of R1, R2, R3, or R4 comprises A1. In some embodiments, R1 is C1-C12 alkyl or 3-12 membered heterocycle. In some embodiments, R1 is Methyl. In some embodiments, R1 is 3-12 membered heterocycle, e.g.,
Figure imgf000021_0001
, . In some embodiments, Rb is H. In some embodiments, R2 is C6-C20 aryl that is optionally substituted with one or more substituent groups independently selected from Rc. In some embodiments, R2 comprises A1. In some embodiments,
Figure imgf000021_0002
. In some embodiments,
Figure imgf000021_0003
. In some embodiments, Rc is C1–C6 alkyl that is optionally substituted with one or more groups independently selected from halo. In some embodiments, Rc is CHF2. In some embodiments, R3 is a C1-C12 alkyl or 3-12 membered heterocycle that is optionally substituted with one or more groups Re. In some embodiments, R2 and R3 of Formula (III-B) taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re. In some embodiments, R2 and R3 of Formula (III-B) taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring. In some embodiments, R2 and R3 of Formula (III-B) taken together with the nitrogen to which they are
Figure imgf000022_0001
Figure imgf000023_0001
. In some embodiments, Re is H. In some embodiments, R4 is C(O)Rh. In some embodiments, R4 is acetyl, e.g.,
Figure imgf000023_0002
. In some embodiments, Rh is methyl. In some embodiments, the CBP binding moiety has the structure:
Figure imgf000023_0003
Figure imgf000023_0004
. In some embodiments, the CBP binding moiety of Formula (III) has the structure of Formula (III- C):
Figure imgf000023_0005
wherein: X1 is C or N; X2 is C or N; R5 is, independently, C1–C12alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R5 is optionally substituted with one or more groups Rk1k; R6 is, independently, C1-4alkyl, 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), C(O)N(Rh1)2, S(O)N(Rh1)2, S(O)2, C(O)Rh1, C(O)ORh1, S(O)Rh1, or S(O)2Rh1, wherein , wherein C1-C4 alkyl, C6-C20 aryl, C1-C20 heteroaryl, (C6-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 F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh1)2, S(O)2N(Rh1)2, ORh1, S(O)2Rh1, OC(ORh1, C(O)ORh1, N(Rh1)2, N(Rh1)2, N(Rh1)C(O)N(Rh1)2, N(Rh1S(O)2Rh1, N(Rh1)S(O)N(Rh1)2, and N(Rh1)S(O)2N(Rh1)2; R7 is, independently, 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-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 RL1RL1, oxo, F, Cl, Br, I, NO2, N(Ra1)2, CN, C(O)N(Ra1)2, S(O)N(Ra1)2, S(O)2N(Ra1)2, N(Ra1)C(O)Ra1)C(O)ORa1, S(O)Ra1, N(Ra1)S(O)2Ra1, N(Ra1)S(O)N(Ra1)2, and N(Ra1)S(O)2N(Ra1)2; each Ra1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 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 independently selected from oxo and halo; or two Ra1 are taken together with the nitrogen to which they are attached to form a 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; each Rk1 is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RL1)2, CN, C(O)N(RL1)2, S(O)N(RL1)2, S(O)2N(RL1)2, ORL1, OC(RL1OC(O)RL1, RL1C(O)ORL1, C(O)ORL1, N(RL1)RL1C(O)RL1N(RL1)2, RL1N(RL1)2, N(RL1)S(O)RL1, N(RL1)RL1S(O)RL1, RL1N(RL1)RL1S(O)RL1N(RL1)2, or N(RL1)RL1S(O)2N(RL1)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(RL1RL1)2, CN, C(O)N(RL1RL1)2, S(O)N(RL1)2, S(O)2N(RL1)RL1, S(O)RL1, S(O)2RL1 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RL1 is, independently, hydrogen, C1–C6 alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd1)2, CN, C(O)N(Rd1)2, S(O)N(Rd1)2, S(O)2N(Rd1)2, ORd1, SRd1, C(O)Rd1, S(O)Rd1, C(O)N(Rd1)2, N(Rd1)C(O)Rd1, N(Rd1)S(O)Rd1, N(Rd1)S(O)2Rd1, 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(Rd1)2, ORd1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd1 are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rh1 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 C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C44 alkyl that is optionally substituted with one or more groups independently selected from halo; and wherein R7 comprises A1. In some embodiments, the CBP binding moiety has the structure of Formula IV:
Figure imgf000025_0001
Formula IVIV wherein: R11 is, independently, C1-C12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R11 is optionally substituted with one or more groups RMRM; R12 is, independently, C1-C4 alkyl, C(O)N(Rh3)2, S(O)N(Rh3)2, S(O)N(Rh3)2, C(O)Rh3, C(O)ORh3, S(O)Rh3, or S(O)Rh3, wherein any C1-C4alkyl is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh3)2, S(O)N(Rh3)2, N(Rh3)C(O)Rh3)C(O)N(Rh3)2, N(Rh3)C(O)Rh3, N(Rh3)S(O)Rh3, N(Rh3)S(O)2Rh3, N(Rh3)S(O)N(Rh3)2, and N(Rh3)S(O)2N(Rh3)2; R13 is, independently, NR2R3, 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-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 RN1RN1, oxo, F, Cl, Br, I, NO2, N(Ra3)2, CN, C(O)N(Ra3)2, S(O)N(Ra3)2, S(O)2N(Ra3)2, N(Ra3)C(O)ORa3, S(O)Ra3, RN(Ra3)2, N(Ra3)S(O)N(Ra3)2, and N(Ra3)S(O)2N(Ra3)2; R2 is, independently, C6-C20 aryl, C1-C20 heteroaryl, (C6-20 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-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, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is, independently, 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-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or 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 independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; each Rc is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6a lkyl; each Rd is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a 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; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2,S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1S(O)2Rf1, carbocycle, and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, C(O)
Figure imgf000027_0001
alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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; each Ra3 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6alkynyl, 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 independently selected from oxo and halo; or two Ra3 are taken together with the nitrogen to which they are attached to form a 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; each RM is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RN1RN1)2, CN, C()N(RN1RN1)2, S(O)N(RN1RN1)2, S(O)2N(Rc)2, O)ORN1, C(RN1RN1OC(O)O)RN1, S(RN1O)2RN1, OC(O)N(RN1)2, RN1RN1RN1RN1RN1N(RN1)2, N(RN1)RN1C(O)RN1 N(RN1)2, RN1N(RN1)2, N(RN1)S(O)RN1, RN1RN1N(RN1)RN1S(O)2RN1, RN1N(RN1)RN1S(O)RN1N(RN1RN1RN1)2, or N(RN1)RN1S(O)2N(RN1RN1)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(RN1RN1)2, CN, C(O)N(RN1RN1)2, S(O)N(RN1)2, S(O)2N(RN1)RN1RN1RN1RN1RN1S(O)RN1, S(O)2RN1RN1RN1RN1RN1RN1RN1RN1RN1 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RN1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd3)2, CN, C(O)N(Rd3)2, S(O)N(Rd3)2, S(O)2N(Rd3)2, ORd3, SRd3, C(O)Rd3, S(O)2Rd3, C(O)N(Rd3)2, N(Rd3)2, N(Rd3)S(O)Rd3, N(Rd3)S(O)2Rd3, and C1-6alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd3)2, ORd3, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd3 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd3 are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rh3 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; and wherein R13 comprises A1.
Figure imgf000028_0001
In some embodiments, the CBP binding moiety of Formula IV has the structure:
Figure imgf000028_0002
I
Figure imgf000029_0003
,
Figure imgf000029_0001
In some embodiments, R13 C1-C20 heteroaryl, e.g.,
Figure imgf000029_0002
. In some embodiments, the CBP binding moiety of Formula IV has the structure:
Figure imgf000030_0001
In some embodiments, the degradation moiety (B) is a ubiquitin ligase binding moiety. In some embodiments, the degradation moiety (B) 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 (B) comprises the structure of Formula V:
Figure imgf000030_0002
Formula V, wherein RB1a is, independently, H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3a is, independently, A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4a is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5a is, independently, H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; RB6a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one and only one of RB1a and RB3a is A2 or C(O)A2. In some embodiments, the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-A):
Figure imgf000031_0001
Formula V-A, wherein RB1a is, independently, H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3a is, independently, A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4a is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB6a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one and only one of RB1a and RB3a is A2 or C(O)A2. In some embodiments, the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-B):
Figure imgf000032_0001
Formula V-B, wherein RB1a is, independently, H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB2a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3a is, independently, A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4a is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5a is, independently, H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; RB6a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one and only one of RB1a and RB3a is A2 or C(O)A2. In some embodiments,
Figure imgf000032_0002
, wherein each RB6 is, independently, 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol; RB9 is, independently, H, or optionally substituted C1–C6 alkyl; RB10 is, independently, H, or optionally substituted C1–C6 alkyl, and v2 is 0, 1, 2, 3, or 4. In some embodiments,
Figure imgf000032_0003
. In some
Figure imgf000033_0001
Figure imgf000033_0004
In some
Figure imgf000033_0002
, wherein each RB6 is, independently, 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol; RB11 is optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl; RB9 is, independently, H, or optionally substituted C1–C6 alkyl; RB10 is, independently, H, or optionally substituted C1-C6 alkyl, and v2 is 0, 1, 2, 3, or 4.
Figure imgf000033_0005
In some
Figure imgf000033_0003
Figure imgf000034_0001
Figure imgf000034_0003
each RB6 is, independently, 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, hydroxy, thiol, or optionally substituted amino; each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl; and RB9 and RB10 are, independently, H, or optionally substituted C1–C6 alkyl. In some embodiments,
Figure imgf000034_0002
, wherein v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, 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, hydroxy, thiol, or optionally substituted amino; each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl; and RB9 and RB10 are, independently, H, or optionally substituted C1–C6 alkyl. In some embodiments, RB6a is .
Figure imgf000035_0001
In some embodiments, the degradation moiety of formula V has the structure:
Figure imgf000035_0002
Figure imgf000036_0001
derivative or analog thereof. In some embodiments, the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-C):
Figure imgf000037_0001
Formula V-C-C, wherein RB1 is, independently, H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB3 is, independently, A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl, C3-C10 carbocyclyl, or optionally substituted C1–C6 alkyl wherein the C1–C6 alkyl, C1-C6 heteroalkyl, C3-C10 carbocyclyl, C6-C10 aryl, C1-C6 alkyl, C3-C10 carbocyclyl, or C6-C10 aryl is substituted with A2 and/or one of more groups of RJ2; RB4 is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl, optionally substituted C3- C10 carbocyclyl,optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl; RB5 is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is, independently, 0, 1, 2, 3, or 4; each RB6 is, independently, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-6 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol, RB9 is, independently, H, or optionally substituted C1-C6 alkyl; and each RJ2 is, independently, hydrogen, optionally substituted C1–C6 alkyl, optionally substituted C3-C12 carbocyclyl, and optionally substituted C3-C12 heterocyclyl, wherein each C1–C6 alkyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, thio, C1–C6 alkoxy, C3–C12 carbocyclyl, C3–C12 heterocyclyl, or C1-C6 alkyl that is optionally substituted with A2 and/or one or more groups independently selected from oxo and halo; and wherein one of RB1 and RB3 is A2 or C(O)A2, or a pharmaceutically acceptable salt thereof. In some embodiments, RB9 is H. In some embodiments, RB9 is optionally substituted C1–C6 alkyl. In some embodiments, RB9 is methyl. In some embodiments, RB4 is H. In some embodiments, RB5 is H. In some embodiments, RB1 is A2. In some embodiments, RB1 is C(O)A2. In some embodiments, RB3 is optionally substituted C1–C6 alkyl.
Figure imgf000038_0001
In some embodiments, RB6 is optionally substituted C2-C9 heteroaryl.
Figure imgf000038_0002
Figure imgf000039_0001
thereof. In some embodiments, RB6 is halogen or optionally substituted C2-C6 alkynyl. In some embodiments, RB6 is optionally substituted C1–C6 heteroalkyl. In some embodiments, optionally substituted C1–C6 heteroalkyl is methoxy. In some embodiments, the structure of Formula V-C is
Figure imgf000039_0002
thereof. In some embodiments, the degradation moiety of Formula (V) comprises the structure of Formula V-D:
Figure imgf000039_0003
Formula V-DD, wherein RB1 is, independently, H, A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2 is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is, independently, A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4 is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5 is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is, independently, 0, 1, 2, 3, or 4; each RB6 is, independently, 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, hydroxy, thiol, or optionally substituted amino; and each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl, RB9 and RB10 are, independently, H, or optionally substituted C1–C6 alkyl, wherein one of RB1 and RB3 is A2, or a pharmaceutically acceptable salt thereof. In some embodiments, RB1 is H. In some embodiments, RB1 is A2. In some embodiments, RB2 is H. In some embodiments, RB3 is optionally substituted C1–C6 alkyl or optionally substituted C1–C6 heteroalkyl wherein any C1–C6 alkyl, and C1–C6 heteroalkyl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(Rf3)2, CN, C(O)N(Rf3)2, S(O)N(Rf3)2, S(O)2N(Rf3)2, O)Rf3, C(Rf3O)Rf3, Rf3C(O)Rf3, C(O)N(Rf3)2, N(Rf3)Rf3C(O)Rf3, Rf3N(Rf3)S(O)Rf3, N(Rf3)Rf3S(O)2Rf3, carbocycle, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In some embodiments, RB3 is , or . In some embodiments,
Figure imgf000040_0001
. In some embodiments, RB4 is H. In some embodiments, RB5 is H. In some embodiments, RB6 is H. In some embodiments, RB7 is H, or optionally substituted C1-6 alkyl. In some embodiments, RB7 is methyl. In some embodiments, RB8 is H. In some embodiments, RB9 is H, or optionally substituted C1-6 alkyl. In some embodiments, RB9 is H. In some embodiments, RB9 is methyl. In some embodiments, RB10 is H, or optionally substituted C1-6 alkyl. In some embodiments, RB10 is H. In some embodiments, RB10 is methyl.
Figure imgf000041_0001
analog thereof. In some embodiments, the degradation moiety has the structure:
Figure imgf000042_0001
. In some embodiments, the degradation moiety has the structure:
Figure imgf000042_0002
. In some embodiments, the degradation moiety comprises the structure of Formula V-E:
Figure imgf000042_0003
Formula V-E RC1 is, independently, optionally substituted C1–C6 alkyl; RC2 is, independently, A2, or optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl, that is substituted with A2 and/or one or more groups RJ; RC3 is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RC4 is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is, independently, 0, 1, 2, 3, or 4; each of RC5 and RC6 is, independently, H, or optionally substituted C1–C6 alkyl; each RC7 is, independently, 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, hydroxy, thiol, or optionally substituted amino; each of RC8 and RC9 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl; and each RJ is, independently, hydrogen, C1–C6 alkyl, carbocyclyl, and heterocyclyl, wherein each C1- C6 alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, or C1–C6 alkyl that is optionally substituted with A2 and/or one or more groups independently selected from oxo and halo; or a pharmaceutically acceptable salt thereof. In some embodiments,
Figure imgf000043_0001
. In some embodiments, RC2 is optionally substituted C2-C9 heteroaryl that is substituted with A2. In some embodiments, RC3 is H. In some embodiments, RC4 is H. In some embodiments, v2 is 0. In some embodiments, each of RC5 and RC6 is, independently, H or methyl. In some embodiments, each of RC8 and RC9 is, independently, H or methyl. In some embodiments, the degradation moiety has the structure:
Figure imgf000043_0002
or analog thereof. In some embodiments, the degradation moiety of Formula (V) comprises the structure of Formula V-FF:
Figure imgf000044_0001
Formula V-FF, wherein RB1 is, independently, H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB3 is, independently, A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4 is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5 is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one of RB1 and RB3 is A2 or C(O)A2, or a pharmaceutically acceptable salt thereof. In some embodiments, RB4 is H. In some embodiments, RB5 is H. In some embodiments, RB1 is A2. In some embodiments, RB1 is C(O)A2. In some embodiments, RB3 is optionally substituted C1–C6 alkyl.
Figure imgf000044_0002
In some embodiments, the degradation moiety has the structure of Formula V-G:
Figure imgf000044_0003
derivative or analog thereof. In some embodiments, the compound is any one of compounds in Table 1. Table 1. Compounds of the invention
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000046_0002
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000082_0002
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0002
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000104_0002
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0002
Table 2. Compounds 1A to 28A of the invention
Figure imgf000109_0003
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000111_0002
Figure imgf000112_0001
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. In another aspect, the invention features a method of decreasing the levels and/or activity of a 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 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 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. In some embodiments, the cell is a cancer cell. In another aspect, the invention features a method of treating a CBP-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 CBP-related disorder is cancer. In a further aspect, the invention features a method of inhibiting CBP, 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 CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, 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 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 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, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric 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 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, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, 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 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 cancer is gastric cancer. In some embodiments, the breast cancer is found to be ER positive i.e. the cancer cells contain estrogen receptors. 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. In some embodiments, the prostate cancer is CRPC i.e. castration-sensitive prostate cancer. In an aspect, the disclosure features a method of treating a CBP-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 pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. In some embodiments, the CBP-related disorder is cancer. In some embodiments, the CBP-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, 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 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, 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 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 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, 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, 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 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 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, 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 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, 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, 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 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 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; 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. 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®, 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, 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 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, 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 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 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, 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, 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 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 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, 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 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, 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, 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 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 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 (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. 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 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, 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 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 to have CBP mutations. In some embodiments of any of the foregoing methods, the CBP 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 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. In another aspect, the disclosure provides a method of treating a disorder related to CBP (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 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 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 of treating gastric cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof. In another aspect, the disclosure provides a method of treating inflammatory and/or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof. In some embodiments, the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis. In some embodiments, the inflammatory and/or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, refractory, moderate- to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post- polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile idiopathic arthritis. In some embodiments, the inflammatory and/or autoimmune disorder is non-infectious non- anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus. In some embodiments, the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis. In some embodiments, the method further comprises administering to the subject a JAK inhibitor. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib. In another aspect, the disclosure provides a method of treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway, the method including administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, the member of the JAK-STAT pathway is a janus kinase (JAK). In some embodiments, the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT). In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis. In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, refractory, moderate-to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L, polycythemia vera, steroid- refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile idiopathic arthritis. In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is non-infectious non-anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus. In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis. In another aspect, the disclosure provides a method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof. In another aspect, the disclosure provides a method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof. In another aspect, the disclosure provides a method of suppressing a memory CD8+ T cell response in a subject in a subject having or at risk of developing an inflammatory response, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof. An aspect of the present invention relates to a method of treating a disorder related to CBP such as inflammation and/or autoimmune disorders in a subject in need thereof. In some embodiments, the compound is administered in an 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 T cell (e.g., CD8+ memory T cells) activity, (b) reduced inflammation, (c) reduced thrombopoiesis, (d) reduced B cell proliferation, (e) increased survival of subject, and (f) increased progression free survival of a subject. In some embodiments, treating an inflammatory disorder and/or autoimmune disorder can result in a reduction in T cell (e.g., CD8+ memory T cells) activity. In some embodiments, for example, after treatment, T cell (e.g., CD8+ memory T cells) activity 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. In some embodiments, treating an inflammatory disorder and/or autoimmune disorder can result in a reduction in inflammation. In some embodiments, for example, after treatment, inflammation 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. In some embodiments, treating an inflammatory disorder and/or autoimmune disorder can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition, or a downstream affect such as CBP degradation). In some embodiments, inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF-γ, IL-6, IL- 11, IL-13, IL-25, IL-27, and/or IL-31, which in turn can affect the immune system response. Other cytokines that interact with JAK1, JAK3, and/or TYK2 include IL-10, IL-22, type 1 IFNs (α/β), IL-2, IL-4, IL- 7, IL-9, IL-15, and IL-21. In another aspect, the disclosure provides a method for treating a viral infection in a subject in 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)), 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., JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), or Togaviridae family (e.g., Rubella virus). In another aspect, the invention features a method of treating melanoma, 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. In another aspect, the invention features a method of reducing tumor growth of melanoma, 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. In another aspect, the invention features a method of suppressing metastatic progression of melanoma, 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. In another aspect, the invention features a method of suppressing metastatic colonization of melanoma, 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. In another aspect, the invention features a method of reducing the level and/or activity of CBP and/or EP300 in a melanoma, 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. In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, 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 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 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 of any of the above aspects, the effective amount of the compound reduces the level 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 the percent of reduction of the level of EP300. In some embodiments, the effective amount of the compound that reduces the level of CBP 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 EP300. In some embodiments, the effective amount of the compound that reduces the level of CBP 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 EP300. 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%, 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 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 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. 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 99%). 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%, 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 (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more). In some embodiments, the subject has cancer. In some embodiments, the cancer expresses CBP and/or EP300 protein and/or the cell or subject has been identified as expressing CBP and/or EP300. In some embodiments, the cancer expresses CBP protein and/or the cell or subject has been identified as expressing 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 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 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 (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 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, 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 CBP and/or EP300 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 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 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 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 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, 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). 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 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 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. 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 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, 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). 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 “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-C6 alkyl C6-C10 aryl, C1-C10 alkyl C6-C10 aryl, or C1-C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each are further substituted with 1, 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups. 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 groups and unsaturated carbocyclyl radicals. A carbocyclylene is a divalent carbocyclyl group. The term “cycloalkyl,” as used herein, refers to a saturated, non-aromatic, and monovalent mono- di-, or tricyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. The cycloalkyl group may be fully saturated or contain 1 or more double or triple bonds, provided that no ring is aromatic. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. The term “cycloalkoxy” as used herein, refers to cycloalkyl-O- groups (e.g., cyclopropoxy and cyclobutoxy). 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 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 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 can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyl groups. 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, 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 “heteroarylalkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-C6 alkyl C2-C9 heteroaryl, C1-C10 alkyl C2-C9 heteroaryl, or C1-C20 alkyl C2- C9 heteroaryl). In some embodiments, the alkyl and the heteroaryl each are further substituted with 1, 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups. 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 aromatic. 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 heteroocyclyl group. The term “hydroxyl,” as used herein, represents an –OH group. The term “thiol,” as used herein, represents an –SH group. 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 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl 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 thioalkoxy), heteroaryl (e.g., substituted and unsubstituted thiazole, substituted and unsubstituted pyridine, substituted and unsubstituted benzothiazole, substituted and unsubstituted furan, substituted and unsubstituted pyrazole, etc.), 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, 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. 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 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 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 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," 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 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 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. 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, 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 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 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 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 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 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 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 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 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. As used herein, the term “CBP” refers to the Creb-binding protein in a human cell. As used herein, the term “CBP-related disorder” refers to a disorder that is caused or affected by the level of activity of CBP. As used herein, the term “CBP loss of function mutation” refers to a mutation in CBP that leads to the protein having diminished activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity). Exemplary CBP loss of function mutations include, but are not limited to, a homozygous CBP mutation and chromosomal translocations. As used herein, the term “CBP loss of function disorder” refers to a disorder (e.g., cancer) that exhibits a reduction in CBP activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity). 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 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, 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, 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 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, 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, 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 CBP (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 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 CBP 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 CBP. The amount of a given agent that reduces the level and/or activity of CBP 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 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 CBP of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of an agent that reduces the level and/or activity of CBP 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 protein (e.g., CBP). 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 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 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, mg/mL, μg/mL, ng/mL) or percentage relative to total protein in a sample. By “decreasing the activity of CBP” is meant decreasing the level of an activity related to CBP, or a related downstream effect. The activity level of a CBP 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 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 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 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, 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, 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), 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 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 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 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, 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, 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. 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. 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 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 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 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 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. 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 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. 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 described herein may retain or improve upon the biological activity of the original material. 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 moiety, wherein the compound interacts with a protein (e.g., CBP) 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., CBP. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., CBP. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1 and 2 are a series of graphs illustrating the dose dependent depletion of CBP and EP300 levels in osteosarcoma cell line in the presence of a CBP-selective degrader as described in Example 536. Figure 3 is a graph illustrating the effect on cell growth of four bladder cancer cell lines (UM-UC-3, ScaBER, 647V and 639V) in the presence of a CBP degrader as described in Example 537. Figure 4 is a graph illustrating the effect on cell growth of two gastric cancer cell lines (IM95 and AGS) as described in Example 538. Figure 5 is a graph illustrating the effect on cell growth of two colorectal cancer cell lines (HT29 and RKO) as described in Example 539. Figure 6 is a series of graphs illustrating the results of the WB evaluation of the percent of remaining CBP and EP300 protein level (normalized to vehicle) after treatment with our CBP selective degrader @ 20mg/kg and 50mg/kg at 2H, 6H and 24H post last dose as described in Example 540. Figure 7 is a volcano plot illustrating all proteins identified in the proteome database, for the treated (with compound 6) and untreated groups taken at a 6H timepoint post treatment. Purple dots represent all the bromodomain proteins identified in this analysis. Results indicate that using a CBP selective degrader we observe statistically significant and selective downregulation of CBP over EP300 as described in Example 541. Figure 8 is a graph illustrating the Platelet count on Day 14: Dose-Response Platelet Decrease with GNE- 781, Absence of Thrombocytopenia with exemplified compound 132 as described in Example 542. DETAILED DESCRIPTION OF THE INVENTION The present disclosure features compositions and methods useful for the treatment of CBP- related disorders (e.g., cancer and infection). The disclosure further features compositions and methods useful for inhibition of the level and/or activity of CBP, 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 CBP, or a related downstream effect, or reduce the level of CBP in a cell or subject. Exemplary compounds described herein have the structure according to Formula I. A-L-B Formula I, wherein A is a CBP binding moiety; B is a degradation moiety; and L has the structure of Formula II: A1–(F)-(E)m–C-A2, Formula II wherein A1 is a bond between the linker and A; A2 is a bond between B and the linker; m is, independently, 0 or 1; C is, independently, absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; Figure 4 is a graph illustrating the effect on cell growth of two gastric cancer cell lines (IM95 and AGS) as described in Example 538. Figure 5 is a graph illustrating the effect on cell growth of two colorectal cancer cell lines (HT29 and RKO) as described in Example 539. Figure 6 is a series of graphs illustrating the results of the WB evaluation of the percent of remaining CBP and EP300 protein level (normalized to vehicle) after treatment with our CBP selective degrader @ 20mg/kg and 50mg/kg at 2H, 6H and 24H post last dose as described in Example 540. Figure 7 is a volcano plot illustrating all proteins identified in the proteome database, for the treated (with compound 6) and untreated groups taken at a 6H timepoint post treatment. Purple dots represent all the bromodomain proteins identified in this analysis. Results indicate that using a CBP selective degrader we observe statistically significant and selective downregulation of CBP over EP300 as described in Example 541. Figure 8 is a graph illustrating the Platelet count on Day 14: Dose-Response Platelet Decrease with GNE- 781, Absence of Thrombocytopenia with exemplified compound 132 as described in Example 542. Figure 9A is a graph illustrating tumor volume in response to dosing of FHT-76118 (Compound 142) and FHT-77559 over time. Figure 9B is a graph illustrating the body weight in response to dosing of FHT-76118 (Compound 142) and FHT-77559 over time. Figure 9C is a graph illustrating PK/PD effect of FHT-77559 over CBP 3 mg/kg, 1 mg/kg, 0.3 mg/kg, and 0.1 mg/kg. Figure 9D is a graph illustrating the PK/PD effect of FHT-77559 over c-MYC 3 mg/kg, 1 mg/kg, 0.3 mg/kg, and 0.1 mg/kg. Figure 10A is a graph illustrating the tumor volume over time in response to dosing of FHT-76118 (compound 142) and FHT-77559. Figure 10B is a graph illustrating the body weight change over time in response to dosing of FHT-76118 (compound 142) and FHT-77559. Figure 10C is a graph illustrating the PK/PD effect of FHT-76118 (Compound 142) and FHT-77559 over CBP. Figure 10D is a graph illustrating the PK/PD effect of FHT-76118 (Compound 142) and FHT-77559 over c- MYC. Figure 11A is a graph illustrating the tumor volume over time in response to dosing of FHT-76118 (compound 142) and FHT-77559. Figure 11B is a graph illustrating the body weight change over time in response to dosing of FHT-76118 (compound 142) and FHT-77559. Figure 11C is a graph illustrating the PK/PD effect of FHT-76118 (Compound 142) and FHT-77559 over CBP. Figure 11D is a graph illustrating the PK/PD effect of FHT-76118 (Compound 142) and FHT-77559 over c- MYC. DETAILED DESCRIPTION OF THE INVENTION The present disclosure features compositions and methods useful for the treatment of CBP- related disorders (e.g., cancer and infection). The disclosure further features compositions and methods useful for inhibition of the level and/or activity of CBP, 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 CBP, or a related downstream effect, or reduce the level of CBP in a cell or subject. Exemplary compounds described herein have the structure according to Formula I. A-L-B Formula I, wherein A is a CBP binding moiety; B is a degradation moiety; and L has the structure of Formula II: A1–(F)-(E)m–C-A2, Formula II wherein A1 is a bond between the linker and A; A2 is a bond between B and the linker; m is, independently, 0 or 1; C is, independently, absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; E is, independently, absent ,O, S, NRN, optionally substituted C1–10 alkylene, optionally substituted C2–10 alkenylene, optionally substituted C2–10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–10 heteroalkylene; each RN is, independently, H, optionally substituted C1–4 alkyl, optionally substituted C2–4 alkenyl, optionally substituted C2–4 alkynyl, optionally substituted C2–6 heterocyclyl, optionally substituted C6–12 aryl, or optionally substituted C1–7 heteroalkyl; F is, independently, optionally substituted C3-C10 carbocyclylene, optionally substituted C2–10 heterocyclylene, optionally substituted C6-C10 arylene, or optionally substituted C2-C9 heteroarylene, or a pharmaceutically acceptable salt thereof. CBP and Janus Kinase (JAK) Pathway Protein kinases (PKs) regulate diverse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines, low-molecular weight polypeptides or glycoproteins, regulate many pathways involved in the E is, independently, absent ,O, S, NRN, optionally substituted C1–10 alkylene, optionally substituted C2–10 alkenylene, optionally substituted C2–10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–10 heteroalkylene; each RN is, independently, H, optionally substituted C1–4 alkyl, optionally substituted C2–4 alkenyl, optionally substituted C2–4 alkynyl, optionally substituted C2–6 heterocyclyl, optionally substituted C6–12 aryl, or optionally substituted C1–7 heteroalkyl; F is, independently, optionally substituted C3-C10 carbocyclylene, optionally substituted C2–10 heterocyclylene, optionally substituted C6-C10 arylene, or optionally substituted C2-C9 heteroarylene, or a pharmaceutically acceptable salt thereof. CBP and Janus Kinase (JAK) Pathway Protein kinases (PKs) regulate diverse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines, low-molecular weight polypeptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and can modulate both pro-inflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. Signaling of a wide range of cytokines involves the Janus kinase family (JAKs) of protein tyrosine kinases and Signal Transducers and Activators of Transcription (STATs). There are four known mammalian JAKs: JAK1 (Janus kinase- 1), JAK2, JAK3 (also known as Janus kinase, leukocyte; JAKL; and L- JAK), and TYK2 (protein-tyrosine kinase 2). There are seven mammalian STAT family members that have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. It has been observed that in memory CD8+ T cells, Janus kinase 2 (JAK2) hyperactivation is coupled to the phosphorylation of CBP, and that phosphorylated CBP is important for CD8+ memory T- cell recall response (J Biol Chem.2019 Feb 15; 294(7): 2397–2406). It was suggested that JAK2- catalyzed phosphorylation allows CBP to bind with higher affinity to acetylated histone peptides such as H3 and increases the number of acetylated histone markers that CBP recognizes. This may indicate a mechanism that could contribute to initiation of transcriptional programs in memory CD8+ T cells. Further, it was observed that CBP is essential for conventional effector and memory CD8+ T-cell formation. Thus, treatment with JAK inhibitors (e.g., JAK2 inhibitors) may also inhibit CBP via non-phosphorylation of CBP. The JAK-STAT pathway plays a role in transduction of cytokines and growth factor signals in inflammatory and autoimmune diseases. Globally approved JAK inhibitors include abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, and upadacitinib. Other JAK inhibitors include AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, and ritlecitinib. In one aspect, the present disclosure provides a method of treating inflammatory and/or autoimmune disorders, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering to the subject a JAK inhibitor. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib. In some embodiments, the JAK inhibitor is AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib. Filgotinib, oclacitinib, and upadacitinib are JAK1 inhibitors. Filgotinib (e.g., Jyseleca, Europe) is approved for use in moderate to severe rheumatoid arthritis. Upadacitinib (e.g., Rinvoq) is approved for use in moderate-to-severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, and refractory, moderate-to-severe atopic dermatitis. Filgotinib showed promising response to Crohn’s disease and ulcerative colitis and was also tested in psoriatic arthritis. Oclacitinib is approved for treatment of atopic dermatitis and pruritus associated with allergic dermatitis in dogs. In some embodiments, the JAK inhibitor is a JAK1 inhibitor. In some embodiments, the JAK inhibitor is filgotinib, oclacitinib, or upadacitinib. In some embodiments, the JAK inhibitor is filgotinib or upadacitinib. In some embodiments, the inflammatory and/or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, and refractory, moderate-to-severe atopic dermatitis. Fedratinib and pacritinib are JAK2 inhibitors. Fedratinib (e.g., Inrebic) is approved for use in intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. Pacritinib (e.g., Vonjo) is approved for use in intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. Pacritinib acts as an inhibitor of both JAK2 and FLT3 that could be used to overcome resistance in existing acute myeloid leukaemia (AML) treatments. Pacritinib was tested in glioblastoma multiforme in combination with temozolomide. In some embodiments, the JAK inhibitor is a JAK2 inhibitor. In some embodiments, the JAK2 inhibitor is fedratinib or pacritinib. In some embodiments, the disorder is intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis or intermediate- or high-risk primary or secondary (post- polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. Abrocitinib, baricitinib, and ruxolitinib are JAK1/2 inhibitors. Abrocitinib (e.g., Cibinqo) is approved for use in refractory, moderate-to-severe atopic dermatitis. Baricitinib (e.g., Olumiant) is approved for use in moderate-to-severe rheumatoid arthritis. Ruxolitinib (e.g., Jakafi) is approved for use in intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease. Baricitinib was authorized for emergency use for treatment of COVID-19 in combination with remdesivir. Baricitinib was shown to improve symptoms of systemic lupus erythematosus and decrease inflammation/pruritus in atopic dermatitis when used with topical corticosteroids. Baricitinib is being studied in Aicardi goutieres syndrome and primary sjogren's syndrome. The combination of ruxolitinib and ERBB1/2/4 inhibitors also displayed synergistic anticancer activity against lung, breast, and ovarian cancer cells. In some embodiments, the JAK inhibitor is a JAK1/2 inhibitor. In some embodiments, the JAK1/2 inhibitor is abrocitinib, baricitinib, or ruxolitinib. In some embodiments, the inflammatory and/or autoimmune disorder is refractory, moderate-to-severe atopic dermatitis, moderate-to-severe rheumatoid arthritis, intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post- essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, or chronic graft-versus-host disease. In some embodiments, the inflammatory and/or autoimmune disorder is a result of a COVID-19 infection in the lung. In some embodiments, the inflammatory and/or autoimmune disorder is systemic lupus erythematosus, inflammation/pruritus in atopic dermatitis, Aicardi goutieres syndrome or primary sjogren's syndrome. Tofacitinib is a JAK1/2/3 inhibitor. Tofacitinib (e.g., Xeljanz) is approved for use in active psoriatic arthritis, moderate-to severe-rheumatoid arthritis, moderate-to-severe active ulcerative colitis, particular course juvenile idiopathic arthritis, and active ankylosing spondylitis. Trials are underway to study tofacitinib in COVID-19 related lung problems. Tofacitinib is being studied in combination with abrocitinib for treatment of toxic epidermal necrolysis. In some embodiments, the JAK inhibitor is a JAK1/2/3 inhibitor. In some embodiments, the JAK1/2/3 inhibitor is tofacitinib. In some embodiments, the inflammatory and/or autoimmune disorder is active psoriatic arthritis, moderate-to severe-rheumatoid arthritis, moderate-to-severe active ulcerative colitis, particular course juvenile idiopathic arthritis, and active ankylosing spondylitis. In some embodiments, the inflammatory and/or autoimmune disorder is a result of a COVID-19 infection in the lung. In some embodiments, the inflammatory and/or autoimmune disorder is toxic epidermal necrolysis. Delgocitinib is a non-selective JAK inhibitor that is approved for use in atopic dermatitis in Japan. Delgocitinib was tested and showed improvement in psoriasis and chronic hand eczema. In some embodiments the JAK inhibitor is delgocitinib. In some embodiments, the inflammatory and/or autoimmune disorder is atopic dermatitis. In some embodiments, the inflammatory and/or autoimmune disorder is psoriasis or chromic hand eczema. Peficitinib is a pan-JAK inhibitor approved for use in rheumatoid arthritis in Japan. In some embodiments the pan-JAK inhibitor is peficitinib. In some embodiments, the inflammatory and/or autoimmune disorder is rheumatoid arthritis. Brepocitinib is being evaluated in active non-infectious non-anterior uveitis, dermatomyositis, and cicatricial alopecia. Cerdulatinib is being evaluated for relapsed/refractory peripheral T-cell lymphoma, chronic lymphcytic leukemia, small lymphocytic lymphoma, B-cell non-hodgkin lymphoma, follicular lymphoma, T- cell lymphoma and vitiligo. Decernotinib is a JAK3 inhibitor being evaluated for rheumatoid arthritis. Deucravacitinib is being evaluated in pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pstulosis, crohn’s disease, ulcerative colitis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, and systemic lupus erythematosus, among others. Gandotinib is a JAK2 inhibitor being evaluated for myeloproliferative disorders including myelofibrosis, graft-versus host disease, and rheumatoid arthritis. Itacitinib is a JAK1 inhibitor being evaluated for acute graft-versus-host disease. Momelotinib is being evaluated for primary myelofibrosis, polycythemia vera myelofibrosis, post- essential thrombocytopenia myelofibrosis, and non-small cell lung cancer, among others. Nezulcitinib is being evaluated in COVID-19 related lung problems. Ritlecitinib is a JAK3 inhibitor being evaluated for nonsegmental vitiligo, cutaneous T-cell lymphoma, cicatricial alopecia, and alopecia areata. In some embodiments, the JAK inhibitor is brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, icacitinib, momelotinib, nezulcitinib,or ritlecitinib. In one aspect, the present disclosure provides a method of treating inflammatory and/or autoimmune disorders, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound as described herein is administered as a replacement therapy for treating a disease associated with JAK activity. In some embodiments, the disease associated with JAK activity is an inflammatory and/or autoimmune disorder. In some embodiments, the inflammatory and/or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, crohn’s disease, refractory, moderate- to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post- polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile idiopathic arthritis. In some embodiments, the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, crohn’s disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis. In some embodiments, the inflammatory and/or autoimmune disorder is non-infectious non- anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus. In some embodiments, the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis. In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, crohn’s disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method of treating inflammatory and/or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis. In some embodiments, the method further comprises administering to the subject a JAK inhibitor. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib. In another aspect, the present disclosure provides a method of treating a disease, disorder, or medical condition mediated by JAK activity, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder, or medical condition mediated by JAK activity is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis. In another aspect, the present disclosure provides a method of treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the member of the JAK-STAT pathway is a janus kinase (JAK). In some embodiments, the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT). In some embodiments, the treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis. In another aspect, the present disclosure provides a method of inducing immune tolerance in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method of suppressing a memory CD8+ T cell response in a subject in a subject having or at risk of developing an inflammatory response, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder. In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is a skin disorder. In some embodiments, the skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease or pancreatic cancer. In some embodiments, the cancer is lymphoma, leukemia, or multiple myeloma. In some embodiments, the myeloproliferative disorder is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD). In some embodiments, the myeloproliferative disorder is myelofibrosis. In some embodiments, the myeloproliferative disorder is primary myelofibrosis (PMF). In some embodiments, the myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV MF). In some embodiments, the myeloproliferative disorder is post- essential thrombocythemia myelofibrosis (Post-ET MF). Pharmaceutical Uses 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 CBP, e.g., by inhibiting the activity or level of the CBP in a cell within a mammal. An aspect of the present invention relates to methods of treating disorders related to CBP such as cancer in a subject in need thereof. In some embodiments, the compound is administered in an 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 Treating cancer can result in a reduction in size or volume of a tumor. For example, after 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 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 organs distant from the primary tumor site. For example, after treatment, the number of metastatic 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 50x). An aspect of the present invention relates to methods of treating disorders related to CBP such as inflammation and/or autoimmune disorders in a subject in need thereof. In some embodiments, the compound is administered in an 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 T cell (e.g., CD8+ memory T cells) activity, (b) reduced inflammation, (c) reduced thrombopoiesis, (d) reduced B cell proliferation, (e) increased survival of subject, and (f) increased progression free survival of a subject. Treating inflammatory disorders and/or autoimmune disorders can result in a reduction in T cell (e.g., CD8+ memory T cells) activity. For example, after treatment, T cell (e.g., CD8+ memory T cells) activity 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. T cell activity may be measured by any reproducible means of measurement. Treating inflammatory disorders and/or autoimmune disorders can result in a reduction in inflammation. For example, after treatment, inflammation 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. T cell activity may be measured by any reproducible means of measurement. Treating inflammatory disorders and/or autoimmune disorders can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition, or a downstream affect such as CBP degradation). Specifically, each cytokine receptor is paired with a JAK pair. When the JAK pair is cross-linked by its cytokine, the JAKs phosphorylate each other and also phosphorylate the cytokine receptor, which creates a STAT binding site for a STAT to then also become phosphorylated. In some embodiments, inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF-γ, IL-6, IL-11, IL-13, IL-25, IL-27, and/or IL-31, which in turn can affect the immune system response. Other cytokines that interact with JAK1, JAK3, and/or TYK2 include IL-10, IL-22, type 1 IFNs (α/β), IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.Treating cancer, inflammatory disorders, and/or autoimmune disorders 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 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. Treating cancer, inflammatory disorders, and/or autoimmune disorders 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 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. 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, inflammatory disorders, and/or autoimmune disorders or symptoms associated therewith, or in combination with other types of therapies to treat cancer, inflammatory disorders, and/or autoimmune disorders. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, 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 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), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl 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 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, 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 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, 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; 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 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; 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 coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; 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 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 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); 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); 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. 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 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 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; 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 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 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 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. 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 second agent may be a Janus Kinase (JAK) inhibitor. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib. 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 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. 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. 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 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 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 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 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 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 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 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 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. Dosages 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 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). 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). Kits The invention also features kits including (a) a pharmaceutical composition including an agent that reduces the level and/or activity of CBP 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 CBP 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. Examples ACN acetonitrile Ac2O acetic anhydride tBuOK potassium tert-butoxide DCM dichloromethane opropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide dppf bis(diphenylphosphino)ferrocene ESI electrospray ionization Et3N or TEA triethylamine EtOAc ethyl acetate EtOH ethyl alcohol FA formic acid FCC flash column chromatography GPhos Pd G6 TES Bromo[Dicyclohexyl[3-(1,1-dimethylethoxy)-6-methoxy- 2',6'-bis(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](4- ((2-(trimethylsilyl)ethoxy)carbonyl)benzen-1- ide)palladium(II) h hours HATU 2-(3H-[ 1,2,3 ]triazolo[ 4,5-b ]pyridin-3-yl)-l, 1,3 ,3- tetramethylisouronium HPLC high performance liquid chromatography KOAc potassium acetate L liter LCMS liquid chromatography / mass spectrometry LiHMDS lithium hexamethyldisilazide MeOH methyl alcohol mL milliliter mmol millimole mg milligrams MHz megahertz MS mass spectrometry MTBE methyl t-butylether m/z mass/charge ratio NBS N-bromosuccinimide nm nanometer NMR nuclear magnetic resonance ppm parts per million rt room temperature RT retention time Ruphos Pd G3 (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′- biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II) methanesulfonate SFC supercritical fluid chromatography TFA trifluoroacetic acid THF tetrahydrofuran Xantphos Pd G4 (SP-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9H- xanthen-4-yl]diphenylphosphine-κP](methanesulfonato-κ O)[2′-(methylamino-κN)[1,1′-biphenyl]-2-yl-κC]- Palladium XPhos Pd G3 (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate EPhos Pd G4 Methanesulfonato{Dicyclohexyl[3-(1-methylethoxy)- 2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2- yl]phosphine}(2'-methylamino-1,1'-biphenyl-2- yl)palladium(II) Materials Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere. Preparation of Intermediates Intermediate 1: Preparation of 1-{3-[7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3,4-dihydro- 2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone
Figure imgf000151_0001
Step 1. tert-Butyl 3-amino-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate A solution of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (20 g, 89 mmol) in EtOH (200 mL) was treated with hydrazine hydrate (80%) (6.7 g, 130 mmol) at 0°C. The reaction mixture was stirred for 2 h at 80°C. The reaction mixture was concentrated under reduced pressure, diluted with water (1.5 L) and extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: CH2Cl2 / MeOH (20:1)) affording the title compound (16 g, 67 mmol) as white solid. LCMS (ESI) m/z [M+H]+ = 239.1. Step 2 tert Butyl 3bromo 1467tetrahydro5Hpyrazolo[4,3-c]pyridine-5-carboxylate CuBr2 (15.5 g, 69 mmol) was added to a stirred solution of tert-Butyl 3-amino-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (15 g, 63 mmol) in ACN (100 mL).3-methylbutyl nitrite (11.1 mL, 63 mmol) was then added dropwise at 0°C. The reaction mixture was stirred for an additional 3 h at 60°C. The mixture was allowed to cool down to room temperature. The mixture was diluted with EtOAc (500 mL), washed with saturated NH4Cl (aq.) (500 mL x 7), brine (500 mL x 2), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: PE / THF (3:1)) affording the semi-pure product, which was then purified by trituration with PE / EtOAc (5:1) to afford title compound (10.2 g, 34 mmol) as white solid. LCMS (ESI) m/z [M+H]+ = 302.0 Step 3. tert-Butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-5-carboxylate Cs2CO3 (32.4 g, 99.3 mmol) was added to a stirred solution of tert-Butyl 3-bromo-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (10 g, 33.1 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (8.95 g, 49.6 mmol) in DMF (100 mL). The reaction mixture was stirred for 3.5 h at 80°C. The resulting mixture was then diluted with water (700 mL) and extracted with EtOAc (700 mL x 2). The organic layers were combined and washed with brine (1 L x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by FCC (Eluent: PE / (THF:MTBE=1:1) (1.5:1)) to afford two isomers. The second eluting isomer was collected and concentrated under reduced pressure. The residue was purified by reverse FCC (C18 silica gel; mobile phase, ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford the title compound (6.7 g, 17 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 386.1. Step 4. tert-Butyl 3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)- 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate t-BuONa (2.31 g, 24.1 mmol) and RuPhos Pd G3 (671 mg, 0.80 mmol) were added to a stirred solution of tert-Butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (3.1 g, 8.0 mmol) and 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (1.5 g, 8.0 mmol) in 1,4- dioxane (30 mL). The reaction mixture was stirred for 8 h at 85°C. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: PE / EtOAc (1:1)) affording the title compound (3.1 g, 6.3 mmol) as yellow solid. LCMS (ESI) m/z [M+H]+ = 489.2. Step 5. tert-Butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H- pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate NBS (1.0 g, 5.6 mmol) was added in portions at 0 °C to a stirred solution of tert-Butyl 3-(7-(difluoromethyl)- 3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine- 5-carboxylate (3.1 g, 6.3 mmol) in ACN (30.0 mL). After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: PE / EtOAc (1:1)) affording the title compound (3.5 g, 6.2 mmol) as yellow solid. LCMS (ESI) m/z [M+H]+ = 567.2. Step 6.6-Bromo-7-(difluoromethyl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline A mixture of tert-Butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran- 4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.5 g, 6.1 mmol) in DCM (28 mL) and TFA (7 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (700 mL) and extracted with EtOAc (700 mL x 3). The organic layers were combined and washed with brine (600 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, to afford intermediate 7 (2.5 g, 5.3 mmol) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 467.1. Step 7.1-(3-(6-Bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)- 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one Ac2O (596 mg, 5.8 mmol) was added in portions at 0°C to a stirred mixture of 6-Bromo-7-(difluoromethyl)- 1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4- tetrahydroquinoline (2.5 g, 5.3 mmol) and TEA (1.6 g, 15.9 mmol) in DCM (25.0 mL). After stirring at room temperature for 2 h, the reaction mixture was diluted with water (600 mL) and extracted with CH2Cl2 (600 mL x 3). The organic layers were combined and washed with brine (500 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by FCC (Eluent: CH2Cl2 / MeOH (20:1)) to afford the title compound (2.1 g, 4.1 mmol) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ = 7.32 (s, 1H), 7.12 – 6.59 (m, 2H), 4.37 – 4.24 (m, 1H), 4.18 (s, 2H), 4.01 – 3.91 (m, 2H), 3.74 (t, J = 5.8 Hz, 2H), 3.62 – 3.55 (m, 2H), 3.49 (td, J = 11.7, 2.3 Hz, 2H), 2.92 – 2.70 (m, 4H), 2.08 (s, 2H), 2.03 – 1.89 (m, 5H), 1.81 (dt, J = 9.4, 4.1 Hz, 2H) ppm. LCMS (ESI) m/z [M+H]+ = 509.1. Step 8.1-{3-[7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro- 2H- quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone KOAc (0.58 g, 5.89 mmol) and Pd(dppf)Cl2CH2Cl2 (0.24 g, 0.294 mmol) were added to a stirred solution of 1-{3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1- (oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-5-yl}ethanone (1 g, 1.96 mmol) and bis(pinacolato)diboron (1.25 g, 4.91 mmol) in dioxane (20 mL). The resulting mixture was stirred for 2 h at 80°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 saturated brine (100 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by FCC (Eluent: EtOAc / PE (0 to 100%)) to afford the title compound (1.59 g, crude) as a brown solid that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 557.0. Intermediate 2: 1-(3-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one
Figure imgf000154_0001
Step 1. tert-Butyl 3-(3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridine-5-carboxylate RuPhos Pd G3 (108 mg, 0.13 mmol) and t-BuONa (498 mg, 5.2 mmol) were added To a stirred solution of tert-butyl3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (500 mg, 1.3 mmol) and tetrahydroquinoline (172 mg, 1.3 mmol) in dioxane (7 mL). The reaction mixture was stirred for 2 h at 80°C. The reaction mixture was then diluted with EtOAc (100 mL), washed with water (50 mL x 2) and brine (50 mL x 1). The organic layer was dried over Na2SO4, filtered and evaporated to afford the crude product. The residue was purified by FCC (Eluent: CH2Cl2 / MeOH (10:1)) to afford the title compound (451 mg, 1.0 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 439.2. Step 2. tert-Butyl 3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate NBS (74.7 mg, 0.42 mmol) was added in portions at 0°C to a stirred solution of tert-butyl 3-(3,4- dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (230 mg, 0.52 mmol) in ACN (3 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EtOAc (30 mL), washed with water (30 mL x 2) and brine (30 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 63% B to 80% B in 9 min, 80% B; Wave Length: 254/220 nm; RT1(min): 7.68) to afford the title compound (112 mg, 0.21 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 517.4. Step 3.6-Bromo-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)- 1,2,3,4-tetrahydroquinoline A solution of tert-Butyl 3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7- t t h d 5H l [43 ] idi 5 b l t (112 mg, 0.22 mmol) in DCM (0.9 mL) and TFA (0.3 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to afford Intermediate 4 (138 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]+ = 417.35. Step 4.1-(3-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one Acetic anhydride (37.1 mg, 0.36 mmol) was added dropwise at 0°C to a stirred solution of 6-Bromo-1-(1- (tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (138 mg, 0.33 mmol) and TEA (100 mg, 0.99 mmol) in DCM (2 mL). The reaction mixture was stirred for 1h at room temperature. The reaction mixture was concentrated under reduced pressure and purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford the title compound (84 mg,0.18 mmol) as a off-white solid. LCMS (ESI) m/z [M+H]+ = 453.3. Intermediate 3: 1-(3-(6-Bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one
Figure imgf000155_0001
Step 1. tert-Butyl 3-bromo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate A solution of tert-butyl 3-bromo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (500 mg, 1.66 mmol) in DMF (10 mL) was treated with NaH (119 mg, 5.0 mmol) at 0°C. After stirring at 0°C for 30 minutes, MeI (352 mg, 2.48 mmol) was added. The reaction mixture was stirred for additional 2 h at room temperature. The reaction was quenched by the addition of saturated NH4Cl (aq.) (30 mL) at 0°C, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (Eluent: PE / THF (8:1)) to obtain semi-pure product. The product was then purified by reversed-phase FCC (column, C18 silica gel; mobile phase, MeOH in Water (10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (450 mg, 1.4 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 315.9. Step 2. tert-Butyl 3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridine-5-carboxylate RuPhos Pd G3 (106 mg, 0.13 mmol) and t-BuONa (365 mg, 3.8 mmol) were added to a stirred solution of tert-butyl 3-bromo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (400 mg, 1.26 mmol) and 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (232 mg, 1.26 mmol) in dioxane (12 mL). The reaction mixture was stirred for 1 h at 100°C. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (80 mg, 0.19 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 419.2. Step 3. tert-Butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate NBS (29.7 mg, 0.17 mmol) was added at 0 °C to a stirred solution of tert-butyl 3-(7-(difluoromethyl)-3,4- dihydroquinolin-1(2H)-yl)-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 3 (70 mg, 0.17 mmol) in ACN (1 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (30 mL x 2) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FCC (Eluent: PE / EA 1:1) affording the title compound (107 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]+ = 497.2. Step 4.6-Bromo-7-(difluoromethyl)-1-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)- 1,2,3,4-tetrahydroquinoline A solution of tert-Butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.20 mmol) and TFA (1 mL) in DCM (3 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford the title compound (165 mg, crude) as a black oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ =397.0. Step 5.1-(3-(6-Bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one Acetic anhydride (61.6 mg, 0.60 mmol) was added at 0°C to a stirred solution of 6-Bromo-7-(difluoromethyl)- 1-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (160 mg, 0.40 mmol) and TEA (122 mg, 1.21 mmol) in DCM (4 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with DCM (50 mL) and washed with water (30 mL x 2) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FCC (Eluent: CH2Cl2 / MeOH (20:1)) affording the title compound (69 mg, 0.16 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 439.1. Intermediate 4: 1-(3-(7-bromo-6-(difluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-1- (tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one
Figure imgf000157_0001
Step 1.1-(2-chloroethoxy)-4-(difluoromethyl)-2-nitrobenzene LDA (2M in THF, 39.5 ml, 79.1 mmol) was added dropwise to a solution of 2-chloroethanol (5.09 g, 63.4 mmol) in THF (110 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 15 min. A solution of 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (10.1 g, 52.8 mmol) in THF (10mL) was added to the reaction mixture at room temperature. After stirring for 2h, was added water (150 mL), and extracted with EA (300 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 30% EA in heptane) to afford the title compound (13.0 g, 51.8 mmol) as an off-white solid. LCMS (ESI) m/z [M+H]+ = 252.1. Step 2.2-(2-chloroethoxy)-5-(difluoromethyl)aniline Iron powder (17.3 g, 310.8 mmol, 6 eq) was added to a stirred solution of 1-(2-chloroethoxy)-4- (difluoromethyl)-2-nitrobenzene (13.0 g, 51.8 mmol) in AcOH (60 mL). After stirring for 4 hours, the reaction was quenched with water (150 mL) and extracted with EA (300 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by FCC (Eluent: 0 to 25% EA in heptane) to afford the title compound (8.90 g, 40.4 mmol) as an off-white solid. LCMS (ESI) m/z [M+H]+ = 222.1. Step 3.6-(difluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine KI (10.3 g, 62.6 mmol) and K2CO3 (12.9 g, 93.9 mmol) were added to a stirred solution of 2-(2-chloroethoxy)- 5-(difluoromethyl)aniline (6.95 g, 31.3 mmol) in DMAc (35 mL). The reaction mixture was heated at 90°C for 7 h. The reaction was then cooled to room temperature and quenched with water (150 mL). The reaction mixture was then extracted with EA (300 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure The residue was purified by FCC (Eluent: 0 to 25% EA in heptane) to afford the title compound (5.79 g, 28.8 mmol) as an off- white solid LCMS (ESI) m/z [M+H]+ = 1861 Intermediate 5: 1-(3-(7-bromo-6-(difluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-1- (tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one
Figure imgf000158_0001
Step 1. tert-Butyl 3-amino-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate Hydrazine hydrate (50-60% in water) (105 mL, 1.35 mol) was added to a solution of tert-butyl 3-cyano-4- oxopiperidine-1-carboxylate (10 g, 0.45 mol) in EtOH (600 mL). The resulting mixture was stirred for 2 h at 80°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was diluted with water (1.5 L) and extracted with DCM (1 L x 3). The combined organic layers were washed with brine (1 L x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (107 g, 445 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 239.1. Step 2. tert-Butyl 3-bromo-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate CuBr2 (108 g, 484 mmol) and 3-methylbutyl nitrite (64.4 mL, 484 mmol) were added to a stirred solution of tert-butyl 3-amino-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 2 (106.6 g, 445 mmol) in anhydrous MeCN (170 mL) at 0°C. The resulting mixture was stirred for 2 h at 60°C. The reaction mixture was then diluted with EtOAc (1 L) and washed with sat. NH4Cl (aq.) (600 mL x 4), 1 M HCl (600 mL x 3), and brine (600 mL x 2). The organic phases were combined and dried over anhydrous Na2SO4 and removed the solvents under reduced pressure. The crude was dried under a high vacuum for overnight to obtain the reddish solid. Methyl tert-butyl ether (MTBE) was added portion-wise to the crude and stirred to make a slurry. The solid was filtered off and washed with minimum amount of MTBE and heptane to afford the title compound (68 g, 224 mmol) as an off-white crystalline solid. LCMS (ESI) m/z [M+H]+ = 304.0. zolo[4,3-c]pyridine-5-carboxylate Cs2CO3 (63.3 g, 203 mmol) was added to a stirred solution of tert-butyl 3-bromo-1H,4H,6H,7H-pyrazolo[4,3- c]pyridine-5-carboxylate (20.5 g, 67.8 mmol) and oxan-4-yl methanesulfonate (18.3 g, 101.7 mmol) in DMAc (130 mL). The resulting mixture was stirred for 3.5 h at 80°C. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (400 mL x 2). The organic layers were combined and washed with brine (100 mL). The organic layer was then dried over anhydrous Na2SO4 and removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 45% EA in heptane) to obtain two isomers. The retention time of the desired isomer was higher than that of the undesired isomer. The fractions containing the desired isomer were combined and solvents were removed to afford the title compound (13.1 g, 34.0 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 386.2. Step 4.3-Bromo-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine TFA (15 mL) was added to a solution of tert-butyl 3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine- 5-carboxylate (21.6 g, 55.6 mmol) in DCM (60 mL). The reaction mixture was stirred for 4 h. The reaction was then concentrated under reduced pressure and TFA was co-evaporated with toluene (20 mL x 2) to afford the title compound (~24 g, crude) as a yellow gum. The crude was used for the next step without further purification. LCMS (ESI) m/z [M+H]+ = 288.1. Step 5.1-(3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1-one TEA (19.3 mL, 138 mmol) was addedt to a solution of 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine (15.8 g, 55.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 15 min. The mixture was cooled to 0°C and added acetic anhydride (5.75 mL, 60.9 mmol) was added in two portions. After 2 h, water (150 ml) was added to quench the reaction. The crude was extracted with DCM (300 mL x 3), washed with brine (100 mL), dried over anhydrous Na2SO4 and removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 5% MeOH in DCM) to afford the title compound (15.8 g, 47.6 mmol) as an off-white solid. LCMS (ESI) m/z [M+H]+ = 328.1. Step 6.1-(3-(6-(difluoromethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4- yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one Cs2CO3 (20.7 g, 63.6 mmol) and XPhos Pd G3 (2.15 g, 2.5 mmol) was added to a stirred solution of 7- (difluoromethyl)-1,2,3,4-tetrahydroquinoline 7 (3.94 g, 21.2 mmol) and 1-(3-bromo-1-(tetrahydro-2H-pyran- 4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (8.99 g, 27.4 mmol) in nitrogen degassed 1,4-dioxane (100 mL). The resulting mixture was stirred for 18 h at 120°C. The reaction was then cooled to room temperature and quenched with water (300 mL). The crude was extracted with EA (300 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, and removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 5% MeOH in DCM) to afford the title compound (9.07 g, 21.0 mmol) as an off-white solid. LCMS (ESI) m/z [M+H]+ = 433.1. Step 7.1-{3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl}ethanone NBS (3.73 g, 21.0 mmol) was added to a stirred solution of 1-(3-(6-(difluoromethyl)-2,3-dihydro-4H- benzo[b][1,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1-one (9.07 g, 21.0 mmol) in MeCN (100 mL) in 3 portions at 0 °C. After stirring for 2 h, the resulting mixture was diluted with water (100 mL) and extracted with EA (400 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 5% MeOH in DCM) to afford the title compound (10.6 g, 20.7 mmol) as an off-white solid. LCMS (ESI) m/z [M+H]+ = 511.1. Intermediate 6: (2S,4R)-1-(L-Valyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
Figure imgf000160_0001
Step 1. tert-Butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate Ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (2.7 g, 11 mmol) was added to a stirred solution of (1S)- 1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethanamine (2 g, 9.2 mmol) and (2S,4R)-1-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (2.1 g, 9.2 mmol) in DCM (20 mL). The reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with DCM (100 mL), washed with water (50 mL x 2) and brine (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (1.06 g, 2.5 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 432.2. S ( S ) ((S) ( ( 5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TFA (2 mL) was added to a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (1 g, 2.3 mmol) in DCM (8 mL). The reaction mixture was stirred for 1h at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude product that was purified by reverse phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (682 mg, 2.1 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 332.1. Step 3. tert-Butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate HATU (936 mg, 2.5 mmol) was added to a stirred solution of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (680 mg, 2.0 mmol), (2S)-2-[(tert- butoxycarbonyl)amino]-3-methylbutanoic acid (446 mg, 2.0 mmol) and DIEA (796 mg, 6.2 mmol) in DMF (7 mL). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with water (70 mL x 2) and brine (70 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by reverse phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (578 mg, 1.1 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 531.3. Step 4. (2S,4R)-1-(L-Valyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide To a stirred solution of tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (80 mg, 0.15 mmol) in DCM (1 mL) was added TFA (0.3 mL). The resulting mixture was stirred for 1h at room temperature. The reaction mixture was concentrated under reduced pressure to afford the title compund (71 mg, crude) as a white solid. LCMS (ESI) m/z [M+H]+ = 431.2. Intermediate 7: tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene- 2-carboxylate
Figure imgf000161_0001
Step 1. tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate LiHMDS (792 mg, 4.73 mmol) was added dropwise at -78°C to a stirred solution of tert-butyl 6-oxo-2- azaspiro[33]heptane-2-carboxylate (500 mg 236 mmol) in THF (5 mL). The mixture was stirred for 0.5 h and then 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (1.69 g, 4.73 mmol) was added into the mixture. The reactio mixture was warmed and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by reverse phase FCC affording the title compound (220 mg, 0.64 mmol) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 329. Step 2. tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.3]hept-5-ene-2- carboxylate KOAc (252 mg, 2.56 mmol) and Pd(dppf)Cl2 (46.9 mg, 0.064 mmol) was added at room temperature to a stirred solution of tert-butyl 6-(trifluoromethanesulfonyloxy)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (220 mg, 0.64 mmol) and bis(pinacolato)diboron (325 mg, 1.28 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred for 2 h at 80°C. The reaction mixture was concentrated under reduced pressure and purified by FCC (Eluent: PE / EtOAc (12:1)) affording the title compound (100 mg, 0.31 mmol) as a black solid. LCMS (ESI) m/z: [M+H]+ = 322. Intermediate 8: tert-Butyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azaspiro[5.5]undec-8- ene-3-carboxylate
Figure imgf000162_0001
Step 1. tert-Butyl 9-(((trifluoromethyl)sulfonyl)oxy)-3-azaspiro[5.5]undec-8-ene-3-carboxylate Lithium bis(trimethylsilyl)amide (0.06 mL, 0.56 mmol) was added dropwise at -78°C to a stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (100 mg, 0.37 mmol) in THF (3 mL). After stirring for 1 h at -78°C, a solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (200mg, 0.56 mmol) in THF (5 mL) was added dropwise. The reaction was warmed to room temperature and stirred for 4h. The reaction was quenched with saturated NH4Cl (aq.). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (Eluent: PE / EtOAc (5:1)) affording the title compound (1.3 g, 3.3 mmol) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 399.4. Step 2. tert-Butyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azaspiro[5.5]undec-8-ene-3- carboxylate Pd(dppf)Cl2 (238 mg, 0.33 mmol) was added to a solution of tert-butyl 9-(((trifluoromethyl)sulfonyl)oxy)-3- azaspiro[5.5]undec-8-ene-3-carboxylate (1.3 g, 3.3 mmol), bis(pinacolato)diboron (1.65 g, 6.5 mmol), and KOAc (958 mg, 9.8 mmol) in dioxane (20 mL). The solution was stirred at 80°C for 3 h. The precipitated solids were collected by filtration and washed with EtOAc (50 mL x 2). The crude product was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (1.03 g, 2.7 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 377.3 Intermediate 9: 7-bromopyrido[3,2-d]pyrimidine-2-carboxylic acid
Figure imgf000163_0001
Step 1. Ethyl [(5-bromo-2-formylpyridin-3-yl)carbamoyl]formate Ethyl chloroglyoxylate (441 mg, 3.23 mmol) was added in portions at 0oC to a stirred solution of 3-amino- 5-bromopyridine-2-carbaldehyde (500 mg, 2.49 mmol) and pyridine (590 mg, 7.46 mmol) in DCM (6 mL). The resulting mixture was stirred for 1h at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with DCM (60 mL), washed with water (60 mL x 2) and saturated brine (60 mL x 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (755 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]+ = 301.1. Step 2. Ethyl 7-bromopyrido[3,2-d]pyrimidine-2-carboxylate CH3COONH4 (1.93 g, 25.1 mmol) in portions at room temperature to a stirred solution of ethyl [(5-bromo- 2-formylpyridin-3-yl)carbamoyl]formate (755 mg, 2.51 mmol) in HOAc (25 mL). The resulting mixture was stirred for 1h at 115oC. The reaction mixture was diluted with water (75 mL), the resulting mixture was neutralized to pH 7 with 1N NaOH (aq.), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated brine (300 mL x 1), dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford the title compound (480 mg, 1.70 mmols) as a reddish brown solid. 1H NMR (300 MHz, DMSO-d6) δ = 9.85 (s, 1H), 9.36 (d, J = 2.2 Hz, 1H), 9.06 (dd, J = 2.2, 0.9 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). LCMS (ESI) m/z [M+H]+ = 282.1. Step 3.7-bromopyrido[3,2-d]pyrimidine-2-carboxylic acid LiOH.H2O (134 mg, 3.19 mmol) was added to a stirred solution of ethyl 7-bromopyrido[3,2-d]pyrimidine-2- carboxylate (300 mg, 1.06 mmol) in MeOH (4 mL) and H2O (1mL). The resulting mixture was stirred for 1h at 15oC. The mixture was neutralized to pH 5~6 with 1 N HCl (aq.). The resulting mixture was concentrated under reduced pressure. This afforded the title compounds (351 mg, 1.38 mmols) as a brown yellow solid. LCMS (ESI) m/z [M+H]+ = 254.0 Intermediate 10: 7-bromoquinazoline-2-carboxylic acid
Figure imgf000164_0001
Step 1. Ethyl [(5-bromo-2-formylphenyl)carbamoyl]formate Ethyl chloroglyoxylate (512 mg, 3.75 mmol) was added dropwise at 0oC to a stirred mixture of 2-amino-4- bromobenzaldehyde (500 mg, 2.50 mmol) and pyridine (593 mg, 7.50 mmol) in DCM (5 mL). The resulting mixture was stirred for an additional 1 h at room temperature. The reaction was quenched with water (100 mL). The mixture was extracted with DCM (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure affording the title compound (1.2 g, crude) as a yellow oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 299.9. Step 2. Ethyl 7-bromoquinazoline-2-carboxylate CH3COONH4 (3.08 g, 40.0 mmol) was added in portions at room temperature to a stirred mixture of ethyl [(5-bromo-2-formylphenyl)carbamoyl]formate (1.20 g, 4.00 mmol) in AcOH (36 mL). The resulting mixture was stirred for additional 1 h at 115oC. The resulting mixture was neutralized to pH 7 with 1N NaOH (aq.) and was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (0 %~100%) to afford the title compound (420 mg, 1.50 mmols) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.80 (d, J = 0.9 Hz, 1H), 8.46 (d, J = 0.8 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.08 (dd, J = 8.7, 1.9 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). LCMS (ESI) m/z [M+H]+ = 281.0 Step 3.7-bromoquinazoline-2-carboxylic acid LiOH.H2O (179 mg, 4.27 mmol) was added to a stirred solution of ethyl 7-bromoquinazoline-2-carboxylate (300 mg, 1.07 mmol) in MeOH (4 mL) and H2O (1 mL). The resulting mixture was stirred for 1h at 15oC. The mixture was acidified to pH 5 with 1N HCl (aq.). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), 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, MeOH in Water (0.1% TFA), 0% to 100% gradient in 30 min; detector, UV 254 nm affording the title compound (200 mg, 0.79 mmols) as a white solid. LCMS (ESI) m/z [M+H]+ = 252.0 Intermediate 11: 1-Bromo-3-cyclopropylimidazo[1,5-a]pyrazine
Figure imgf000165_0001
Step 1.1-Chloro-2-(difluoromethyl)-5-fluoro-4-nitrobenzene DAST (19.8 g, 122.8 mmol) was added to a stirred solution of 2-chloro-4-fluoro-5-nitrobenzaldehyde (5.0 g, 24.6 mmol) in DCM (50 mL) at 0 °C. The resulting mixture was stirred for 16 h at rt. The reaction was quenched by the addition of sat. NH4HCO3 (aq.) (100 mL) at 0 °C. The resulting mixture was 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 residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (20:1) to afford the title compound (4.9 g) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 226.0. Step 2. Methyl 2-[5-chloro-4-(difluoromethyl)-2-nitrophenoxy]acetate K2CO3 (2.5 g, 17.7 mmol) was added to a stirred solution of 1-chloro-2-(difluoromethyl)-5-fluoro-4- nitrobenzene (2.0 g, 8.9 mmol) and methyl 2-hydroxyacetate (1.6 g, 17.7 mmol) in DMF (20 mL). The resulting mixture was stirred for 4 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 15 min; detector, UV 254 nm) affording the title compound (2.05 g) as a grey solid. LCMS (ESI) m/z [M+H]+ =296.0. Step 3.7-Chloro-6-(difluoromethyl)-2,4-dihydro-1,4-benzoxazin-3-one AcOH (4 mL) and Fe (2.1 g, 37.2 mmol) was added to a stirred solution of methyl 2-[5-chloro-4- (difluoromethyl)-2-nitrophenoxy]acetate (2.0 g, 7.4 mmol) and H2O (10 mL) in EtOH (10 mL). The resulting mixture was stirred at 80 °C for an additional 1 h. The resulting mixture was neutralized to pH = 8 with saturated Na2CO3 (aq.) and extracted with EtOAc (50 mL x 3). The combined organic 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 PE/EtOAc (10:1) to afford the title compound (1.1 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 234.0. Step 4.7-Chloro-6-(difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine A solution of 7-chloro-6-(difluoromethyl)-2,4-dihydro-1,4-benzoxazin-3-one (700 mg, 3.0 mmol) and BH3- THF (5 mL, 48.0 mmol) in THF (10 mL) was stirred for 1 h at 60 °C. The reaction was quenched with MeOH vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the title compound (624 mg) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.15 – 6.78 (m, 3H), 6.26 (t, J = 2.4 Hz, 1H), 4.19 – 4.11 (m, 2H), 3.33 – 3.25 (m, 2H). LCMS (ESI) m/z [M+H]+ =220.0. Intermediate 12: 6-Chloro-7-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine
Figure imgf000166_0001
Step 1.5-Bromo-2-chloro-3-(difluoromethyl)pyridine DAST (43.9 g, 272.2 mmol) was added dropwise to a stirred mixture of 5-bromo-2-chloropyridine-3- carbaldehyde (20.0 g, 90.7 mmol) in DCM (100 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for an additional 2 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 (aq.) at 0 °C. The mixture was extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (20:1) to afford the title compound (18.8 g) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.41 (s, 1H), 7.51 – 6.92 (m, 1H). Step 2. N-(6-chloro-5-(difluoromethyl)pyridin-3-yl)-1,1-diphenylmethanimine t-BuONa (9.3 g, 96.5 mmol), XantPhos (8.6 g, 14.8 mmol) and Pd2(dba)3 (6.8 g, 7.4 mmol) was added to a stirred mixture of 5-bromo-2-chloro-3-(difluoromethyl)pyridine (18.0 g, 74.2 mmol) and diphenylmethanimine (13.5 g, 74.2 mmol) in toluene (200 mL) under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (300 mL), then extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (34.2 g, crude) as brown oil. The crude product was used in SI) m/z [M+H]+ = 342.95. Step 3.6-Chloro-5-(difluoromethyl)pyridin-3-amine 1M HCl (200 mL, 200 mmol) was added dropwise to a stirred solution of N-(6-chloro-5- (difluoromethyl)pyridin-3-yl)-1,1-diphenylmethanimine (34.2 g, 99.8 mmol) in THF (200 mL) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was diluted with water (200 mL), then extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford the title compound (9.4 g) as a light yellow oil. LCMS (ESI) m/z [M+H]+ = 179.10.1H NMR (300 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.26 (d, J = 2.9 Hz, 1H), 7.05 (t, J = 54.3 Hz, 1H), 5.85 (s, 2H). Step 4.2-Bromo-6-chloro-5-(difluoromethyl)pyridin-3-amine NBS (9.37 g, 52.6 mmol) in ACN (50 mL) was added dropwise at 0 °C to a stirred solution of 6-chloro-5- (difluoromethyl)pyridin-3-amine (9.4 g, 52.6 mmol) in ACN (100 mL). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed under reduced pressure. The residue was quenched with saturated Na2S2O3 (aq.). The resulting mixture was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10:1) to afford the title compound (11.8 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 256.8 & 258.8.1H NMR (300 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.08 (t, J = 54.0 Hz, 1H), 6.06 (s, 2H). Step 5. Ethyl (E)-3-(3-amino-6-chloro-5-(difluoromethyl)pyridin-2-yl)acrylate K2CO3 (19.0 g, 137.5 mmol) and Pd(dppf)Cl2 (3.4 g, 4.6 mmol) was added to a stirred mixture of 2-bromo- 6-chloro-5-(difluoromethyl)pyridin-3-amine (11.8 g, 45.8 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)prop-2-enoate (8.8 mg, 0.039 mmol) in dioxane (100 mL) and H2O (20 mL) under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 60 °C under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL), then extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10:1) to afford the title compound (9.1 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 276.80. Step 6. Ethyl 3-(3-amino-6-chloro-5-(difluoromethyl)pyridin-2-yl)propanoate Rh(PPh3)3Cl (1.5 g, 1.6 mmol) was added to a stirred solution of ethyl (E)-3-(3-amino-6-chloro-5- (difluoromethyl)pyridin-2-yl)acrylate (9.1 g, 32.9 mmol) in MeOH (150 mL). The resulting mixture was stirred for 1 h at room temperature under hydrogen atmosphere. The solvent was removed under reduced pressure. The mixture was filtered, the filter cake was washed with EtOAc (200 mL x 2). The filtrate was concentrated under reduced pressure to afford the title compound (9.2 g, crude). The crude product was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 279.00 Step 7.6-Chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one AcOH (5.7 mL, 99.0 mmol) was added dropwise to a stirred solution of ethyl 3-(3-amino-6-chloro-5- (difluoromethyl)pyridin-2-yl)propanoate (9.2 g, 33.0 mmol) in EtOH (90 mL) at room temperature. The resulting mixture was stirred for 3 h at 80 °C. The solvent was removed under reduced pressure. The mixture was neutralized to pH 8 with saturated NaHCO3 (aq.). The mixture was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4. 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 the title compound (5.5 g) as a white solid. LCMS (ESI) m/z [M+H]+ = 233.2.1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.47 (s, 1H), 7.16 (t, J = 54.1 Hz, 1H), 3.14 – 2.98 (m, 2H), 2.73 – 2.57 (m, 2H). Step 8.6-Chloro-7-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine BH3-THF (70.93 mL, 70.94 mmol) was added dropwise to a stirred solution of 6-chloro-7-(difluoromethyl)- 3,4-dihydro-1,5-naphthyridin-2(1H)-one (5.5 g, 23.6 mmol) in THF (50 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched by the addition of MeOH (100 mL) at 0 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10:1) to afford the title compound (4.53 g) as a white solid. LCMS (ESI) m/z [M+H]+ = 219.00.1H NMR (400 MHz, DMSO-d6) δ 7.19 – 6.83 (m, 2H), 6.36 (s, 1H), 3.26 – 3.11 (m, 2H), 2.77 (t, J = 6.5 Hz, 2H), 1.95 – 1.77 (m, 2H). Intermediate 13: 3-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-(oxan-4- yl)pyrazolo[4,3-b]pyridine-5-carboxamide
Figure imgf000168_0001
Step 1. Methyl 3-bromo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate NBS (1.00 g, 5.645 mmol) was added in portions to a stirred mixture of methyl 1H-pyrazolo[4,3-b]pyridine- 5-carboxylate (1 g, 5.64 mmol) in ACN (10 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of sat. Na2S2O5 (aq.) (20 mL) at room OAc (50mL 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 reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (903 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 256.1 Step 2. Methyl 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate Cs2CO3 (2.04 g, 6.25 mmol) was added to a stirred mixture of methyl 3-bromo-1H-pyrazolo[4,3-b]pyridine- 5-carboxylate (800 mg, 3.12 mmol) and oxan-4-yl methanesulfonate (563 mg, 3.12 mmol) in DMF (8 mL). The resulting mixture was stirred for 4 h at 100°C under the title compound nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (420 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 340.1 Step 3. Methyl 3-[7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)pyrazolo[4,3- b]pyridine-5-carboxylate XPhos Pd G3 (1.24 mg, 0.002 mmol) and Cs2CO3 (766 mg, 2.35 mmol) were added to a stirred mixture of methyl 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (400 mg, 1.18 mmol) and 7- (difluoromethyl)-1,2,3,4-tetrahydroquinoline (215 mg, 1.18 mmol) in dioxane (4 mL). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 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 reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (320 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 442.5 Step 4. Methyl 3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4- yl)pyrazolo[4,3-b]pyridine-5-carboxylate NBS (156.48 mg, 0.879 mmol) was added in portions at 0 °C to a stirred solution of methyl 3-[7- (difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (389 mg, 0.879 mmol) in ACN (5 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (180 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 521.4 Step 5.3-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)pyrazolo[4,3- b]pyridine-5-carboxylic acid LiOH.H2O (39.8 mg, 0.948 mmol) was added in portions at room temperature to a stirred mixture of methyl 3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5- carboxylate (165 mg, 0.316 mmol) in MeOH (2 mL) and H2O (2 mL). Without any additional work-up the crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (134 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 507.3 Step 6.3-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-(oxan-4- yl)pyrazolo[4,3-b]pyridine-5-carboxamide HATU (146.15 mg, 0.384 mmol) was added to a stirred mixture of 3-[6-bromo-7-(difluoromethyl)-3,4- dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylic acid (130 mg, 0.256 mmol), 2M methylamine in THF (0.128 mL, 0.256 mmol) and DIEA (66.2 mg, 0.512 mmol) in DMF (2 mL). The resulting mixture was stirred for 1 h at room temperature. Without any additional work-up. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (80 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 520.4 Intermediate 14: 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-N-methyl-1- (oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxamide
Figure imgf000170_0001
Step 1. Methyl 3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-1-(oxan-4- yl)pyrazolo[4,3-b]pyridine-5-carboxylate Xantphos Pd G4 (81.3 mg, 0.085 mmol) was added to a stirred solution of methyl 3-bromo-1-(oxan-4- yl)pyrazolo[4,3-b]pyridine-5-carboxylate (287.4 mg, 0.845 mmol) , K3PO4 (538 mg, 2.54 mmol), XantPhos (97.7 mg, 0.169 mmol) and 2-chloro-3-(difluoromethyl)-5,6,7,8-tetrahydro-1,5-naphthyridine (185 mg, 0.845 mmol) in dioxane (4 mL). The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (231.3 mg) as a brown oil. LCMS (ESI) m/z [M+H]+ = 478.1. Step 2.3-[6-Chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-N-methyl-1-(oxan-4- yl)pyrazolo[4,3-b]pyridine-5-carboxamide TCFH (108 mg, 0.384 mmol) was added to a stirred solution of methyl 3-[6-chloro-7-(difluoromethyl)-3,4- dihydro-2H-1,5-naphthyridin-1-yl]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylate (88.9 mg, 0.192 mmol), NMI (47.21 mg, 0.576 mmol) and methylamine (5.95 mg, 0.192 mmol) in ACN (1.5 mL). The resulting mixture was stirred for 1 h at room temperature under air atmosphere. Without any additional work-up, the crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (72.3 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ =477.1. Intermediate 15: tert-Butyl 3-[(4-chlorophenyl)(methyl)amino]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b] pyridine-5-carboxamide.
Figure imgf000171_0001
Step 1. Methyl 3-[(4-chlorophenyl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5- carboxylate XPhos Pd G3 (28.03 mg, 0.059 mmol) was added to a stirred solution of methyl 3-bromo-1-(oxan-4- yl)pyrazolo[4,3-b]pyridine-5-carboxylate (200 mg, 0.588 mmol), 4-chloro-N-methylaniline (83.2 mg, 0.588 mmol) and Cs2CO3 (383 mg, 1.18 mmol) in dioxane (5 mL). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm) affording the title compound (152 mg) as a yellow green oil. LCMS (ESI) m/z [M+H]+ = 401.5 Step 2.3-[(4-Chlorophenyl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5-carboxylic acid LiOH.H2O (75.9 mg, 1.81 mmol) was added to a stirred solution of methyl 3-[(4- chlorophenyl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[43-b]pyridine-5-carboxylate (145 mg, 0.362 mmol) in THF (4 mL) and H2O (2 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was acidified to pH 5 with HCl (aq.) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 20% to 60% gradient in 15 min; detector, UV 254 nm) affording the title compound (122 mg) as a yellow green oil. LCMS (ESI) m/z [M+H]+ = 387.1. Step 3. tert-Butyl 3-[(4-chlorophenyl)(methyl)amino]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b] pyridine-5-carboxamide HATU (170 mg, 0.446 mmol) was added to a stirred solution of 3-[(4-chlorophenyl)(methyl)amino]-1-(oxan- 4-yl)pyrazolo[4,3-b]pyridine-5-carboxylic acid (115 mg, 0.297 mmol), methanamine hydrochloride (20.1 mg, 0.297 mmol) and DIEA (154 mg, 1.19 mmol) in DMF (3 mL). The mixture was stirred for 2 h at room temperature. Without any additional work-up, The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 20% to 60% gradient in 15 min; detector, UV 254 nm) affording the title compound (88 mg) as a yellow green solid. LCMS (ESI) m/z [M+H]+ = 400.2. Intermediate 16: 3-[(6-Chloropyridin-3-yl)(methyl)amino]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b] pyridine -5-carboxamide.
Figure imgf000172_0001
Step 1. Methyl 3-[(6-chloropyridin-3-yl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5- carboxylate XPhos Pd G3 (37.3 mg, 0.044 mmol) was added to a stirred mixture of 3-bromo-1-(oxan-4-yl)pyrazolo[4,3- b]pyridine-5-carboxylate (150 mg, 0.441 mmol), 6-chloro-N-methylpyridin-3-amine (62.87 mg, 0.441 mmol), and Cs2CO3 (287.34 mg, 0.882 mmol) in toluene (5 mL) was The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (78 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 402.1. Step 2.3-[(6-Chloropyridin-3-yl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5- carboxylic acid LiOH (19.4 mg, 0.810 mmol) was added to a stirred solution of methyl 3-[(6-chloropyridin-3- yl)(methyl)amino]-1-(oxan-4-yl)pyrazolo[4,3-b]pyridine-5- carboxylate (65 mg, 0.162 mmol) in THF (2 mL) and H2O (2 mL). The resulting mixture was stirred for 1h at room temperature. The resulting mixture was acidified to pH 5 with 1 M solution of HCl (aq.) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (58 mg) as a yellow solid that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 388.1. Step 3.3-[(6-Chloropyridin-3-yl)(methyl)amino]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-b] pyridine -5- carboxamide HATU (66.2 mg, 0.174 mmol) was added to a stirred mixture of 3-[(6-chloropyridin-3-yl)(methyl)amino]-1- (oxan-4-yl)pyrazolo[4,3-b]pyridine-5- carboxylic acid (45 mg, 0.116 mmol), methanamine hydrochloride (9.40 mg, 0.139 mmol), and DIEA (30 mg, 0.232 mmol) in DMF (2 mL). The resulting mixture was stirred for 1 h at room temperature. Without any additional work-up, The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (46 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 401.1. Intermediate 17: 1-{1-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-(oxolan-3-yl)- 5H,6H,8H-imidazo[1,5-a]pyrazin-7-yl}ethenone.
Figure imgf000173_0001
Step 1. N-(Pyrazin-2-ylmethyl)oxolane-3-carboxamide Oxolane-3-carbonyl chloride (5 g, 37.16 mmol) was added dropwise at 00C to a stirred solution of 1- (pyrazin-2-yl)methanamine (4.06 g, 37.16 mmol), and TEA (7.52 g, 74.32 mmol) in DCM (60 mL). The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was concentrated under vacuum. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (4.6 g) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 208.1. Step 2.3-(Oxolan-3-yl)imidazo[1,5-a]pyrazine POCl3 (3.40 g, 22.20 mmol) was added dropwise at 0 °C to a stirred solution of N-(pyrazin-2- ylmethyl)oxolane-3-carboxamide (4.6 g, 22.20 mmol), and DMF (1.62 g, 22.20 mmol) in MeCN (60 mL). The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4HCO3 (aq.) (350 ml) at room temperature. The mixture was extracted with (CH2Cl2/MeOH=10:1) (450 mL x 2) and washed with saturated brine (300 mL x 1). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (18:1) to afford the title compound (2.5 g) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 190.1. Step 3.1-Bromo-3-(oxolan-3-yl)imidazo[1,5-a]pyrazine NBS (2.35 g, 13.21 mmol) was added to a stirred solution of 3-(oxolan-3-yl)imidazo[1,5-a]pyrazine (2.5 g, 13.21 mmol) in ACN (25 mL). The mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (2.1 g) as an orange solid. LCMS (ESI) m/z [M+H]+ = 268.0. Step 4.7-(Difluoromethyl)-1-[3-(oxolan-3-yl)imidazo[1,5-a]pyrazin-1-yl]-3,4-dihydro-2H-quinoline XPhos Pd G3 (994 mg, 1.18 mmol) was added to a stirred solution of 1-bromo-3-(oxolan-3-yl)imidazo[1,5- a]pyrazine (2.1 g, 7.83 mmol), 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (1.43 g, 7.83 mmol) and t- BuONa (22.19 g, 23.50 mmol) in 1,4-dioxane (25 mL). The mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (10 mL x 3). The filtrate was concentrated under reduced pressure. The mixture was diluted with EtOAc (200 mL), washed with saturated brine (200 mL x 1). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (16:1) to afford the title compound (2.08 g) as an orange solid. LCMS (ESI) m/z [M+H]+ = 371.1. Step 5.6-Bromo-7-(difluoromethyl)-1-[3-(oxolan-3-yl)imidazo[1,5-a]pyrazin-1-yl]-3,4-dihydro-2H- quinoline A solution of NBS (1.10 g, 6.18 mmol) in HFIP (10 mL) was added dropwise at -10 °C to a stirred solution of 7-(difluoromethyl)-1-[3-(oxolan-3-yl)imidazo[1,5-a]pyrazin-1-yl]-3,4-dihydro-2H-quinoline (2.08 g, 5.62 mmol) in HFIP (20 mL). The mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (801 mg) as a brown solid. LCMS (ESI) m/z [M+H]+ = 449.1. Step 6.6-Bromo-7-(difluoromethyl)-1-[3-(oxolan-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl]-3,4- dihydro-2H-quinoline PtO2 (40.4 mg, 0.178 mmol) was added to a stirred solution of 6-bromo-7-(difluoromethyl)-1-[3-(oxolan-3- yl)imidazo[1,5-a]pyrazin-1-yl]-3,4-dihydro-2H-quinoline (400 mg, 0.890 mmol) in MeOH (8 mL). The resulting mixture was stirred for 3 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (20 mL x 2). The filtrate was concentrated under reduced pressure to afford the title compound (426 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 453.2. Step 7.1-{1-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-(oxolan-3-yl)-5H,6H,8H- imidazo[1,5-a]pyrazin-7-yl}ethenone Ac2O (115.12 mg, 1.128 mmol) was added dropwise at 00C to a stirred solution of 6-bromo-7- (difluoromethyl)-1-[3-(oxolan-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl]-3,4-dihydro-2H-quinoline (426 mg, 0.940 mmol) and TEA (285 mg, 2.82 mmol) in DCM (6 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (184 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 495.2. Intermediate 18: 1-{1-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-isopropyl- 5H,6H,8H-imidazo[1,5-a]pyrazin-7-yl}ethenone.
Figure imgf000175_0001
Step 1.2-Methyl-N-(pyrazin-2-ylmethyl)propanamide Propanoyl chloride, 2-methyl- (2.93 g, 27.49 mmol) was added dropwise at 0°C to a stirred solution of 1- (pyrazin-2-yl)methanamine (3 g, 27.49 mmol) and TEA (5.56 g, 54.98 mmol) in DCM (30 mL). The resulting mixture was stirred at 0 °C for an additional 1 h. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH2Cl2 (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (5.26 g, crude) as a brown oil that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 180.1. Step 2.3-Isopropylimidazo[1,5-a]pyrazine POCl3 (2.08 mL, 22.32 mmol) was added dropwise at 0°C to a stirred solution of 2-methyl-N-(pyrazin-2- ylmethyl)propanamide (4 g, 22.32 mmol) and DMF (1.73 mL, 22.32 mmol) in ACN (40 mL). The resulting mixture was stirred for 1 h at 80 °C. The reaction was quenched with water/ice at 0 °C. The resulting mixture was basified to pH 8 with saturated Na2CO3 (aq.) and extracted with CH2Cl2 (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (2.36 g) as a red oil. LCMS (ESI) m/z [M+H]+ = 162.1. Step 3.1-Bromo-3-isopropylimidazo[1,5-a]pyrazine NBS (552.04 mg, 3.102 mmol) was added in portions at 0°C to a stirred solution of 3-isopropylimidazo[1,5- a]pyrazine (500 mg, 3.10 mmol) in ACN (5 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (518 mg) as a red oil. LCMS (ESI) m/z [M+H]+ = 240.0. Step 4.7-(Difluoromethyl)-1-{3-isopropylimidazo[1,5-a]pyrazin-1-yl}-3,4-dihydro-2H-quinoline XPhos Pd G3 (141 mg, 0.167 mmol) and t-BuONa (472 mg, 4.998 mmol) were added to a stirred solution of 1-bromo-3-isopropylimidazo[1,5-a]pyrazine (400 mg, 1.67 mmol) and 7-(difluoromethyl)-1,2,3,4- tetrahydroquinoline (305 mg, 1.67 mmol) in dioxane (5 mL). The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 15 min; detector, UV 254 nm) affording the title compound (461 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 343.2. Step 5.6-Bromo-7-(difluoromethyl)-1-{3-isopropylimidazo[1,5-a]pyrazin-1-yl}-3,4-dihydro-2H- quinoline NBS (207.9 mg, 1.168 mmol) was added in portions at -15°C To a stirred solution of 7-(difluoromethyl)-1- {3-isopropylimidazo[1,5-a]pyrazin-1-yl}-3,4-dihydro-2H-quinoline (400 mg, 1.168 mmol) in HFIP (5 mL). The resulting mixture was stirred for 1 h at -15 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (10mmol/L NH4HCO3), 0% to 100% gradient in 15 min; detector, UV 254 nm) affording the title compound (357 mg) as a white solid. LCMS (ESI) m/z [M+H]+ = 421.1. Step 6.6-Bromo-7-(difluoromethyl)-1-{3-isopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl}-3,4- dihydro-2H-quinoline PtO2 (16.2 mg, 0.071 mmol) was added to a stirred solution of 6-bromo-7-(difluoromethyl)-1-{3- isopropylimidazo[1,5-a]pyrazin-1-yl}-3,4-dihydro-2H-quinoline (150 mg, 0.356 mmol) in MeOH (3 mL). The resulting mixture was stirred for 30 min at room temperature under 10 atm of hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL x 3). The filtrate was concentrated under reduced pressure to afford the title compound (158 mg, crude) as a yellow solid that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 425.1. Step 7.1-{1-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-isopropyl-5H,6H,8H- imidazo[1,5-a]pyrazin-7-yl}ethenone TEA (112.24 mg, 1.110 mmol) was added dropwise at room temperature to a stirred solution of 6-bromo- 7-(difluoromethyl)-1-{3-isopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl}-3,4-dihydro-2H-quinoline (158 mg, 0.370 mmol) and acetic anhydride (37.8 mg, 0.370 mmol) in DCM (3 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (10mmol/L NH4HCO3), 0% to 100% gradient in 10 min; detector, UV 254 nm) affording the title compound (87 mg) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ = 7.29 (s, 1H), 7.10 – 6.64 (m, 1H), 6.57 (d, J = 7.8 Hz, 1H), 4.39 (d, J = 23.2 Hz, 2H), 4.08 (s, 1H), 3.95 (d, J = 5.6 Hz, 1H), 3.82 (t, J = 5.5 Hz, 2H), 3.53 – 3.42 (m, 2H), 3.13 – 2.93 (m, 1H), 2.81 (s, 2H), 2.16 – 1.86 (m, 5H), 1.19 (dd, J = 6.8, 3.5 Hz, 6H). LCMS (ESI) m/z [M+H]+ = 467.1. Intermediate 19: 1-{1-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-3-isopropyl- 5H,6H,8H-imidazo[1,5-a]pyrazin-7-yl}ethenone.
Figure imgf000177_0001
Step 1.7-Chloro-6-(difluoromethyl)-4-{3-isopropylimidazo[1,5-a]pyrazin-1-yl}-2,3-dihydro-1,4- benzoxazine XPhos Pd G3 (94.6 mg, 0.112 mmol) was added to a stirred solution of 1-bromo-3-isopropylimidazo[1,5- a]pyrazine (268 mg, 1.118 mmol), K3PO4 (712 mg, 3.35 mmol) and 7-chloro-6-(difluoromethyl)-3,4-dihydro- 2H-1,4-benzoxazine (245.5 mg, 1.118 mmol) in dioxane (3.5 mL). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (256.2 mg) as a red oil. LCMS (ESI) m/z [M+H]+ = 379.1. Step 2.7-Chloro-6-(difluoromethyl)-4-{3-isopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl}-2,3- dihydro-1,4-benzoxazine [RhCl2CP]2 (22.7 mg, 0.037 mmol) was added to a stirred solution of 7-chloro-6-(difluoromethyl)-4-{3- isopropylimidazo[1,5-a]pyrazin-1-yl}-2,3-dihydro-1,4-benzoxazine (139 mg, 0.367 mmol) and KI (121.8 mg, 0.734 mmol) in TEA (0.58 mL) and formic acid (0.42 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was basified to pH 8 with NaHCO3 (aq). The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, to afford the title compound (154.6 mg) as a reddish brown oil. LCMS (ESI) m/z [M+H]+ = 383.1. Step 3.1-{1-[7-Chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-3-isopropyl-5H,6H,8H- imidazo[1,5-a]pyrazin-7-yl}ethanone Ac2O (40.0 mg, 0.392 mmol) was added to a solution of 7-chloro-6-(difluoromethyl)-4-{3-isopropyl- 5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl}-2,3-dihydro-1,4-benzoxazine (150 mg, 0.392 mmol) and TEA (119 mg, 1.176 mmol) in DCM (1 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (85.4 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 425.2. Intermediate 20: 1-{1-[(4-Chlorophenyl)(methyl)amino]-3-isopropyl-5H,6H,8H-imidazo[1,5- a]pyrazin-7-yl}ethenone.
Figure imgf000178_0001
Step 1. N-(4-Chlorophenyl)-3-isopropyl-N-methylimidazo[1,5-a]pyrazin-1-amine Cs2CO3 (2.24 g, 6.87 mmol) and XPhos Pd G3 (193.90 mg, 0.229 mmol) was added to a stirred solution of 1-bromo-3-isopropylimidazo[1,5-a]pyrazine (550 mg, 2.29 mmol), 4-chlor-N-methylanilin (324 mg, 2.29 mmol) in dioxane (10 mL) The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 60% gradient in 15 min; detector, UV 254 nm) affording the title compound (469 mg) as a red oil. LCMS (ESI) m/z [M+H]+ = 301.2. Step 2. N-(4-Chlorophenyl)-3-isopropyl-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-amine (Cp*RhCl2)2 (116 mg, 0.146 mmol) was added to a stirred solution of N-(4-chlorophenyl)-3-isopropyl-N- methylimidazo[1,5-a]pyrazin-1-amine (440 mg, 1.46 mmol) in HCOOH (5 mL) and TEA (7 mL). The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was basified to pH 8 with saturated Na2CO3 (aq.) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 100% EtOAc in PE. Pure fractions were evaporated to dryness to afford the title compound (365 mg) as a brown oil. LCMS (ESI) m/z [M+H]+ = 305.2. Step 3.1-{1-[(4-Chlorophenyl)(methyl)amino]-3-isopropyl-5H,6H,8H-imidazo[1,5-a]pyrazin-7- yl}ethanone Ac2O (176 mg, 1.72 mmol) was added to a stirred solution of N-(4-chlorophenyl)-3-isopropyl-N-methyl- 5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-amine (350 mg, 1.148 mmol) and TEA (349 mg, 3.44 mmol) in DCM (5 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 100% EtOAc in PE. Pure fractions were evaporated to dryness to afford the title compound (267 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 347.2. Intermediate 21: 1-(1-(6-Chloro-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-3-morpholino-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethan-1-one.
Figure imgf000179_0001
Step 1. N-(Pyrazin-2-ylmethyl)morpholine-4-carboxamide Morpholine-4-carbonyl chloride (2.50 g, 13.37 mmol) was added dropwise at 0 °C to a stirred solution of 1- (pyrazin-2-yl)methanamine (1.82 g, 16.72 mmol) in DCM (40 mL). The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (3.6 g) as a white solid. LCMS (ESI) m/z [M+H]+ = 223.0. Step 2.4-(Imidazo[1,5-a]pyrazin-3-yl)morpholine POCl3 (7.13 mL, 76.49 mmol) was added to a stirred solution of N-(pyrazin-2-ylmethyl)morpholine-4- carboxamide (3.4 g, 15.30 mmol) and pyridine (12.37 mL, 152.98 mmol) and DMF (0.24 mL, 3.06 mmol) in ACN (50 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of water/ice (100 mL) at 0 °C and basified to pH 8 with saturated Na2CO3 (aq.). The resulting mixture was extracted with CH2Cl2 (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 residue was purified by silica gel column chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (1.1 g) as a red solid. LCMS (ESI) m/z [M+H]+ = 205.0. Step 3.4-(1-Bromoimidazo[1,5-a]pyrazin-3-yl)morpholine NBS (436 mg, 2.45 mmol) was added to a stirred solution of 4-(imidazo[1,5-a]pyrazin-3-yl)morpholine (500 mg, 2.45 mmol) in ACN (1 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (408 mg) as a dark red solid. LCMS (ESI) m/z [M+H]+ = 282.8. Step 4.4-(1-(6-Chloro-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)imidazo[1,5-a]pyrazin-3- yl)morpholine Cs2CO3 (1.04 g, 3.18 mmol) and XPhos Pd G3 (89.7 mg, 0.106 mmol) were added to a stirred mixture of 4-{1-bromoimidazo[1,5-a]pyrazin-3-yl}morpholine (300 mg, 1.06 mmol) and 2-chloro-3-(difluoromethyl)- 5,6,7,8-tetrahydro-1,5-naphthyridine (196 mg, 0.901 mmol) in dioxane (10 mL). The resulting mixture was stirred for 6 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (108 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 420.1. Step 5.4-(1-(6-Chloro-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazin-3-yl)morpholine [Rh(Cp*)Cl2]2 (15.4 mg, 0.025 mmol) was added to a stirred mixture of 4-(1-(6-chloro-7-(difluoromethyl)- 3,4-dihydroquinolin-1(2H)-yl)imidazo[1,5-a]pyrazin-3-yl)morpholine (100 mg, 0.25 mmol) in HCOOH (0.5 mL, 13.25 mmol) and TEA (0.7 mL, 5.036 mmol). The resulting mixture was stirred for 4 h at room temperature. The resulting mixture was basified to pH 8 with saturated NaHCO3 (aq.) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (97 mg, crude) as brown solid that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 424.0. Step 6.1-(1-(6-Chloro-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-3-morpholino-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethan-1-one Ac2O (35.7 uL, 0.378 mmol) was added to a stirred solution of 4-(1-(6-chloro-7-(difluoromethyl)-3,4- dihydroquinolin-1(2H)-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)morpholine (80 mg, 0.189 mmol) and TEA (78.7 uL, 0.567 mmol) in DCM (3 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (43 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 466.1. Intermediate 22: 1-{1-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-cyclopropyl- 5H,6H,8H-imidazo[1,5-a]pyrazin-7-yl}ethenone.
Figure imgf000181_0001
Step 1. N-(Pyrazin-2-ylmethyl)cyclopropanecarboxamide Cyclopropane carbonyl chloride (9.58 g, 91.63 mmol) was added dropwise at 0°C to a stirred solution of 1- (pyrazin-2-yl)methanamine (10 g, 91.63 mmol) and TEA (25.47 mL, 183.3 mmol) in DCM (100 mL). The resulting mixture was stirred for an additional 1 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with CH2Cl2 (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 to afford the title compound (17.6 g, crude) as a yellow solid that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 178.1. Step 2.3-Cyclopropylimidazo[1,5-a]pyrazine POCl3 (6.31 mL, 67.72 mmol) was added dropwise at 0°C to a stirred solution of N-(pyrazin-2- ylmethyl)cyclopropanecarboxamide (12 g, 67.72 mmol) and DMF (5.24 mL, 67.72 mmol) in ACN (100 mL). The resulting mixture was stirred at 80 °C for an additional 1 h. The reaction was quenched by the addition of water/ice (100 mL) at 0 °C and basified to pH 8 with saturated Na2CO3 (aq.). The resulting mixture was extracted with CH2Cl2 (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried ncentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (5.6 g) as a red oil. LCMS (ESI) m/z [M+H]+ = 160.1. Step 3.1-Bromo-3-cyclopropylimidazo[1,5-a]pyrazine NBS (2.80 g, 15.70 mmol) was added dropwise at 0°C to a stirred solution of N-(pyrazin-2- ylmethyl)cyclopropanecarboxamide (2.5 g, 15.70 mmol) in ACN (25 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of sat. sodium hyposulfite (aq.) (50 mL) and extracted with EtOAc (50 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 residue was purified by silica gel column chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (3 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 238.0. Step 4.1-{3-Cyclopropylimidazo[1,5-a]pyrazin-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline1- bromo-3-cyclopropylimidazo[1,5-a]pyrazine XPhos Pd G3 (284 mg, 0.336 mmol) was added to a stirred mixture of 1-bromo-3-cyclopropylimidazo[1,5- a]pyrazine (800 mg, 3.360 mmol), 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (616 mg, 3.360 mmol) and t-BuONa (969 mg, 10.08 mmol) in toluene (8 mL). The resulting mixture was stirred for 1h at 80 °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 reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (728 mg) as a brick red solid. LCMS (ESI) m/z [M+H]+ = 341.1. Step 5.6-Bromo-1-{3-cyclopropylimidazo[1,5-a]pyrazin-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H- quinoline NBS (345 mg, 0.162 mmol) was added in portions at -15°C to a stirred mixture of 1-{3- cyclopropylimidazo[1,5-a]pyrazin-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline1-bromo-3- cyclopropylimidazo[1,5-a]pyrazine (600 mg, 0.147 mmol) in HFIP (6 mL). The resulting mixture was stirred for 1h at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (192 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 419.0. Step 6.6-Bromo-1-{3-cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl}-7-(difluoromethyl)-3,4- dihydro-2H-quinoline PtO2 (20.6 mg, 0.091 mmol) was added to a stirred mixture of 6-bromo-1-{3-cyclopropylimidazo[1,5- a]pyrazin-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline (190 mg, 0.453 mmol) in MeOH (5 mL). The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL x 2). The filtrate was concentrated under reduced pressure to afford the title compound (170mg, crude) as yellow solid that was used directly without further purification. Step 7.1-{1-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-cyclopropyl-5H,6H,8H- imidazo[1,5-a]pyrazin-7-yl}ethanone Ac2O (114 uL, 1.21 mmol) and TEA (112 uL, 0.80 mmol) was added to a stirred mixture of 6-bromo-1-{3- cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline (170 mg, 0.402 mmol) in DCM (2 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to give the residue. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (109 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 465.1. Intermediate 23: 1-{1-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-3-cyclopropyl- 5H,6H,8H-imidazo[1,5-a]pyrazin-7-yl}ethanone.
Figure imgf000183_0001
Step 1.7-Chloro-4-{3-cyclopropylimidazo[1,5-a]pyrazin-1-yl}-6-(difluoromethyl)-2,3-dihydro-1,4- benzoxazine t-BuONa (350.1 mg, 3.64 mmol) and XPhos Pd G3 (154.2 mg, 0.182 mmol) were added to a stirred solution of 7-chloro-6-(difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine (400 mg, 1.82 mmol), and 1-bromo-3- cyclopropylimidazo[1,5-a]pyrazine (520.4 mg, 2.18 mmol) in dioxane (4 mL). The resulting mixture was stirred for an additional 1 h at 80 °C. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 1), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm) affording the title compound (619 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 377.1. Step 2.7-Chloro-4-{3-cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl}-6-(difluoromethyl)-2,3- dihydro-1,4-benzoxazine A solution of 7-chloro-4-{3-cyclopropylimidazo[1,5-a]pyrazin-1-yl}-6-(difluoromethyl)-2,3-dihydro-1,4- benzoxazine (600 mg, 1.59 mmol) and PtO2 (72.3 mg, 0.318 mmol) in MeOH (10 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The precipitated solids were collected by filtration and washed with MeOH (5 mL x 3). The filtration was concentrated under vacuum to afford the title compound (509 mg, crude) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 381.1. Step 3.1-{1-[7-Chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-3-cyclopropyl-5H,6H,8H- imidazo[1,5-a]pyrazin-7-yl}ethenone TEA (239.2 mg, 2.36 mmol) was added to a stirred solution of 7-chloro-4-{3-cyclopropyl-5H,6H,7H,8H- imidazo[1,5-a]pyrazin-1-yl}-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazine (300 mg, 0.788 mmol), and Ac2O (160.8 mg, 1.576 mmol) in DCM (5 mL). The resulting mixture was stirred for an additional 1 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm) affording the title compound (286 mg) as a yellow oil.1H NMR (300 MHz, DMSO-d6) δ = 7.19 – 6.53 (m, 3H), 4.44 (d, J = 12.6 Hz, 2H), 4.36 – 4.23 (m, 2H), 4.21 – 4.10 (m, 2H), 3.87 (t, J = 5.5 Hz, 2H), 3.55 (dq, J = 10.5, 6.0, 5.1 Hz, 2H), 2.08 (d, J = 7.6 Hz, 3H), 2.00 – 1.90 (m, 1H), 0.98 – 0.54 (m, 4H). LCMS (ESI) m/z [M+H]+ = 423.1. Intermediate 24: 1-(1-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-3-(oxetan-3-yl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethan-1-one.
Figure imgf000184_0001
Step 1. N-(Pyrazin-2-ylmethyl)oxetane-3-carboxamide CDI (4.76 g, 29.38 mmol) was added in portions at 0 °C to a stirred solution of oxetane-3-carboxylic acid (2 g, 19.47 mmol) in THF (15 mL). After 30 min, 1-(pyrazin-2-yl)methanamine (2.36 g, 21.55 mmol) was added to the above mixture. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (2.2 g) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 194.3. Step 2.3-(Oxetan-3-yl)imidazo[1,5-a]pyrazine Burgess reagent (3.95 g, 8.28 mmol) was added at 0 °C to a stirred solution of N-(pyrazin-2- ylmethyl)oxetane-3-carboxamide (1.60 g, 8.28 mmol) in DCM (10 mL). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (648 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 176.1. Step 3.1-Bromo-3-(oxetan-3-yl)imidazo[1,5-a]pyrazine NBS (487.7 mg, 2.740 mmol) was added to a stirred solution of 3-(oxetan-3-yl)imidazo[1,5-a]pyrazine(480 mg, 2.74 mmol) in ACN (5 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (590 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 253.9. Step 4.7-(Difluoromethyl)-1-(3-(oxetan-3-yl)imidazo[1,5-a]pyrazin-1-yl)-1,2,3,4-tetrahydroquinoline t-BuONa (453.9 mg, 4.72 mmol) and XPhos Pd G3 (133.3 mg, 0.158 mmol) were added to a stirred solution of 1-bromo-3-(oxetan-3-yl)imidazo[1,5-a]pyrazine (400 mg, 1.57 mmol) and 7-(difluoromethyl)-1,2,3,4- tetrahydroquinoline (288.4 mg, 1.57 mmol) in toluene (5 mL). The resulting mixture was stirred for 2 h at 80°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 residue was purified by silica gel column chromatography, elution gradient 0 to 100% EtOAc in PE. Pure fractions were evaporated to dryness to afford the title compound (372 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 357.1. Step 5.6-Bromo-7-(difluoromethyl)-1-(3-(oxetan-3-yl)imidazo[1,5-a]pyrazin-1-yl)-1,2,3,4- tetrahydroquinoline NBS (184.8 mg, 1.04 mmol) was added dropwise at -10 °C to a stirred solution of 7-(difluoromethyl)-1-(3- (oxetan-3-yl)imidazo[1,5-a]pyrazin-1-yl)-1,2,3,4-tetrahydroquinoline (370 mg, 1.04 mmol) in HFIP (5 mL). The resulting mixture was stirred for 2 h at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (144 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 435.0. Step 6.6-Bromo-7-(difluoromethyl)-1-(3-(oxetan-3-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)- 1,2,3,4-tetrahydroquinoline PtO2 (11.7 mg, 0.051 mmol) was added to a stirred solution of 6-bromo-7-(difluoromethyl)-1-(3-(oxetan-3- yl)imidazo[1,5-a]pyrazin-1-yl)-1,2,3,4-tetrahydroquinoline (112 mg, 0.257 mmol) in MeOH (4 mL). The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL x 2). The filtrate was concentrated under reduced pressure to afford the title compound (123 mg, crude) as a yellow solid that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 439.0. Step 7.1-(1-(6-Bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-3-(oxetan-3-yl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)ethan-1-one Ac2O (55.8 mg, 0.546 mmol) was added to a stirred solution of 6-bromo-7-(difluoromethyl)-1-(3-(oxetan-3- yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-1,2,3,4-tetrahydroquinoline (120 mg, 0.273 mmol), and TEA (82.9 mg, 0.819 mmol) in DCM (3 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (72 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 481.0. Intermediate 25: 1-{1-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-cyclobutyl- 5H,6H,8H- imidazo[1,5-a]pyrazin-7-yl}ethenone.
Figure imgf000186_0001
Step 1. N-(Pyrazin-2-ylmethyl)cyclobutanecarboxamide Cyclobutanecarbonyl chloride (3.26 g, 27.49 mmol) was added dropwise at 0°C to a stirred mixture of 1- (pyrazin-2-yl)methanamine (3 g, 27.49 mmol) and Et3N (2.78 g, 27.49 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (100 mL) at 0 °C and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (4.63 g) as a black oil that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 192.1. Step 2.3-Cyclobutylimidazo[1,5-a]pyrazine POCl3 (3.61 g, 23.53 mmol) was added dropwise at 0°C to a stirred mixture of N-(pyrazin-2- ylmethyl)cyclobutanecarboxamide (4.5 g, 23.53 mmol), and DMF (1.72 g, 23.5 mmol) in ACN (50 mL). The resulting mixture was stirred at 80°C for 1 h. The reaction was quenched by the addition of water (200 mL) at 0 °C. The resulting mixture was neutralized to pH 7 with saturated Na2CO3 (aq.). The resulting mixture was extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (3.1 g) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 174.2. Step 3.1-Bromo-3-cyclobutylimidazo[1,5-a]pyrazine NBS (1.13 g, 6.35 mmol) was added in portions at 0°C to a stirred mixture of 3-cyclobutylimidazo[1,5- a]pyrazine (1.1 g, 6.35 mmol) in ACN (10 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (1.61 g, crude) as a yellow oil that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 252.1. Step 4.1-{3-Cyclobutylimidazo[1,5-a]pyrazin-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline XPhos Pd G3 (0.34 g, 0.397 mmol) was added to a stirred mixture of 1-bromo-3-cyclobutylimidazo[1,5- a]pyrazine (1 g, 3.97 mmol), 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (0.73 g, 3.97 mmol) and t- BuONa (1.14 g, 11.90 mmol) in toluene (10 mL). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (0.97 g) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 355.3. Step 5.6-Bromo-1-{3-cyclobutylimidazo[1,5-a]pyrazin-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H- quinoline NBS (276.2 mg, 1.55 mmol) was added in portions at 0°C to a stirred mixture of 1-{3-cyclobutylimidazo[1,5- a]pyrazin-1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline (500 mg, 1.41 mmol) in 1,1,1,3,3,3- hexafluoropropan-2-ol (5 mL). The resulting mixture was stirred for 2 h at -15 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (283 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 433.3. Step 6.6-Bromo-1-{3-cyclobutyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl}-7-(difluoromethyl)- 3,4- dihydro-2H-quinoline PtO2 (21 mg, 0.092 mmol) was added to a stirred mixture of 6-bromo-1-{3-cyclobutylimidazo[1,5-a]pyrazin- 1-yl}-7-(difluoromethyl)-3,4-dihydro-2H-quinoline (200 mg, 0.462 mmol) in MeOH (3 mL). The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (80 mL x 3). The filtrate was concentrated under reduced pressure to afford the title compound (198 mg) as a yellow oil that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 437.3. Step 7.1-{1-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-3-cyclobutyl-5H,6H,8H- imidazo[1,5-a]pyrazin-7-yl}ethanone Acetic anhydride (53.2 mg, 0.521 mmol, 1.2) was added dropwise at 0°C to a stirred mixture of 6-bromo-1- {3-cyclobutyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-1-yl}-7-(difluoromethyl)- 3,4-dihydro-2H-quinoline (190 mg, 0.434 mmol) and TEA (175.8 mg, 1.74 mmol) in DCM (2 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 100% EtOAc in PE. Pure fractions were evaporated to dryness to afford the title compound (102 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 479.2. Intermediate 26: 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-N,1-dimethylindole-3- carboxamide
Figure imgf000188_0001
Step 1.5-Bromo-N,1-dimethylindole-3-carboxamide HATU (2.24 g, 5.90 mmol) was added to a solution of methanamine hydrochloride (0.27 g, 4.00 mmol), 5- bromo-1-methylindole-3-carboxylic acid (1 g, 3.93 mmol) and DIEA (1.53 g, 11.81 mmol) in DMF (10 mL). The resulting mixture was stirred for 1 h at room temperature. Without any additional work-up, the crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (720 mg) as a off-white solid. LCMS (ESI) m/z [M+H]+ = 267.1. Step 2.5-[6-Chloro-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-N,1-dimethylindole-3- carboxamide t-BuONa (143.9 mg, 1.498 mmol) and XPhos Pd G3 (63.4 mg, 0.075 mmol) were added to a solution of 5- bromo-N,1-dimethylindole-3-carboxamide (200 mg, 0.749 mmol) and 6-chloro-7-(difluoromethyl)-1,2,3,4- tetrahydroquinoline (163 mg, 0.749 mmol) in dioxane (5 mL). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 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 reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (119 mg) as a Brown yellow solid. LCMS (ESI) m/z [M+H]+ = 404.1. Intermediate 27: 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-N,1-
Figure imgf000189_0001
Step 1. Methyl 5-bromo-1-methylpyrrolo[3,2-b]pyridine-3-carboxylate DMF-DMA (6 mL, 7.47 mmol) was added to a stirred solution of methyl 5-bromo-1H-pyrrolo[3,2-b]pyridine- 3-carboxylate (600 mg, 2.35 mmol) in MeOH (3 mL). The resulting mixture was stirred for 4 h at 80°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (10mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (325 mg) as a white solid. LCMS (ESI) m/z [M+H]+ = 269.1. Step 2. Methyl 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-methylpyrrolo[3,2- b]pyridine-3-carboxylate RuPhos Pd G3 (62.2 mg, 0.074 mmol) was added to a stirred solution of methyl 5-bromo-1- 743 mmol), 6-chloro-7-(difluoromethyl)-1,2,3,4- tetrahydroquinoline (161.8 mg, 0.743 mmol), and Cs2CO3 (484.3 mg, 1.49 mmol) in dioxane (2 mL). The mixture was stirred for 2h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (161 mg) as a light yellow solid. LCMS (ESI) m/z [M+H]+ =406.1. Step 3.5-[6-Chloro-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-methylpyrrolo[3,2-b]pyridine- 3-carboxylic acid LiOH (41.3 mg, 1.72 mmol) was added to a stirred solution of methyl 5-[6-chloro-7-(difluoromethyl)-3,4- dihydro-2H-quinolin-1-yl]-1-methylpyrrolo[3,2-b]pyridine-3-carboxylate (140 mg, 0.345 mmol) in THF (0.5 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was acidified to pH 5 with HCl (aq.). The resulting mixture was extracted with CH2Cl2 (30 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (108 mg) as a light yellow solid. LCMS (ESI) m/z [M+H]+ = 392.1. Step 4.5-[6-Chloro-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-N,1-dimethylpyrrolo[3,2- b]pyridine-3-carboxamide HATU (145.6 mg, 0.383 mmol) was added to a stirred mixture of 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro- 2H-quinolin-1-yl]-1-methylpyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.255 mmol), methanamine hydrochloride (20.7 mg, 0.306 mmol) and DIEA (66 mg, 0.510 mmol) in DMF (1 mL). The resulting mixture was stirred for 1 h at room temperature. Without any additional work-up, The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (75 mg) as a white solid.
Intermediate 28: 5-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-N,1- dimethylpyrrolo[2,3-c]pyridine-3-carboxamide.
Figure imgf000191_0001
Step 1. Methyl 5-chloro-1-methylpyrrolo[2,3-c]pyridine-3-carboxylate A solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (300 mg, 1.53 mmol) in MeOH (2 mL) and DMF-DMA (2 mL) was stirred for overnight at 80°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 30% to 70% gradient in 10 min; detector, UV 254 nm) affording the title compound (254 mg) as a light yellow solid. LCMS (ESI) m/z [M+H]+ = 225.1. Step 2. Methyl 5-[7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-methylpyrrolo[2,3-c]pyridine-3- carboxylate RuPhos Pd G3 (94.6 mg, 0.113 mmol) and t-BuONa (217.3 mg, 2.26 mmol) were added to a stirred solution of methyl 5-chloro-1-methylpyrrolo[2,3-c]pyridine-3-carboxylate (254 mg, 1.13 mmol) and 7- (difluoromethyl)-1,2,3,4-tetrahydroquinoline (207.2 mg, 1.13 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 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 reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 30% to 60% gradient in 10 min; detector, UV 254 nm) affording the title compound (96 mg) as a yellow green solid. LCMS (ESI) m/z [M+H]+ = 372.5. Step 3. Methyl 5-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-methylpyrrolo[2,3- c]pyridine-3-carboxylate NBS (46.0 mg, 0.258 mmol) was added to a stirred solution of methyl 5-[7-(difluoromethyl)-3,4-dihydro-2H- quinolin-1-yl]-1-methylpyrrolo[2,3-c]pyridine-3-carboxylate (96 mg, 0.258 mmol) in ACN (1 mL). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of sat. sodium hyposulfite (aq.) (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers ( ) rous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (80 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 450.1. Step 4.5-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-methylpyrrolo[2,3-c]pyridine- 3-carboxylic acid LiOH.H2O (37.3 mg, 0.890 mmol) was added to a stirred solution of methyl 5-[6-bromo-7-(difluoromethyl)- 3,4-dihydro-2H-quinolin-1-yl]-1-methylpyrrolo[2,3-c]pyridine-3-carboxylate (80 mg, 0.178 mmol) in THF (2 mL) and H2O (1 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (67 mg) as a yellow green solid. LCMS (ESI) m/z [M+H]+ = 436.3. Step 5.5-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-N,1-dimethylpyrrolo[2,3- c]pyridine-3-carboxamide HATU (70.1 mg, 0.185 mmol) and DIEA (79.4 mg, 0.616 mmol) were added to a stirred solution of 5-[6- bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-methylpyrrolo[2,3-c]pyridine-3-carboxylic acid (67 mg, 0.154 mmol) and methanamine hydrochloride (10.4 mg, 0.154 mmol) in DMF (1 mL). The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (45 mg) as a yellow green solid. LCMS (ESI) m/z [M+H]+ = 449.3. Intermediate 29: Ethyl 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate
Figure imgf000192_0001
Step 1. Ethyl 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate 2-bromopropanedial (1.00 g, 6.62 mmol) was added to a stirred solution of ethyl 3-amino-5-methyl-2H- pyrazole-4-carboxylate (1 g, 5.91 mmol) in AcOH (15 mL). The resulting mixture was stirred for 3 h at 125°C. The resulting mixture was diluted with water (30 mL) and neutralized to pH = 7 with NH4HCO3 (aq.). The resulting mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (containing 0.1% FA) affording the title compound (1.14 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 284.0. Intermediate 30: Methyl 7-bromo-1,5-naphthyridine-2-carboxylate
Figure imgf000193_0001
Step 1. Methyl 1,5-naphthyridine-2-carboxylate Pd(dppf)Cl2CH2Cl2 (0.99 g, 1.22 mmol) was added to a solution of 2-chloro-1,5-naphthyridine (1 g, 6.08 mmol) and Et3N (1.84 g, 18.23 mmol) in MeOH (15 mL. The resulting mixture was stirred for 4 h at 100°C under 10 atm with carbon monoxide atmosphere. The resulting mixture was diluted with water (400 mL) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 0 to 100% EtOAc in petroleum ether) affording the title compound (823 mg) as a dark red solid. LCMS (ESI) m/z [M+H]+ = 189.06. Step 2. Methyl 7-bromo-1,5-naphthyridine-2-carboxylate NBS (454 mg, 2.55 mmol) was added in portions at 0°C to a stirred solution of methyl 1,5-naphthyridine-2- carboxylate (400 mg, 2.13 mmol) in AcOH (5 mL). The resulting mixture was stirred at 120°C for 4h. The resulting mixture was quenched with sat. Na2S2O3 (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by FCC (elution gradient 0 to 100% EtOAc in petroleum ether) affording the title compound (328 mg) as a grey solid. LCMS (ESI) m/z [M+H]+ = 266.97. Intermediate 31: 1-(3-{[4-chloro-3-(difluoromethyl)phenyl](methyl)amino}-1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl)ethenone
Figure imgf000193_0002
Step 1.4-Bromo-1-chloro-2-(difluoromethyl)benzene DAST (18.36 g, 113.9 mmol) was added dropwise at 0°C to a stirred solution of 5-bromo-2- chlorobenzaldehyde (5 g, 22.78 mmol) in DCM (60 mL). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by saturated aqueous NH4HCO3 (500 mL) at 0 °C and extracted with CH2Cl2 (600 mL x 3). The combined organic layers were washed with brine (600 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by FCC (elution gradient 0 to 100% EtOAc in petroleum ether) affording the title compound (4 g) as a white liquid. LCMS (ESI) m/z [M+H]+ = 240.93. Step 2. N-[4-Chloro-3-(difluoromethyl)phenyl]-1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-amine XPhos Pd G3 (194 mg, 0.229 mmol) was added to a stirred solution of 4-bromo-1-chloro-2- (difluoromethyl)benzene (553 mg, 2.29 mmol), 1-(oxan-4-yl) pyrazolo[4,3-c]pyridin-3-amine (500 mg, 2.29 mmol) and Cs2CO3 (2.24 g, 6.87 mmol) in dioxane (8 mL). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% TFA)) affording the title compound (651 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 379.11. Step 3. N-[4-Chloro-3-(difluoromethyl)phenyl]-N-methyl-1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-amine NaH (95.0 mg, 2.38 mmol, 60% purity) was added at 0°C to a stirred solution of N-[4-chloro-3- (difluoromethyl)phenyl]-1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-amine (450 mg, 1.19 mmol) in DMF (10 mL). The resulting mixture was stirred for 0.5 h at room temperature. To the above mixture was added CH3I (101 mg, 0.713 mmol) dropwise over 3 min at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was diluted with H2O (100 mL) and extracted with CH2Cl2 (200 mL x 3). The combined organic layers were washed with brine (200 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% TFA)) affording the title compound (240 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 393.12. Step 4. N-[4-Chloro-3-(difluoromethyl)phenyl]-N-methyl-1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo [4,3- c]pyridin-3-amine (Cp*RhCl2)2 (42.2 mg, 0.068 mmol) was added to a stirred solution of N-[4-chloro-3-(difluoromethyl)phenyl]- N-methyl-1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-amine (268 mg, 0.682 mmol) in HCOOH (2 mL) and TEA (2.8 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by saturated aqueous NH4HCO3 (50 mL) at 0 °C and extracted with CH2Cl2 (80 mL x 3). The combined organic layers were washed with brine (80 mL), then dried over anhydrous sodium sulfate, filtered and concentrated affording the title compound (292 mg, crude) that was used in the next step without further purification. LCMS (ESI) m/z [M+H]+ = 397.15. Step 5.1-(3-{[4-Chloro-3-(difluoromethyl)phenyl](methyl)amino}-1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl)ethanone Acetic anhydride (82.6 mg, 0.810 mmol) was added at 0°C to a stirred solution of N-[4-chloro-3- (difluoromethyl)phenyl]-N-methyl-1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo [4,3-c]pyridin-3-amine (292 mg, 0.736 mmol) and TEA (223 mg, 2.21 mmol) in DCM (4 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.1% FA)) affording the title compound (185 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 439.16. Intermediate 32: 6-bromo-4-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid
Figure imgf000195_0001
Step 1.1-Amino-3-bromo-5-methylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate Amino 2,4,6-trimethylbenzenesulfonate (3.75 g, 17.44 mmol) was added to a stirred solution of 3-bromo-5- methylpyridine (2 g, 11.63 mmol) in DCM (20 mL). The resulting mixture was stirred for 2 h at 80°C. The precipitated solids were collected by filtration with PE. The solid was dried under reduced pressure to afford the title compound (2 g, crude) as a white solid that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 387.03. Step 2.2,3-Dimethyl 6-bromo-4-methylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate K2CO3 (535 mg, 3.87 mmol) was added to a stirred solution of 1-amino-3-bromo-5-methylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (500 mg, 1.29 mmol) and dimethyl acetylenedicarboxylate (275 mg, 1.94 mmol) in DMF (10 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 0 to 60% EtOAc in petroleum ether) affording the title compound (388 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 327.99. Step 3.6-Bromo-4-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid A solution of 2,3-dimethyl 6-bromo-4-methylpyrazolo[1,5-a]pyridine-2,3-dicarboxylate (380 mg, 1.17 mmol) in sulfuric acid (8 mL) was stirred for 2 h at 120°C. The resulting mixture was diluted with water (50 mL) and neutralized to pH 5 with K2CO3. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic 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 flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title +H]+ = 255.97. Intermediate 33: Ethyl 7-bromo-5-fluoroquinazoline-2-carboxylate
Figure imgf000196_0001
Step 1. Ethyl [(5-bromo-3-fluoro-2-formylphenyl)carbamoyl]formate Ethyl chloroglyoxylate (407 mg, 2.98 mmol) was added dropwise at 0°C to a stirred solution of 2-amino-4- bromo-6-fluorobenzaldehyde (500 mg, 2.29 mmol) and pyridine (544 mg, 6.88 mmol) in DCM (10 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with H2O (100 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (1.1 g, crude) as a yellow oil that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 318.0. Step 2. Ethyl 7-bromo-5-fluoroquinazoline-2-carboxylate CH3COONH4 (1.87 g, 24.21 mmol) was added in portions to a stirred solution of ethyl [(5-bromo-3-fluoro- 2-formylphenyl)carbamoyl]formate (1.1 g, 2.42 mmol, 70%) in AcOH (3 mL). The resulting mixture was stirred for 1 h at 115°C. The reaction mixture was diluted with water (50 mL), neutralized to pH = 7 with 1M NaOH (aq.) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 0 to 60% EtOAc in petroleum ether) affording the title compound (465 mg) as an off-white solid. LCMS (ESI) m/z [M+H]+ = 299.0. Intermediate 34: Methyl 1-{3-[(6-chloropyridin-3-yl)(methyl)amino]-1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl}ethenone
Figure imgf000196_0002
Step 1.1-{3-[(6-Chloropyridin-3-yl)amino]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5- yl}ethanone GPhos Pd G6 TES (6.63 g, 7.01 mmol) was added to a stirred solution of 1-[3-bromo-1-(oxan-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (23 g, 70.08 mmol), 6-chloropyridin-3-amine (9.01 g, 70.08 mmol) and sodium trimethylsilanolate (15.72 g, 140.1 mmol) in THF (300 mL). The mixture was stirred at xture was concentrated under reduced pressure. The mixture was diluted with water (1000 mL). The resulting mixture was extracted with EtOAc (1000 mL x 3). The combined organic layers were washed with brine (500 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% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm affording the title compound (12.76 g) as a light yellow solid. LCMS (ESI) m/z [M+H]+ = 376.1. Step 2. Methyl 1-{3-[(6-chloropyridin-3-yl)(methyl)amino]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-5-yl}ethanone NaH (1.62 g, 67.58 mmol) was added in portions at 0℃ to a stirred solution of 1-{3-[(6-chloropyridin-3- yl)amino]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (12.7 g, 33.79 mmol) in DMF (200 mL). After 15 min, a solution of CH3I (4.80 g, 33.79 mmol) in DMF (10 mL) was added to the above solution. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was quenched by the addition of sat. NH4Cl (aq.) (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with saturated brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to give the crude product. 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 affording the title compound (7.5 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 390.2. Intermediate 34: Methyl 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-6-bromo-7- fluoro-3,4-dihydro-2H-quinoline-4-carboxylate.
Figure imgf000197_0001
Step 1. Methyl 7-fluoroquinoline-4-carboxylate Pd(dppf)Cl2CH2Cl2 (1.44 g, 1.77 mmol) was added to a solution of 4-bromo-7-fluoroquinoline (2 g, 8.85 mmol) and TEA (2.69 g, 26.54 mmol) in MeOH (60 mL). The resulting mixture was stirred for overnight at 100°C under 20 atm with carbon monoxide atmosphere. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (200 mL x 3) The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (2.1 g, crude) as a brown solid. LCMS (ESI) m/z [M+H]+ = 206.1. Step 2. Methyl 7-fluoro-1,2,3,4-tetrahydroquinoline-4-carboxylate PtO2 (1.39 g, 6.14 mmol) was added to a solution of methyl 7-fluoroquinoline-4-carboxylate (2.1 g, 10.24 mmol) in MeOH (50 mL). The resulting mixture was stirred for 2 h at room temperature under 10 atm of hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (1.6 g) as a brown oil. LCMS (ESI) m/z [M+H]+ = 210.1. Step 3. Methyl 7-fluoro-1-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydro-2H-quinoline-4- carboxylate XPhos Pd G3 (0.61 g, 0.717 mmol) was added to a stirred solution of methyl 7-fluoro-1,2,3,4- tetrahydroquinoline-4-carboxylate (1.5 g, 7.17 mmol), 3-bromo-1-(oxan-4-yl) pyrazolo[4,3-c]pyridine (2.02 g, 7.17 mmol) and Cs2CO3 (7.01 g, 21.51 mmol) in dioxane (30 mL). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (734 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 411.2. Step 4. Methyl 7-fluoro-1-[1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydro-2H- quinoline-4-carboxylate PtO2 (387 mg, 1.70 mmol) was added to a solution of methyl 7-fluoro-1-[1-(oxan-4-yl)pyrazolo[4,3- c]pyridin-3-yl]-3,4-dihydro-2H-quinoline-4-carboxylate (700 mg, 1.70 mmol) in MeOH (40 mL) was added The resulting mixture was stirred for 2 h at room temperature under 10 atm of hydrogen atmosphere. The resulting mixture was filtered through a celite pad and concentrated under reduced pressure to afford the title compound (603 mg, crude) as a white solid that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 415.2. Step 5. Methyl 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-fluoro-3,4-dihydro- 2H-quinoline-4-carboxylate Ac2O (296 mg, 2.90 mmol) was added to a stirred solution of methyl 7-fluoro-1-[1-(oxan-4-yl)- 4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydro-2H-quinoline-4-carboxylate (600 mg, 1.45 mmol) and TEA (586 mg, 5.79 mmol) in DCM (12 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (512 mg) as a white solid. LCMS (ESI) m/z [M+H]+ = 457.2. Step 6. Methyl 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-6-bromo-7-fluoro-3,4- dihydro-2H-quinoline-4-carboxylate NBS (191 mg, 1.07 mmol) was added in portions at 0°C to a stirred solution of methyl 1-[5-acetyl-1-(oxan- 4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-fluoro-3,4-dihydro-2H-quinoline-4-carboxylate (500 mg, 1.10 mmol) in MeCN (6 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was quenched with sat. Na2S2O3 (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The residue was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (517 mg) as a white solid.1H NMR (300 MHz, DMSO-d6) δ = 7.36 (d, J = 7.9 Hz, 1H), 6.33 (t, J = 12.4 Hz, 1H), 4.30 (p, J = 6.5 Hz, 1H), 4.22 – 4.04 (m, 2H), 4.03 – 3.88 (m, 3H), 3.86 – 3.66 (m, 5H), 3.61 – 3.38 (m, 4H), 2.91 – 2.69 (m, 2H), 2.25 (dd, J = 13.8, 3.9 Hz, 1H), 2.15 – 1.88 (m, 6H), 1.88 – 1.72 (m, 2H). LCMS (ESI) m/z [M+H]+ = 535.1. Intermediate 35: 1-{3-[3-(Difluoromethyl)-4-iodophenoxy]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c] pyridin-5-yl}ethenone
Figure imgf000199_0001
Step 1. tert-Butyl 3-[3-(difluoromethyl)-4-nitrophenoxy]-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5- carboxylate 2-(difluoromethyl)-4-fluoro-1-nitrobenzene (1.60 g, 8.36 mmol) was added to a stirred solution of tert-butyl 3-hydroxy-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (2 g, 8.36 mmol) and DIEA (2.16 g, 16.73 mmol) in DMSO (20 mL). The resulting mixture was stirred for 2 h at 100°C. 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 (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (1.5 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 411.4. Step 2. tert-Butyl 3-[3-(difluoromethyl)-4-nitrophenoxy]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c] pyridine-5-carboxylate Cs2CO3 (2.38 g, 7.31 mmol) was added to a stirred mixture of tert-butyl 3-[3-(difluoromethyl)-4- nitrophenoxy]-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.5 g, 3.66 mmol) and oxan-4-yl methanesulfonate (0.66 g, 3.66 mmol) in DMF (10 mL). The resulting mixture was stirred for 4 h at 120°C. 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 (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (180 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 495.5. Step 3. tert-Butyl 3-[4-amino-3-(difluoromethyl)phenoxy]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridine-5-carboxylate Pd/C (64.6 mg, 0.606 mmol) was added to a stirred solution of tert-butyl 3-[3-(difluoromethyl)-4- nitrophenoxy]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c] pyridine-5-carboxylate (100 mg, 0.202 mmol) in MeOH (5 mL). The resulting mixture was stirred for 2 h at room temperature under 10 atm of hydrogen atmosphere. The resulting mixture was filtered with celite, and the filtrate was concentrated and dried under vacuum to afford the title compound (82 mg, crude) as a white solid that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 465.5. Step 4. tert-Butyl 3-[3-(difluoromethyl)-4-iodophenoxy]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c] pyridine-5-carboxylate KI (108.6 mg, 0.654 mmol) was added in portions at 0°C to a stirred solution of tert-butyl 3-[4-amino-3- (difluoromethyl)phenoxy]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate (152 mg, 0.327 mmol), TsOH (113 mg, 0.654 mmol) and NaNO2 (45.2 mg, 0.654 mmol) in ACN (2 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (102 mg) as a colorless oil. LCMS (ESI) m/z [M+H]+ = 576.4. Step 5.3-[3-(Difluoromethyl)-4-iodophenoxy]-1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c] pyridine TFA (1 mL, 13.46 mmol) was added to a stirred mixture of tert-butyl 3-[3-(difluoromethyl)-4-iodophenoxy]- 1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c] pyridine-5-carboxylate (102 mg, 0.177 mmol) in DCM (4 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to afford the title compound (75 mg, crude) as a yellow oil that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 576.4. Step 6.1-{3-[3-(difluoromethyl)-4-iodophenoxy]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c] pyridin-5- yl}ethanone Ac2O (16.2 mg, 0.158 mmol) was added to a stirred solution of 3-[3-(difluoromethyl)-4-iodophenoxy]-1- (oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c] pyridine (75 mg, 0.158 mmol) and TEA (31.9 mg, 0.316 mmol) in ACN (1 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (60 mg) as a yellow oil. LCMS (ESI) m/z [M+H]+ = 527.3. Intermediate 36: 1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-7-fluoro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl trifluoromethanesulfonate
Figure imgf000201_0001
Intermediate 36 Step 1.2-(Benzyloxy)-3,6-difluoro-5-nitropyridine Benzyl alcohol (850 mg, 7.86 mmol) was added to a stirred solution of 2,3,6-trifluoro-5-nitropyridine (1.4 g, 7.86 mmol), TBAHS (267 mg, 0.786 mmol) and NaOH (314 mg, 7.86 mmol) in DCM (15 mL). The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (400 mL) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (1.5 g, crude) as a yellow solid that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 267.1. Step 2. Methyl 2-{[6-(benzyloxy)-5-fluoro-3-nitropyridin-2-yl]oxy}acetate Methyl 2-hydroxyacetate (947 mg, 10.52 mmol) was added to a stirred mixture of 2-(benzyloxy)-3,6-difluoro- 5-nitropyridine (1.4 g, 5.26 mmol) and K2CO3 (1.45 g, 10.52 mmol) in DMF (20 mL). The resulting mixture was stirred for 1h at room temperature. The resulting mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 10 to 100% EtOAc in petroleum ether) affording the title compound (1.5 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 337.1. Step 3.6-(Benzyloxy)-7-fluoro-1H,3H-pyrido[2,3-b][1,4]oxazin-2-one Fe (1.25 g, 22.30 mmol) was added to a stirred solution of methyl 2-{[6-(benzyloxy)-5-fluoro-3-nitropyridin- 2-yl]oxy}acetate (1.5 g, 4.46 mmol) in EtOH (10 mL), AcOH (2 mL) and H2O (8 mL). The resulting mixture was stirred for 1h at 80°C. After the reaction was completed, filtered while hot and concentrated under reduced pressure to give crude product. The crude product was purified by FCC (elution gradient 0 to 100% EtOAc in petroleum ether) affording the title compound (853 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 275.1. Step 4.6-(Benzyloxy)-7-fluoro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine BH3-THF (8 mL, 83.59 mmol) was added dropwise at 0 °C to a stirred solution of 6-(benzyloxy)-7-fluoro- 1H,3H-pyrido[2,3-b][1,4]oxazin-2-one (840 mg, 3.06 mmol) in THF (8 mL). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with MeOH (50 mL) at 0°C, diluted with H2O (300 mL) and extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 0 to 100% EtOAc in petroleum ether) affording the title compound (785 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 261.1. Step 5.6-(Benzyloxy)-7-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazine XPhos Pd G3 (504 mg, 0.596 mmol) was added to a stirred mixture of 6-(benzyloxy)-7-fluoro-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazine (775 mg, 2.98 mmol), 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-c]pyridine (1.01 g, 3.57 mmol) and t-BuONa (859 mg, 8.93 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred for 3 h at 80°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (50 mL x 2). The filtrate was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 0 to 10% MeOH in DCM) affording the title compound (989 mg) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 462.2. Step 6.6-(Benzyloxy)-7-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine [Rh(Cp*)Cl2]2 (129.8 mg, 0.210 mmol) at 0°C was added to a stirred solution of 6-(benzyloxy)-7-fluoro-1- (1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (969 mg, 2.10 mmol) in formic acid (5 mL) and TEA (7 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was basified to pH 8 with saturated K2CO3 (aq) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (814 mg, crude) as a brown solid that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 466.2. Step 7.1-(3-(6-(Benzyloxy)-7-fluoro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-(tetrahydro-2H- pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one Ac2O (263 mg, 2.58 mmol) was added to a stirred solution of 6-(benzyloxy)-7-fluoro-1-(1-(tetrahydro-2H- pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (800 mg, 1.72 mmol) and Et3N (869 mg, 8.59 mmol) in DCM (10 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 0 to 10% MeOH in DCM) affording the title compound (666 mg) as a light brown solid. LCMS (ESI) m/z [M+H]+ = 508.2. Step 8.1-(3-(7-Fluoro-6-hydroxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-(tetrahydro-2H- pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one To a stirred solution of 1-(3-(6-(benzyloxy)-7-fluoro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1- (tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (646 mg, 1.27 mmol) in EtOH (20 mL) was added Pd/C (271 mg, 2.55 mmol). The resulting mixture was stirred overnight at room temperature under 1 atm of hydrogen atmosphere The resulting mixture was then filtered with celite, and the filter cake was washed with EtOAc (50 mL x 2). The filtrate was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (389 mg) as a light yellow solid. LCMS (ESI) m/z [M+H]+ = 418.2. Step 9.1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7- fluoro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl trifluoromethanesulfonate 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (487 mg, 1.36 mmol) was added to a stirred solution of 1-(3-(7-fluoro-6-hydroxy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-(tetrahydro- 2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (379 mg, 0.908 mmol) and Et3N (919 mg, 9.08 mmol) in DMF (5 mL). The resulting mixture was stirred for 2 h at room temperature. 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 (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 0 to 10% MeOH in DCM) affording the title compound (287 mg, 0.52 mmol) as a brown solid. LCMS (ESI) m/z [M+H]+ = 550.1. Intermediate 37: Preparation of 1-[3-(6-Bromo-3,4-dihydro-2H-quinoxalin-1-yl)-1-(oxan-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]ethenone
Figure imgf000204_0001
Step 1. tert-Butyl 4-[1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydroquinoxaline-1-carboxylate XPhos Pd G3 (0.54 g, 0.640 mmol) was added to a stirred mixture of tert-butyl 3,4-dihydro-2H-quinoxaline- 1-carboxylate (1 g, 4.27 mmol)，3-bromo-1-(oxan-4-yl)pyrazolo[4,3-c]pyridine (1.20 g, 4.27 mmol) and Cs2CO3 (2.78 g, 8.54 mmol) in 1,4-dioxane. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 10mmol/L NH4HCO3)) affording the title compound (890 mg) as a yellow green solid. LCMS (ESI) m/z [M+H]+ = 436.2. Step 2. tert-Butyl 4-[1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydroquinoxaline- 1-carboxylate PtO2 (158 mg, 0.695 mmol) was added to a stirred solution of tert-butyl 4-[1-(oxan-4-yl)pyrazolo[4,3- c]pyridin-3-yl]-2,3-dihydroquinoxaline-1-carboxylate (890 mg, 2.04 mmol) in MeOH (10 mL). The resulting mixture was sirred for 2 h at room temperature under 10 atm with hydrogen atmosphere. The resulting mixture was then filtered to remove insoluble solids and the filtrate was concentrated to afford the title compound (840 mg, crude) as a white solid that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 440.3. Step 3. tert-Butyl 4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3- dihydroquinoxaline-1-carboxylate TEA (580.1 mg, 5.73 mmol) was added to a stirred mixture of tert-butyl 4-[1-(oxan-4-yl)-4H,5H,6H,7H- pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydroquinoxaline-1-carboxylate (840 mg, 1.91 mmol) and acetic anhydride (390.2 mg, 3.82 mmol) in DCM (9 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (760 mg) as a yellow green solid. LCMS (ESI) m/z [M+H]+ = 482.3. Step 4: tert-Butyl 4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-bromo-2,3- dihydroquinoxaline-1-carboxylate NBS (332.6 mg, 1.87 mmol) was added in portions to a stirred solution of tert-butyl 4-[5-acetyl-1-(oxan-4- yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-2,3-dihydroquinoxaline-1-carboxylate (750 mg, 1.56 mmol) in MeCN (10 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was quenched with sat. Na2S2O3 (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (692 mg) as a yellow green solid. LCMS (ESI) m/z [M+H]+ = 560.2. Step 5.1-[3-(6-Bromo-3,4-dihydro-2H-quinoxalin-1-yl)-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]202yridine-5-yl]202yridine TFA (3 mL) was added dropwise at room temperature to a stirred solution of tert-butyl 4-[5-acetyl-1-(oxan- 4-yl)-4H,6H,7H-pyrazolo[4,3-c]202yridine-3-yl]-7-bromo-2,3-dihydroquinoxaline-1-carboxylate (685 mg, 1.22 mmol) in DCM (8 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% TFA)) affording the title compound (530 mg) as a yellow green solid. LCMS (ESI) m/z [M+H]+ = 460.5. Step 6.1-[3-(6-Bromo-3,4-dihydro-2H-quinoxalin-1-yl)-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-5-yl]ethanone NaBH3CN (212.9 mg, 3.39 mmol) was added in portions at 0 °C to a stirred solution of 1-[3-(6-bromo-3,4- dihydro-2H-quinoxalin-1-yl)-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (520 mg, 1.13 mmol) and HCHO-H2O (67.8 mg, 2.26 mmol) in MeOH (10 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash C18- flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) affording the title compound (486 mg, 1.0 mmol) as yellow green solid. LCMS (ESI) m/z [M+H]+ = 474.5. Intermediate 38: Preparation of 7-Bromo-4-oxo-3H-quinazoline-2-carboxylic acid
Figure imgf000206_0001
Step 1. Ethyl 7-bromo-4-oxo-3H-quinazoline-2-carboxylate A solution of 2-amino-4-bromobenzamide (3 g, 13.95 mmol) in ethyl oxalate (6.12 g, 41.85 mmol) was stirred for 3 days at 120°C. The resulting mixture was allowed to cool down to room temperature and diluted with hexane (20 mL). The precipitated solids were collected by filtration and washed with hexane (5 mL x 3). The solids were dried under reduced pressure to afford the title compound (3.19 g, crude) as a white solid that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 296.9. Step 2. 7-Bromo-4-oxo-3H-quinazoline-2-carboxylic acid A 1N solution of KOH (5.0 mmol) in H2O (5 mL) was added dropwise at 0 °C to a stirred solution of ethyl 7- bromo-4-oxo-3H-quinazoline-2-carboxylate (500 mg, 1.68 mmol) in EtOH (5 mL). The resulting mixture was stirred for 1 h at 80°C. The resulting mixture was acidified to pH = 5 with conc. HCl. The precipitated solids were collected by filtration and washed with water (30 mL x 3). The precipitated solids were dried under reduced pressure to afford the title compound (448 mg, crude) as a white solid that was used directly without further purification. LCMS (ESI) m/z [M+H]+ = 268.9. Intermediate 39: Preparation of 7-Bromo-4-oxo-3H-quinazoline-2-carboxylic acid
Figure imgf000207_0001
Step 1.6-Chloro-7-(difluoromethyl)-1-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)- 1,2,3,4-tetrahydro-1,5-naphthyridine XPhos Pd G3 (90.0 mg, 0.106 mmol) was added to a stirred solution of 3-bromo-1-(oxan-4-yl)pyrazolo[4,3- c]pyridine (5.03 g, 17.84 mmol), 2-chloro-3-(difluoromethyl)-5,6,7,8-tetrahydro-1,5-naphthyridine (3.9 g, 17.84 mmol) and t-BuONa (5.14 g, 53.51 mmol) in toluene (80 mL). The resulting mixture was stirred for 16 h at 100°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 (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by FCC (elution gradient 0 to 10% MeOH in CH2Cl2) affording the title compound (3.5 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 419.9. Step 2.6-Chloro-7-(difluoromethyl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (Cp*RhCl2)2 (515.2 mg, 0.834 mmol) was added to a stirred solution of 6-hloro-7-(difluoromethyl)-1-(1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (3.5 g, 8.34 mmol) in formic acid (20 mL) and TEA (28 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was neutralized to pH 8 with saturated NaHCO3 (aq.) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (3.5 g, crude) as a brown solid that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 424.2. Step 3.1-(3-(6-Chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H- pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one Ac2O (1.56 mL, 16.51 mmol) was added to a stirred solution of 6-chloro-7-(difluoromethyl)-1-(1-(tetrahydro- 2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (3.5 g, 8.26 mmol) and TEA (3.44 mL, 24.77 mmol) in DCM (50 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.1% FA)) affording the title compound (2.8 g, 6.0 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 466.2. Intermediate 40: Preparation of 1-(3-{7-Chloro-2H,3H-pyrido[4,3-b][1,4]oxazin-4-yl}-1-(oxan-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl)ethenone
Figure imgf000208_0001
Step 1. Methyl 2-[(2-chloro-5-nitropyridin-4-yl)oxy]acetate NaH (0.99 g, 41.25 mmol, 60% purity) was added in portions at 0°C to a stirred mixture of methyl 2- hydroxyacetate (2.24 g, 24.87 mmol) in DMF (50 mL). After 0.5 h, 2,4-dichloro-5-nitropyridine (4 g, 20.73 mmol) was added to the reaction mixture. The resulting mixture was stirred for 12 h at room temperature. The resulting mixture was quenched by the saturated aqueous NH4Cl (400 mL) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.1% FA)) affording the title compound (2.43 g) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 247.1. Step 2.7-Chloro-2H,4H-pyrido[4,3-b][1,4]oxazin-3-one Fe (2.72 g, 48.71 mmol) was added to a stirred solution of methyl 2-[(2-chloro-5-nitropyridin-4- yl)oxy]acetate (2.4 g, 9.73 mmol) and AcOH (4 mL) in MeOH (40 mL) and H2O (4 mL). The resulting mixture was stirred at 80°C for 12 h. The resulting mixture was filtered while hot and concentrated under reduced pressure to afford the title compound (1.8 g, crude) as a yellow solid that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 185.1. Step 3.7-Chloro-2H,3H,4H-pyrido[4,3-b][1,4]oxazine TiCl4 (7.71 mg, 0.041 mmol) was added in portions at 0°C to a stirred mixture of 7-chloro-2H,4H-pyrido[4,3- b][1,4]oxazin-3-one (600 mg, 3.25 mmol) and borane-ammonia complex (1.61 g, 52.02 mmol) in toluene (10 mL). The resulting mixture was stirred for 20 h at 70°C. The resulting mixture was quenched by the saturated aqueous Na2CO3 (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.1% FA)) affording the title compound (324 mg) as light yellow solid. LCMS (ESI) m/z [M+H]+ = 171.1. Step 4.3-{7-Chloro-2H,3H-pyrido[4,3-b][1,4]oxazin-4-yl}-1-(oxan-4-yl)pyrazolo[4,3-c]pyridine EPhos Pd G4 (344.6 mg, 0.375 mmol) was added to a stirred solution of 7-chloro-2H,3H,4H-pyrido[4,3- b][1,4]oxazine (160 mg, 0.938 mmol), 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-c]pyridine (264.6 mg, 0.938 mmol), t-BuONa (180.27 mg, 1.88 mmol) and EPhos (100.3 mg, 0.188 mmol) in toluene (3 mL). The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.1% FA)) affording the title compund (190 mg) as a yellow oil. LCMS (ESI) m/z: [M+H]+ = 372.1. Step 5.3-{7-Chloro-2H,3H-pyrido[4,3-b][1,4]oxazin-4-yl}-1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3- c]pyridine bis[(pentamethylcyclopentadienyl)dichloro-rhodium] (56.5 mg, 0.091 mmol) was added at 0°C to a stirred mixture of 3-{7-chloro-2H,3H-pyrido[4,3-b][1,4]oxazin-4-yl}-1-(oxan-4-yl)pyrazolo[4,3-c]pyridine (170 mg, 0.457 mmol) and KI (75.90 mg, 0.457 mmol) in FA (2 mL) and Et3N (2.8 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was quenched by the saturated aqueous K2CO3 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (296 mg) as a red solid that was used in the next step directly without further purification. LCMS (ESI) m/z [M+H]+ = 376.1. Step 6: 1-(3-{7-Chloro-2H,3H-pyrido[4,3-b][1,4]oxazin-4-yl}-1-(oxan-4-yl)-4H,6H,7H-pyrazolo [4,3- c]pyridin-5-yl)ethanone Ac2O (75 mg, 0.735 mmol) was added at 0°C to a stirred mixture of 3-{7-chloro-2H,3H-pyrido[4,3- b][1,4]oxazin-4-yl}-1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c]pyridine (251 mg, 0.668 mmol) and Et3N (338 mg, 3.34 mmol) in DCM (3 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.1% FA)) affording the title compound (256 mg, 0.61 mmol) as a black oil. LCMS (ESI) m/z [M+H]+ = 418.1. The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims. Example 1. Preparation of (2S,4R)-1-((S)-2-(2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H- pyrazol-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide
Figure imgf000210_0001
Step 1. Ethyl 2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetate XPhos Pd 3G (0.33 g, 0.39 mmol) was added to a stirred solution of 1-{3-[6-bromo-7-(difluoromethyl)-3,4- dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (2.0 g, 3.92 mmol), ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate (1.87 g, 6.67 mmol) and K3PO4 (1.67 g, 7.85 mmol) in dioxane (16 mL) and H2O (4 mL). The reaction mixture was stirred for 1 h at 90°C. The reaction mixture was diluted with EtOAc (400 mL), washed with water (300 mL x 2) and brine (300 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (2.03 g, 3.5 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 583.3. Step 2.2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3- yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetic acid To a stirred solution of ethyl 2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)acetate (2.03 g, 3.48 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH.H2O (731 mg, 17.4 mmol). The mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (1.53 g, 2.8 mmol) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ = 7.81 (d, J = 0.8 Hz, 1H), 7.56 (s, 1H), 7.18 – 7.10 (m, 1H), 7.00 – 6.54 (m, 2H), 4.96 (s, 2H), 4.37 – 4.21 (m, 1H), 4.16 (d, J = 11.4 Hz, 2H), 4.02 – 3.90 (m, 2H), 3.81 – 3.66 (m, 2H), 3.60 (t, J = 5.6 Hz, 2H), 3.46 (t, J = 11.7 Hz, 2H), 2.94 – 2.71 (m, 4H), 2.08 (s, 2H), 2.05 – 1.91 (m, 5H), 1.89 – 1.74 (m, 2H) ppm. LCMS (ESI) m/z [M+H]+ = 555.2. Step 3. (2S,4R)-1-((S)-2-(2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1- yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide HATU (16.4 mg, 0.043 mmol) was added to a stirred solution of (4-{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}pyrazol-1-yl)acetic acid (20 mg, 0.036 mmol), (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (15.5 mg, 0.036 mmol) and DIEA (14 mg, 0.11 mmol) in DMF (1 mL). The reaction mixture was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC (Column: Xselect Peptide CSH C18 19*150mm 5μm, 1; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 52% B in 7 min, 52% B; Wave Length: 254/220 nm; RT1(min): 6.25) affording the title compound (16.5 mg, 0.017 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.98 (s, 1H), 8.61 (t, J = 5.9 Hz, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 7.41 (q, J = 8.1 Hz, 4H), 7.12 (s, 1H), 6.95 – 6.53 (m, 2H), 5.18 (d, J = 3.5 Hz, 1H), 5.05 – 4.90 (m, 2H), 4.54 (d, J = 9.3 Hz, 1H), 4.49 – 4.38 (m, 2H), 4.40 – 4.23 (m, 3H), 4.23 – 4.07 (m, 3H), 4.05 – 3.88 (m, 2H), 3.81 – 3.54 (m, 7H), 2.89 – 2.76 (m, 4H), 2.44 (s, 3H), 2.08 (s, 2H), 1.96 (s, 7H), 1.85 – 1.74 (m, 2H), 0.94 (s, 9H) ppm. LCMS (ESI) m/z [M+H]+ = 966.4. The following examples in TABLE 3 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 1. TABLE 3
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
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Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
51 52
Figure imgf000233_0001
Figure imgf000233_0002
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
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Figure imgf000243_0001
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Figure imgf000246_0001
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Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
96 97 98
Figure imgf000251_0001
Figure imgf000251_0002
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0002
Example 115: (2S,4R)-1-((S)-2-(2-(6-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2- azaspiro[3.3]heptan-2-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide
Figure imgf000258_0001
Step 1. tert-Butyl 6-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2-azaspiro[3.3]hept-5-ene-2- carboxylate XPhos Pd G3 (33.2 mg, 0.039 mmol) was added to a stirred solution of 1-(3-(6-bromo-7-(difluoromethyl)- 3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1-one (200 mg, 0.39 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- azaspiro[3.3]hept-5-ene-2-carboxylate (126 mg, 0.39 mmol) and Cs2CO3 (256 mg, 0.79 mmol) in dioxane (4 mL) and H2O (1 mL). After stirring at 80°C for, the reaction mixture was concentrated under reduced pressure. The residue was purified by FCC (Eluent: CH2Cl2 / MeOH (10:1)) affording the title compound (126 mg, 0.20 mmol) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 624. Step 2. tert-Butyl 6-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2-azaspiro[3.3]heptane-2- carboxylate 10% Pd/C (98 mg) was added to a stirred solution of tert-butyl 6-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2- azaspiro[3.3]hept-5-ene-2-carboxylate (98 mg, 0.16 mmol) in MeOH (4 mL, 98.8 mmol). Balloon filled hydrogen (g) was charged into the reaction mixture. The reaction was stirred under a hydrogen atmosphere for 3 h at room temperature. The resulting mixture was flushed with nitrogen and filtered through celite. The filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure affording the title compound (88 mg, 0.14 mmol) as a brown oil that was used directly without further purification. LCMS (ESI) m/z: [M+H]+ = 626. Step 3.1-(3-(7-(Difluoromethyl)-6-(2-azaspiro[3.3]heptan-6-yl)-3,4-dihydroquinolin-1(2H)-yl)-1- (tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one TFA (1 mL) was added to a stirred solution of tert-butyl 6-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2- azaspiro[3.3]heptane-2-carboxylate (98mg, 0.16 mmol) in DCM (4 mL). After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure affording the title compound (72 mg, 0.14 mmol) as a colorless oil that was used directly without further purification. LCMS (ESI) m/z: [M+H]+ = 526. Step 4.2-(6-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin- 3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2-azaspiro[3.3]heptan-2-yl)acetic acid NaBH3CN (25.8 mg, 0.41 mmol) was added to a stirred solution of 1-(3-(7-(difluoromethyl)-6-(2- azaspiro[3.3]heptan-6-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (72 mg, 0.14 mmol), and dihydroxyacetic acid (37.8 mg, 0.41 mmol) in MeOH (3 mL). Atter stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (56 mg, 0.10 mmol) as a yellow oil. LCMS (ESI) m/z: [M+H]+ = 584. Step 5. (2S,4R)-1-((S)-2-(2-(6-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2- azaspiro[3.3]heptan-2-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide HATU (24.4 mg, 0.065 mmol) was added to a stirred solution of 2-(6-(1-(5-acetyl-1-(tetrahydro-2H-pyran- 4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)- 2-azaspiro[3.3]heptan-2-yl)acetic acid (25 mg, 0.043 mmol), (2S,4R)-1-[(2S)-2-amino-3,3- dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (18.4 mg, 0.043 mmol) and DIEA (11.1 mg, 0.086 mmol) in DMF (2 mL). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was directly purified by Prep-HPLC (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: 18% B to 37% B in 8 min, 37% B; Wave Length: 254/220 nm; RT1(min): 9.15) affording the title compound (11.8 mg, 0.012 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ = 8.92 (s, 1H), 8.37 (t, J = 6.0 Hz, 1H), 7.52 (d, J = 9.3 Hz, 1H), 7.45 – 7.36 (m, 4H), 7.04 (s, 1H), 6.90 – 6.66 (m, 2H), 5.04 – 4.94 (m, 1H), 4.57 – 4.43 (m, 2H), 4.42 – 4.35 (m, 2H), 4.34 – 4.23 (m, 2H), 4.12 (s, 2H), 4.01 – 3.92 (m, 2H), 3.80 – 3.66 (m, 3H), 3.65 – 3.40 (m, 8H), 3.32 – 3.21 (m, 2H), 3.09 – 3.04 (m, 1H), 2.92 – 2.70 (m, 4H), 2.48 – 2.40 (m, 6H), 2.31 – 2.14 (m, 2H), 2.13 – 1.90 (m, 9H), 1.88 – 1.77 (m, 2H), 0.96 (s, 9H) ppm. LCMS (ESI) m/z: [M+H]+ = 996.45. The following examples in TABLE 4 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 115. TABLE 4
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Example 124: (2S,4R)-1-((S)-2-(2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-1- yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide
Figure imgf000265_0001
Step 1.1-(3-(7-(Difluoromethyl)-6-vinyl-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)- 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one XPhos Pd G3 (133 mg, 0.16 mmol) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (242 mg, 1.6 mmol) were added to a stirred solution of 1-{3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1- (oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (400 mg, 0.78 mmol) and Cs2CO3 (768 mg, 2.4 mmol) in dioxane (4 mL) and H2O (1 mL). The reaction mixture was stirred for 1 h at 80°C. The reaction mixture was diluted with EtOAc (50 mL), washed with water (50 mL x 2) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford the crude product. The residue was purified by FCC (Eluent: CH2Cl2 / MeOH (10:1)) affording the title compound (461 mg, crude) as a brown solid. LCMS (ESI) m/z [M+H]+ = 457.2. Step 2.1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7- (difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde K2OsO4.2H2O (36.4 mg, 0.099 mmol) and 2,6-lutidine (212 mg, 1.98 mmol) were added to a stirred solution of 1-(3-(7-(difluoromethyl)-6-vinyl-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (451 mg, 0.99 mmol) and NaIO4 (845 mg, 3.95 mmol) in dioxane (6 mL) and H2O (2 mL). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 2) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) affording the title compound (343 mg, 0.75 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 459.2. Step 3.1-(3-(7-(Difluoromethyl)-6-ethynyl-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4- yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one Dimethyl (1-diazo-2-oxopropyl)phosphonate (50.3 mg, 0.26 mmol) was added dropwise at 0 °C to a stirred solution of 1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7- (difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (100 mg, 0.22 mmol) and K2CO3 (90.4 mg, 0.65 mmol) in MeOH (1 mL). The reaction mixture was stirred for overnight at room temperature. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) affording the title compound (54 mg, 0.12 mmol) as a light brown solid. LCMS (ESI) m/z [M+H]+ = 455.2. Step 4. Ethyl 2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-1-yl)acetate CuI (22.6 mg, 0.12 mmol) was added to a stirred solution of 1-(3-(7-(difluoromethyl)-6-ethynyl-3,4- dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1-one (54 mg, 0.12 mmol) and ethyl 2-azidoacetate (46.0 mg, 0.36 mmol) in toluene (13 mL). The reaction mixture was stirred overnight at 100°C. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (20 mL), and the resulting mixture was washed with water (20 mL x 2) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by FCC (Eluent: CH2Cl2 / MeOH (20:1)) affording the title compound (65 mg, 0.11 mmol) as a light yellow solid. LCMS (ESI) m/z [M+H]+ = 584.2. Step 5. (2-(4-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin- 3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-1-yl)acetic acid A solution of ethyl 2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-1-yl)acetate (59 mg, 0.10 mmol) and LiOH.H2O (12.7 mg, 0.30 mmol) in THF (0.3 mL), MeOH (0.3 mL) and H2O (0.3 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH = 6 with 1N HCl (aq.). The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 0% to 100% gradient in 20 min; detector, UV 254 nm) affording the title compound (51 mg, 0.092 mmol) as a off-white solid. LCMS (ESI) m/z [M+H]+ = 556.2 Step 6. (2S,4R)-1-((S)-2-(2-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-1- yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide HATU (20.6 mg, 0.054 mmol) and DIEA (29.1 mg, 0.22 mmol) were added to a stirred solution of (2-(4-(1- (5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7- (difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-1-yl)acetic acid (50 mg, 0.090 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}pyrrolidine-2-carboxamide (38.8 mg, 0.090 mmol) in DMF (1 mL). The reaction mixture was stirred for 1 h at room temperature. The crude product was purified by Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min; Wave Length: 220 nm; RT1(min): 7.27) affording the title compound (26.6 mg, 0.28 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ = 8.93 (s, 1H), 8.32 – 8.11 (m, 3H), 7.51 – 7.05 (m, 6H), 6.91 (s, 1H), 5.27 (d, J = 3.2 Hz, 2H), 4.64 – 4.23 (m, 6H), 4.20 (s, 2H), 3.98 (d, J = 11.6 Hz, 2H), 3.81 – 3.69 (m, 3H), 3.63 (q, J = 6.1 Hz, 3H), 3.57 – 3.42 (m, 3H), 2.97 – 2.72 (m, 4H), 2.46 (s, 3H), 2.17 – 1.94 (m, 9H), 1.92 – 1.81 (m, 2H), 1.00 (s, 9H) ppm. LCMS (ESI) m/z [M+H]+ = 968.45. Example 125: (2S,4R)-1-((S)-2-(2-(5-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2- yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide
Figure imgf000267_0001
Step 1. Methyl 2-(5-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)acetate XPhos Pd G3 (49.6 mg, 0.059 mmol) was added to a stirred solution of 1-{3-[7-(difluoromethyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-5-yl}ethanone (163 mg, 0.29 mmol), methyl 2-(6-bromopyrazin-2-yl)acetate (67.7 mg, 0.29 mmol) and Cs2CO3 (191 mg, 0.59 mmol) in dioxane (4 mL) and H2O (1 mL). The reaction mixture was stirred at 80°C for 1 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (30 mL x 2) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (64 mg, 0.11 mmol) as a brown yellow oil. LCMS (ESI) m/z [M+H]+ = 581.2. Step 2.2-(5-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin- 3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2-yl)acetic acid LiOH·H2O (17.3 mg, 0.41 mmol) was added to a stirred solution of methyl 2-(5-(1-(5-acetyl-1-(tetrahydro- 2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4- tetrahydroquinolin-6-yl)pyrazin-2-yl)acetate (60 mg, 0.103 mmol) in MeOH (2.5 mL) and H2O (2.5 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was acidified to pH = 6 with 1N HCl (aq.). The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (45 mg, 0.079 mmol) as a brown yellow solid. LCMS (ESI) m/z [M+H]+ = 567.2. Step 3. (2S,4R)-1-((S)-2-(2-(5-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrazin-2- yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide HATU (53.4 mg, 0.14 mmol) was added to a stirred solution of 2-(5-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4- yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6- yl)pyrazin-2-yl)acetic acid (53 mg, 0.094 mmol), (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy- N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (40.3 mg, 0.094 mmol) and DIEA (24.2 mg, 0.19 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified directly by Prep-HPLC (Column: Xselect Peptide CSH C1819*150mm 5μm, 1; Mobile Phase A: Water (0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 38% B in 8 min, 38% B; Wave Length: 254/220 nm; RT1(min): 10.73) affording the title compound (24.7 mg, 0.025 mmol) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ = 8.93 (s, 1H), 8.77 – 8.71 (m, 1H), 8.67 – 8.56 (m, 1H), 8.29 – 8.16 (m, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.48 – 7.30 (m, 4H), 7.28 – 7.16 (m, 1H), 7.10 – 6.77 (m, 2H), 4.64 – 4.48 (m, 2H), 4.47 – 4.36 (m, 2H), 4.35 – 4.27 (m, 1H), 4.28 – 4.16 (m, 3H), 4.05 – 3.93 (m, 2H), 3.90 (s, 1H), 3.86 (s, 1H), 3.81 (s, 3H), 3.79 – 3.68 (m, 4H), 3.69 – 3.60 (m, 1H), 3.54 – 3.52 (m, 1H), 2.97 – 2.81 (m, 4H), 2.46 (s, 3H), 2.14 – 1.94 (m, 8H), 1.94 – 1.81 (m, 2H), 0.98 (s, 9H) ppm. LCMS (ESI) m/z [M+H]+ = 979.4. The following examples in TABLE 5 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 125. TABLE 5
Figure imgf000269_0001
Figure imgf000270_0001
Example 130: (2S,4R)-1-((S)-2-((5-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrimidin-2- yl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide
Figure imgf000271_0001
Step 1.1-(3-(7-(Difluoromethyl)-6-(2-fluoropyrimidin-5-yl)-3,4-dihydroquinolin-1(2H)-yl)-1- (tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one K2CO3 (271 mg, 1.96 mmol) and Pd(dppf)Cl2.CH2Cl2 (160 mg, 0.20 mmol) were added to a stirred mixture of 1-{3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-5-yl}ethanone (500 mg, 0.98 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidine (264 mg, 1.18 mmol) in dioxane (4 mL) and H2O (1 mL). The reaction mixture was stirred for 2 h at 80°C. The reaction mixture was diluted with EtOAc (50 mL), washed with water (30 mL x 3) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm) affording the title compound (464 mg, 0.88 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 527.2. Step 2. (2S,4R)-1-((S)-2-((5-(1-(5-Acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrimidin-2- yl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (2S,4R)-1-[(2S)-2-Amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}pyrrolidine-2-carboxamide (81.8 mg, 0.19 mmol) was added to a stirred solution of 1-(3- (7-(difluoromethyl)-6-(2-fluoropyrimidin-5-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)- 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (100 mg, 0.19 mmol) and DIEA (73.6 mg, 0.57 mmol) in DMSO (1.5 mL). The reaction mixture was stirred for overnight at 100°C. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 8.47) affording the title compound (18.7 mg, 0.020 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ = 8.95 (s, 1H), 8.35 (t, J = 6.1 Hz, 1H), 8.24 (s, 2H), 7.42 (s, 4H), 7.01 (s, 1H), 6.77 (d, J = 53.3 Hz, 2H), 6.53 – 6.32 (m, 1H), 4.90 (d, J = 3.8 Hz, 1H), 4.74 (d, J = 9.2 Hz, 1H), 4.45 (dt, J = 22.1, 7.1 Hz, 3H), 4.28 (dd, J = 15.3, 5.4 Hz, 2H), 4.19 (s, 2H), 3.95 (t, J = 12.3 Hz, 3H), 3.83 – 3.68 (m, 3H), 3.62 (t, J = 5.6 Hz, 2H), 3.48 (t, J = 11.3 Hz, 2H), 2.87 (s, 4H), 2.46 (s, 3H), 2.03 (dt, J = 16.1, 8.6 Hz, 8H), 1.85 (d, J = 12.9 Hz, 2H), 1.06 (s, 9H) ppm. LCMS (ESI) m/z [M+H]+ = 937.4. Example 131: (2S,4R)-1-[(2S)-2-[(6-{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}pyrazolo[1,5-a]pyrimidin-3-yl)formamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2- carboxamide
Figure imgf000272_0001
Step 1. Ethyl 6-{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}pyrazolo[1,5-a]pyrimidine-3-carboxylate Ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (72.8 mg, 0.270 mmol), XPhos Pd G3 (45.6 mg, 0.054 mmol and K3PO4 (114 mg, 0.540 mmol) were added to a stirred mixture of 1-{3-[7-(difluoromethyl)- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl}ethenone (150 mg, 0.270 mmol), in dioxane (1.2 mL) and H2O (0.3 mL). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by FCC (Eluent: 0 to 10% MeOH in DCM) to afford the title compound (93 mg, 0.15 mmol) as a light yellow oil. LCMS (ESI) m/z [M+H]+ =620.6. Step 2.6-{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}pyrazolo[1,5-a]pyrimidine-3-carboxylic acid LiOH·H2O (22.4 mg, 0.536 mmol) was added to a stirred solution of ethyl 6-{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}pyrazolo[1,5- a]pyrimidine-3-carboxylate (83 mg 0134 mmol) in THF (1 mL) and H2O (1 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (20 mL) and acidified to pH = 5 with 1N solution of HCl (aq.). The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (43 mg, 0.073 mmol) as a light yellow solid that was used directly without further purification. LCMS (ESI) m/z [M+H]+ =592.6. Step 3. (2S,4R)-1-[(2S)-2-[(6-{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}pyrazolo[1,5-a]pyrimidin-3-yl)formamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2- carboxamide HATU (38.6 mg, 0.102 mmol) was added to a stirred solution of 6-{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}pyrazolo[1,5-a]pyrimidine-3- carboxylic acid (40 mg, 0.068 mmol), (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl} pyrrolidine-2-carboxamide hydrochloride (31.6 mg, 0.068 mmol) and DIEA (17.5 mg, 0.136 mmol) in DMF (1 mL). The resulting mixture was stirred for 1 h at room temperature. Without any additional work-up, the resulting 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 Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 57% B in 8min; Wave Length: 220nm nm; RT1(min): 6.96) to afford the title compound (21.7 mg, 0.022 mmol) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (d, J = 2.2 Hz, 1H), 8.94 (s, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.58 (s, 1H), 8.45 – 8.32 (m, 2H), 7.44 – 7.40 (m, 4H), 7.25 (s, 1H), 7.11 – 6.68 (m, 2H), 4.85 (d, J = 9.3 Hz, 1H), 4.54 – 4.20 (m, 7H), 3.98 (d, J = 11.6 Hz, 2H), 3.81 – 3.71 (m, 6H), 3.56 – 3.45 (m, 2H), 3.02 – 2.73 (m, 4H), 2.46 (s, 3H), 2.18 – 1.95 (m, 9H), 1.93 – 1.81 (m, 2H), 1.07 (s, 9H) ppm. LCMS (ESI) m/z [M+H]+ =1004.40. The following examples in TABLE 6 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 131.
TABLE 6
Figure imgf000274_0001
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511
Figure imgf000471_0001
MHz, DMSO-d6) δ = 9.20 – 9.15 (m, 1H), 8.98 (d, J = 3.8 Hz, 1H), 8.63 (d, J = 4.7, 2.1 Hz, 1H), 8.49 (d, J = 7.7 Hz, 1H), 8.44 – 8.37 (m, 2H), 8.11 (d, J = 8.9 Hz, 1H), 7.82 (d, J 512 1029.5 = 9.5 Hz, 1H), 7.68 (s, 1H), 7.44 (d, 2H), 7.38 (d, 2H), 7.34 (s, 1H), 7.18 (dd, J = 2.9, 0.9 Hz, 1H), 6.94 N-methyl-3-(6-{2-[N-(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-methyl- (t, J = 54.6 Hz, 1,3-thiazol-5-yl)phenyl]ethylcarbamoyl}-4-hydroxy-1- 1H), 5.16 (d, J = pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,4,7a- 3.4 Hz, 1H), 5.06 triaza-6-indenyl}-7-(difluoromethyl)-1,2,3,4-tetrahydro-1- – 4.88 (m, 2H), quinolyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazaindene- 4.77 (d, J = 9.6 Hz, 1H), 4.48 (t, J
Figure imgf000472_0001
Figure imgf000473_0001
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Figure imgf000483_0001
Example 535: (2S,4R)-1-[(2S)-2-[(6-{5-[5-Acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]- 3,4-dihydro-1H-isoquinolin-2-yl}pyrazolo[1,5-a]pyrimidin-2-yl)formamido]-3,3-dimethylbutanoyl]-4- hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide
Figure imgf000484_0001
Step 1. tert-Butyl 5-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydro-1H- isoquinoline-2-carboxylate Cs2CO3 (993 mg, 3.05 mmol) and XPhos Pd G3 (129 mg, 0.152 mmol) were added to a stirred solution of 1-[3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (500 mg, 1.52 mmol) and tert- butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (547 mg, 1.52 mmol) in dioxane (0.8 mL) and H2O (0.2 mL). The resulting mixture was stirred for an additional 1 h at 80 °C. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm) affording the title compound (597 mg, 1.24 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ =481.3. Step 2.1-[1-(Oxan-4-yl)-3-(1,2,3,4-tetrahydroisoquinolin-5-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5- yl]ethanone HCl (gas) in 1,4-dioxane (1 mL, 32.9 mmol) was added to a stirred solution of tert-butyl 5-[5-acetyl-1-(oxan- 4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (300 mg, 0.624 mmol) in DCM (2 mL). The resulting mixture was stirred for an additional 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm) affording the title compound (182 mg, 0.48 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 381.2. Step 3. Ethyl 6-{5-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydro-1H- isoquinolin-2-yl}pyrazolo[1,5-a]pyrimidine-2-carboxylate Cs2CO3 (257 mg, 0.788 mmol), EPhos (21.1 mg, 0.039 mmol), and EPhos Pd G4 (36.2 mg, 0.039 mmol) were added to a stirred solution of 1-[1-(oxan-4-yl)-3-(1,2,3,4-tetrahydroisoquinolin-5-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl]ethanone (150 mg, 0.394 mmol) and ethyl 6-bromopyrazolo[1,5-a]pyrimidine-2- carboxylate (106.48 mg, 0.394 mmol) in dioxane (1 mL). The resulting mixture was stirred for 3 h at 80°C. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase FCC with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm affording the title compound (106 mg, 0.19 mmol) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 570.3. Step 4.6-{5-[5-Acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydro-1H- isoquinolin-2-yl}pyrazolo[1,5-a]pyrimidine-2-carboxylic acid A solution of ethyl 6-{5-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydro-1H- isoquinolin-2-yl}pyrazolo[1,5-a]pyrimidine-2-carboxylate (100 mg, 0.176 mmol) and LiOH (16.8 mg, 0.704 mmol) in MeOH (0.5 mL) and H2O (0.5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase FCC with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm affording the title compound (69 mg, 0.13 mmol) as a white solid. LCMS (ESI) m/z [M+H]+ = 542.2. Step 5. (2S,4R)-1-[(2S)-2-[(6-{5-[5-Acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3,4- dihydro-1H-isoquinolin-2-yl}pyrazolo[1,5-a]pyrimidin-2-yl)formamido]-3,3-dimethylbutanoyl]-4- hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide NMI (18.2 mg, 0.222 mmol) and TCFH (46.6 mg, 0.167 mmol) were added to a stirred solution of 6-{5-[5- acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydro-1H-isoquinolin-2-yl}pyrazolo[1,5- a]pyrimidine-2-carboxylic acid (60 mg, 0.111 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4- hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (51.7 mg, 0.111 mmol) in ACN (1 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 41% B in 10 min; Wave Length: 254nm/200nm nm; RT1(min): 13.88) affording the title compound (17.1 mg, 0.018 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ = 8.97 (d, J = 2.5 Hz, 1H), 8.87 (d, J = 2.8 Hz, 1H), 8.66 (s, 1H), 8.44 (s, 1H), 7.67 (d, J = 9.4 Hz, 1H), 7.42 (d, J = 6.1 Hz, 4H), 7.27 (q, J = 7.3 Hz, 3H), 6.99 (s, 1H), 5.03 (d, J = 3.7 Hz, 1H), 4.77 (d, J = 9.6 Hz, 1H), 4.51 (s, 3H), 4.43 – 4.23 (m, 6H), 4.00 (d, J = 11.3 Hz, 2H), 3.86 – 3.64 (m, 4H), 3.62 – 3.44 (m, 4H), 3.08 (s, 2H), 2.90 (s, 2H), 2.47 (s, 3H), 2.09 (s, 7H), 1.88 (d, J = 13.2 Hz, 2H), 1.04 (d, J = 3.4 Hz, 9H) ppm. LCMS (ESI) m/z [M+H]+ =954.3. The following examples in TABLE 7 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 535. TABLE 7
Figure imgf000486_0001
Example 537: U2OS HiBiT Degradation Assay Procedure: A set of two CRISPR knock-in stable U2OS polyclonal cell lines, each with a HiBiT tag fused 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 1, cells were treated with 90 nL DMSO or 90 nL of 3-fold serially DMSO-diluted compounds 17, 6, 133, 134 (10 points in duplicates with 30 μM as final top dose). Subsequently plates were incubated for 24 hours in a standard tissue culture incubator and equilibrated at room temperature for 30 minutes. Nanoluciferase activity was measured by adding 30 μL of freshly prepared Nano-Glo Luciferase Assay Reagent (Promega N1130), shaking the plates for 10 minutes and reading the bioluminescence using an EnVision reader. Results: The Inhibition% was calculated using the following formula: %Inhibition = 100 x (1-LumSample / LumDMSO). The data was fit to a four parameter, non-linear curve fit to calculate IC50 (μM) values using Graphpad PRISM (Figures 1 and 2). Treatment of the cell lines with CBP degraders can result in selective dose-dependent reduction of CBP in osteosarcoma cell lines. CBP degrader evolution has yielded fast kinetics and complete target degradation with selectivity over EP300. Results shown in Table 8. Table 8. Degradation of CBP and EP300
Figure imgf000487_0001
Figure imgf000488_0001
Example 538: CTG Assay on Bladder cancer cell lines Procedure: A set of bladder cell lines (UM-UC-3, ScaBER, 647V, and 639V) in 1640 medium with 10%FBS, 1% Penicillin-Streptomycin at 37°C, 5% CO2. On day 0, the cells were aspirated from the media, washed with sterile 1XPBS and treated with Trypsin. Cell were resuspended in media and the cells were counted with Cell Counter. On day 1, cells were treated with 12uL DMSO or 36uL of 3-fold serially DMSO-diluted compound 1 (10 points in duplicates with 1uM as final top dose). Subsequently plates were incubated over 168 hours in a standard culture incubator (Corning 3764) and equilibrated at room temperature for 15 minutes. Luciferase activity was measured by adding 40 uL of CellTiter-Glo reagent, and reading the luminesce using an Envision reader. Results: The Inhibition% was calculated using the following formula: %Survival = 100x (LumSample / average LumHC). The data was fit to a four parameter, non-linear curve fit to calculate IC50 (μM) values using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom)/(1 + 10^((LogIC50 - X)*HillSlope)). The GI50 for 639V was 0.6 mM, while the GI50 for UM-UC-3 was greater than 10 mM. Treatment of the cell lines with CBP degraders can result in dose-dependent reduction in cell proliferation of EP300mut bladder cancer cell lines as compared to EP300/CBPwt bladder cancer cell lines (Figure 3). Example 528: CTG Assay on gastric cancer cell lines Procedure: A set of gastric cancer cell lines (IM95, AGS) in 1640 medium with 10%FBS, 1% Penicillin- Streptomycin at 37°C, 5% CO2. On day 0, the cells were aspirated from the media, washed with sterile 1XPBS and treated with Trypsin. Cell were resuspended in media and the cells were counted with Cell Counter. On day 1, cells were treated with 12uL DMSO or 36uL of 3-fold serially DMSO-diluted compound 6 (10 points in duplicates with 1uM as final top dose). Subsequently plates were incubated over 168 hours in a standard culture incubator (Corning 3764) and equilibrated at room temperature for 15 minutes. Luciferase activity was measured by adding 40 uL of CellTiter-Glo reagent, and reading the luminesce using an Envision reader. Results: The Inhibition% was calculated using the following formula: %Survival = 100x (LumSample / average LumHC). The data was fit to a four parameter, non-linear curve fit to calculate IC50 (μM) values using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom)/(1 + 10^((LogIC50 - X)*HillSlope)). The GI50 for AGS was 0.04 mM, while the GI50 for IM95 was greater than 10 mM. Treatment of the cell lines with CBP degraders can result in dose-dependent reduction in cell proliferation of EP300mut gastric cancer cell lines as compared to EP300/CBPwt gastric cancer cell lines (Figure 4). Example 539: CTG Assay on colorectal cancer cell lines Procedure: A set of colorectal cancer cell lines (HT29, and RKO) in 1640 medium with 10%FBS, 1% Penicillin-Streptomycin at 37°C, 5% CO2. On day 0, the cells were aspirated from the media, washed with sterile 1XPBS and treated with Trypsin. Cell were resuspended in media and the cells were counted with Cell Counter. On day 1, cells were treated with 12uL DMSO or 36uL of 3-fold serially DMSO-diluted compound 6 (10 points in duplicates with 1uM as final top dose). Subsequently plates were incubated over 168 hours in a standard culture incubator (Corning 3764) and equilibrated at room temperature for 15 minutes. Luciferase activity was measured by adding 40 uL of CellTiter-Glo reagent, and reading the luminesce using an Envision reader. Results: The Inhibition% was calculated using the following formula: %Survival = 100x (LumSample / average LumHC). The data was fit to a four parameter, non-linear curve fit to calculate IC50 (μM) values using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top – Bottom)/(1 + 10^((LogIC50 – X)*HillSlope)). The GI50 for RKO was 0.2 mM, while the GI50 for HT29 was greater than 10 mM. Treatment of the cell lines with CBP degraders can result in dose-dependent reduction in cell proliferation of EP300mut colorectal cancer cell lines as compared to EP300/CBPwt colorectal cancer cell lines (Figure 5). Example 540: CBP Selective PD in CBP/EP300 Wild type Cell Line MM1S Method for Tumor Inoculation Each mouse was inoculated subcutaneously on the right flank with the single cell suspension of MM.1S human multiple myeloma tumor cells (1 x 107) in 100 μL RPMI 1640 with 10% FBS and Matrigel mixture (1:1 ratio) for the tumor development. The treatment started when the mean tumor size reached about 254 mm3.Mice were randomized into each group and treated according to study design. Tumor Measurements The measurement of tumor size was conducted once a week with a caliper and recorded. The tumor volume (mm3) was estimated using the formula: TV=a × b2/2, where “a” and “b” were long and short diameters of a tumor, respectively. Vehicle Vehicle for compound 132: 5% DMSO, 10% solutol, 85% 20% HP-β-CD in water. Samples Collection At the end of study, plasma was collected at 0.5h, 2h, 4h, 6h, 12h and 24h post last dose. The tumors were collected at 2h, 6h and 24h, which were cut into 2 pieces, one piece for WB analysis, one piece snap frozen for backup. Liver, spleen, kidney, lung and muscle (right flank near tumor site) were collected at 2h, snap freeze and store the samples at -80oC. Results The aim of this study was to confirm the in vivo selectivity and assess the PK/PD relationship of compound 132 in the MM.1S xenograft model, which is wild-type for both CBP and EP300. In summary, the treatments were initiated when the mean tumor volume reached 254 mm3 on Day 15 post tumor inoculation (Figure 6). Compound 132 demonstrated a time-dependent PK profile. Notably, a significant (90%) degradation of CBP was observed at 2 and 6 hours post the last dose when administered at a dosage of 50 and 20mg/kg twice daily (BID). Importantly, this pharmacological effect on CBP degradation is accompanied by minimal or no impact on EP300 degradation, thus highlighting the compound's notable in vivo selectivity (Figure 6). Regarding the safety profile, all animals were tolerated well with compound 132. No obvious clinical abnormalities were observed during the study period. Example 541: Global Proteomics in U2OS Osteosarcoma Cell Lines Shows Selectivity for CBP After treatment with compound 6, media was aspirated and cells were twice washed with PBS. Cells were then dissociated from the culture plate using cold PBS with 1mM EDTA, pelleted, and washed twice with cold PBS. Cells were then snap frozen in liquid nitrogen and stored at -800C until lysis. After thawing on ice, cells were then lysed in 100ul 8M Urea, 50mM NaCl with 1x protease inhibitor cocktail. Lysates were then sonicated using ten 1 second pulses and centrifuged at 17,000g for 5 min at 40C. The supernatant lysate was then quantified using a BCA assay (Pierce), 150 ug were taken from each sample and the volume was normalized to 100ul in lysis buffer. Samples were then reduced with 15 mM DTT for 1 hr at room temperature under shaking, alkylated with 20 mM iodoacetamide for 20 minutes in the dark at room temperature under shaking, and methanol-chloroform precipitated. Resulting protein pellets were then resuspended in 100ul of 200 mM 3-[4-(2- Hydroxyethyl)piperazin-1-yl]propane-1-sulfonic acid (EPPS) pH 8.0 and digested overnight with 2ug trypsin/lys-C (Promega). Peptides were then quantified using a fluorometric peptide assay (Pierce).50 mg of peptide was brought to 100 ul in 200 mM EPPS pH 8.0, 25% acetonitrile (ACN). Peptides were then labeled with 5 ul from a 20 ug/ul stock of TMTpro 18-plex labels (Thermo Fisher) in ACN. Samples were briefly vortexed, incubated for 1 hr at room temperature, and quenched with 0.3% hydroxylamine for 15 min at room temperature. Labeling was confirmed using another round of fluorometric peptide assay. After labeling, samples were then combined and dried in a speedvac overnight. Resulting pellets were then resuspended in 1 ml of 1% trifluoroacetic acid, 5% ACN and cleaned using a Sep-Pak cartridge (Waters). The eluted sample was then dried via speedvac and resuspended in 100 ul 10 mM ammonium bicarbonate pH 8.0 and fractionated via basic pH reversed-phase HPLC. Over a 60 min gradient, the sample was fractionated into a 96 well plate by high pH reverse-phase HPLC with a mobile phase A of 5% ACN, 10 mM ammonium bicarbonate pH 8.0 and a mobile phase B of 90% ACN, 10 mM ammonium bicarbonate pH 8.0. Fractions were then combined into 24 fractions to maximize elution coverage. Combined fractions were dried in a speedvac and resuspended in 5% ACN, 5% formic acid.12 fractions were chosen to run on one hour gradients each. Mass spectrometric data were collected on an Oribtrap Lumas couple to an EASY nanoLC-1200 (ThermoFisher) or Vanquish Neo liquid chromatography system. Approximately 2 µg of peptides were loaded on a 75 µm capillary column packed in-house with Sepax GP-C18 resin (1.8 µm, 150 Å, Sepax) to a final length of 35 cm. Peptides for total protein analysis were separated using a 60 minute linear gradient from 14% to 40% acetonitrile in 0.1% formic acid. The mass spectrometer was operated in a data dependent mode. The scan sequence began with FTMS1 spectra (resolution = 120,000; mass range of 350- 1400 m/z; max injection time of 50 ms; AGC target of 5e5; dynamic exclusion for 60 seconds with a +/- 10 ppm window). The most intense precursor ions were selected for ITMS2 analysis via collisional-induced dissociation (CID) in the ion trap (normalized collision energy (NCE) = 35; max injection time = 35ms; isolation window of 0.7 Da; AGC target of 1e4) within a 2 second window. A real-time search (RTS) approach was utilized during data acquisition to only trigger quantitative spectra on high-confidence peptide identifications. Online spectral identification was accomplished via a custom software client that monitors spectral acquisition though a vendor supplied instrument application programming interface and assigns peptide sequences through a probabilistic model, in real-time (Orbitrap Lumos). The RTS client utilized a peptide database composed of in-silico predicated organism specific tryptic peptides. Mass spectra were processed using Proteome Discoverer (ThermoFisher). Database searching included all entries from the Human Reference Proteome (2018-12) as well as a curated list of contaminants. A maximum of two missed cleavages was allowed and the minimum peptide length was set to 7 amino acids. Searches used a 20 ppm precursor ion tolerance for total protein level analysis. Product ion parameters were set to a tolerance of 1.0005, a fragment bin offset of 0.4, and theoretical fragment ions set to 1. TMTpro tag labeling on peptide N-termini and lysine residues (+304.2071 Da) and carbamidomethylation of cysteine residues (+57.0215 Da) were set as a static modification, while oxidation of methionine residues (+15.9949 Da) was set as a variable modification. Peptide-spectrum matches (PSMs) were set to a false discovery rate of 2. For TMT reporter ion quantifications, the summed signal to noise ratio for each TMT channel was extracted and the most confident centroid to the expected mass of the TMT reporter ion was found, with an integration tolerance of 0.001 Daltons. For protein level quantification comparisons, PSMs were subjected to a 2% false discovery rate and the reporter ion counts were summed across all matching PSMs using in- house software as previously described (Huttlin et al., 2010). MS3 spectra with more than one TMTpro reporter ion channels missing per condition, isolation specificities of less than 0.5, or with TMT reporter summed signal to noise ratios of less than 100 were excluded from quantification. Protein quantification values were median normalized to assume equal loading across all channels. The resulting dataset was curated to remove contaminant proteins. Intensity values were subjected to an unpaired two tailed t-test and Log2 transformation fold change analysis. Resulting data was then depicted as a volcano plot using ggPlot packages in R. Bromodomain containing proteins were manually curated and depicted within the volcano plot. CBP selective degrader (compound 6) shows depletion of CBP (~70%) after 6 hours at100 nM without any loss of EP300 or other bromodomain proteins, including BRD4 (Figure 7). Example 542: Selective CBP Degradation Does Not Show Thrombocytopenia in Mice at Pharmacologically Relevant Doses Whole Blood for Hematology (CBC) analysis Standard hematology was measured by ADVIA 2120i (Siemens) at room temperature.30 whole blood from all groups were collected at 15 min and 24 hours (n=3 each timepoint) into 1.5 ml EDTA coated centrifuge tubes post last dose for CBC analysis. Samples Collection At the beginning of the study, the plasma samples were collected at 0.25h, 2h, 6h, 12h (pre-second dose), 12.25h (0.25h post second dose) and 24h (12h post second dose, pre third dose) post first dose for PK analysis (n=3/timepoint). At the end of study, plasma, whole blood, serums were collected for PK, CBC and BC analysis (n=3/timepoint). The plasma samples were collected at 0.25h, 2h, 6h, 12h (pre-last dose), 12.25h (0.25h post last dose) and 24h (12h post last dose) post penultimate dose for PK analysis. The CBC and BC samples were collected at 12.25h (0.25h post last dose) and 24h (12h post last dose). Results Others have reported significant, but reversible, thrombocytopenia for dual CBP/EP300 bromodomain inhibitors (Katavolos et al., Toxicol Pathol, 2020). Dual bromodomain inhibitors were known to decrease platelet counts in vivo and display adverse events related to platelets in the clinic. The observation of decreased platelet counts recapitulated in mice with dual bromodomain inhibitor GNE-781 to a similar degree as reported. Surprisingly, our EP300 degraders show a slight increase in platelets at relevant doses (Figure 8). Regarding the safety profile, animals tolerated well with the treatment of compound 132 during the study period. Additionally, no clinical abnormalities were observed in any of the animals treated. Example 543: U2OS IF Degradation Assay Procedure: A set of two CRISPR knock-in stable U2OS polyclonal cell lines, each with a HiBiT tag fused 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, 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 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 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 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 (Figure 4). Results shown in Table 9. Table 9. IF Degradation of CBP and EP300
Figure imgf000493_0001
Figure imgf000494_0001
Figure imgf000495_0001
Figure imgf000496_0001
Figure imgf000497_0001
Figure imgf000498_0001
Figure imgf000499_0001
Figure imgf000500_0001
Figure imgf000501_0001
Figure imgf000502_0001
Figure imgf000503_0001
Figure imgf000504_0001
Figure imgf000505_0001
Figure imgf000506_0001
Figure imgf000507_0001
Figure imgf000508_0001
ENUMERATED EMBODIMENTS E1. A compound having the structure of Formula I: A-L-B Formula I, wherein A is a CBP binding moiety; B is a degradation moiety; and L has the structure of Formula II: A1–(F)–(E)m–C-A2, Formula II wherein A1 is a bond between the linker and A; A2 is a bond between B and the linker; m is 0 or 1; C is absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; E is absent, O, S, NRN, optionally substituted C1–C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally each RN is, independently, H, optionally substituted C1–C4 alkyl, optionally substituted C2–C4 alkenyl, optionally substituted C2–C4 alkynyl, optionally substituted C2–C6 heterocyclyl, optionally substituted C6– C12 aryl, or optionally substituted C1–C7 heteroalkyl; F is optionally substituted C3-C10 carbocyclylene, optionally substituted C2-C10 heterocyclylene, optionally substituted C6-C10 arylene, or optionally substituted C2-C9 heteroarylene, or a pharmaceutically acceptable salt thereof. E2. The compound of embodiment 1, wherein the CBP binding moiety of Formula III has the structure:
Figure imgf000509_0001
Formula III-B wherein: R1 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C2-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C2-C12 heterocycle of R1 is optionally substituted with A1 and/or one or more groups Rb; R2 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- 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, N(Ra)C(O)ORa)C(O)N(Ra)C(O)N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is C1-C12alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3- 12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2- C4 alkynyl, C3-C5 carbocycle, and C2-C5 heterocycle is optionally substituted with A1 and/or one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)N(Rh)2, S(O)2N(Rh)2, O)ORh, C(OC(O)Rh, OC(O)ORh, —C(O)ORh, N(Rh)2, N(Rh)2, N(Rh)C(O)N(Rh)S(O)Rh, N(Rh)S(O)Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each 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, halo, amino, hydroxyl, C1–C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1–C6 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a 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; each Rb is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, N(Rc)C(O)Rc)C(O)N(Rc, S(O)Rc, S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(Rc)S(O)2N(Rc)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, and C2-C12 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, C(O)N(Rc)2, N(Rc)C(O)2N(Rc)S(O)Rc, N(Rc)S(O)2Rc and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc 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 A1 and/or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, C(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which C3-C12 carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1– C6 alkyl, cyano, N(Rd)2, ORd, C3-C12 heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd 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 A1 and/or 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 Rd are taken together with the nitrogen to which they are attached to form a 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; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C12 carbocyclyl, C3–C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, carbocycle, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or 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, carbocyclyl, heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, SRg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which C3-C12 carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 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 A1 and/or 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 Rg1 are taken together with the nitrogen to which they are attached to form a 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 A1 and/or one or more groups independently selected from halo; wherein one of R1, R2, R3, or R4 comprises A1. E3. The compound of embodiment 2, wherein R1 is C1–C12 alkyl, C2–C12 alkenyl, C2–C12 alkynyl, C3–C12 carbocycle, or C3–C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C3-C12 heterocycle is optionally substituted with A1 and/or one or more groups Rb; R2 is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), or (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6- 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, N(Ra)C(O)ORa)C(O)N(Ra)C(O)N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C3-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C3-C12 heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups Re; R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, C3-C5 heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, and C3-C5 heterocycle is optionally substituted with A1 and/or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)2, N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a 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; each Rb 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(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, N(Rc)C(O)O)N(Rc)2, IRc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)N(Rc)S(O)N(Rc)2, or N(R)S(O)2N(Rc)2, wherein any C1C-6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, N(Rc)C(O)N(Rc)S(O)2N(Rc)S(O)2Rc and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc 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 A1 and/or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, C(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd 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 A1 and/or 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 Rd are taken together with the nitrogen to which they are attached to form a 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; 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(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-9 aryl, and C2-10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, carbocycle, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 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 A1 and/or one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, SRg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 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 A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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 A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1- C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from halo. E4. The compound of embodiment 2 or 3, wherein wherein R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb. E5. The compound of any one of embodiments 2 to 4, wherein R1 is
Figure imgf000513_0001
. E6. The compound of any one of embodiments 2 to 5, wherein R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1 and/or one or more groups Re. E7. The compound of any one of embodiments 2 to 6, wherein R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1 and/or one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring. E8. The compound of any one of embodiments 2 to 7, wherein NR2R3 taken together has the structure:
Figure imgf000514_0001
. E9. The compound of any one of embodiments 2 to 8, wherein R4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. E10. The compound of any one of embodiments 2 to 9, wherein R4 has the structure:
Figure imgf000514_0002
. E11. The compound of any one of embodiments 2 to 10, wherein the CBP binding moiety has the structure:
Figure imgf000514_0003
. E12. The compound of embodiment 1, wherein the CBP binding moiety has the structure:
Figure imgf000514_0004
Formula III-A wherein: R8 is C1-C12 alkyl, C3-C12 carbocycle, or C3-C12 heterocycle, wherein each C1-C12 alkyl, C3-C12 carbocycle, and C3-C12 heterocycle is optionally substituted with one or more groups Ro; R9 is C1-C4 alkyl, C(O)N(Rh2)2, S(O)N(Rh2)2, S(O)2, C(O)Rh2, C(O)ORh2, S(O)2Rh2, C2–C6 heteroaryl, or C2-C9 heterocycle wherein any C1-C4alkyl, C2–C6 heteroaryl, or C2-C9 heterocycle is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)N(Rh2)2, S(O)2N(Rh2)2, O Rh2, S(O)2Rh2, OC(ORh2, —C(O)ORh2, N(Rh2)2, N(Rh2)2, N(Rh2)C(O)N(Rh2)2, N(Rh2)S(O)2Rh2, N(Rh2)S(O)N(Rh2)2, and N(Rh2)S(O)2N(Rh2)2; R10 is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), and (C1-20 heteroaryl)(C1-20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6- 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 Rp, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Ra2)2, CN, C(O)N(Ra2)2, S(O)N(Ra2)2, S(O)2N(Ra2)2, N(Ra2)C(O)ORa2)C(O)N(Ra2)C(O)N(Ra2)S(O)2Ra2, N(Ra2)S(O)N(Ra2)2, and N(Ra2)S(O)2N(Ra2)2; each Ra2 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C2-C12 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C2-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, or C1-C6 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; or two Ra2 are taken together with the nitrogen to which they are attached to form a 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; each RO is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, C2-C9 heteroaryl, F, Cl, Br, I, NO2, N(RP)2, CN, C(O)N(RP)2, S(O)N(RP)2, S(O)2N(RP)2, ORP, SRP, OC(O)ORP, OC(O)ORP, C(O)RP, C(O)ORP, S(O)RP, S(O)2RP, OC(O)N(RP)2, N(RP)C(O)ORP, N(RP)C(O)N(RP)2, N(RP)C(O)RP, N(RP)S(O)RP, N(RP)S(O)2RP, N(RP)S(O)N(RP)2, or N(RP)S(O)2N(RP)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, and C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(RP)2, CN, C(O)N(RP)2, S(O)N(RP)2, S(O)2N(RP)2, ORP, SRP, OC(O)RP, C(O)RP, S(O)RP, S(O)2RP, C(O)N(RP)2, N(RP)C(O)RP, N(RP)S(O)RP, N(Rc2)S(O)2Rc2 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RP 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, carbocyclyl, heterocyclyl, halo, NO2, N(Rd2)2, CN, C(O)N(Rd2)2, S(O)N(Rd2)2, S(O)2N(Rd2)2, ORd2, SRd2, C(O)Rd2, S(O)2Rd2, C(O)N(Rd2)2, N(Rd2)2, N(Rd2)S(O)Rd2, N(Rd2)S(O)2Rd2, and C1–C6 alkyl, which C3-C12 carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd2)2, ORd2, C3-C12 heterocyclyl, and C3-12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6 alkyl; each Rd2 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1C-6 alkoxy, carbocyclyl, or 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, C1C-6 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 Rd2 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; each Rh2 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; and wherein R10 comprises A1. E13. The compound of embodiment 12, wherein R8 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R8 is optionally substituted with one or more groups RO. E14. The compound of embodiment 12, wherein
Figure imgf000516_0001
. E15. The compound of embodiment 12, wherein R9 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. E16. The compound of embodiment 12, wherein R9 has the structure:
Figure imgf000516_0002
. E17. The compound of embodiment 12, wherein the CBP binding moiety has the structure:
Figure imgf000516_0003
. E18. The compound of embodiment 12, wherein R10 has the structure:
Figure imgf000517_0001
, wherein X3 is NRN2, CH2, or O; X4 is N, CH; X5 is N, CH; X6 is NRN2, CH2, or O; R14 is CHF2, CHCl2, CH3, Cl, F, or H, and each RN2 is independently, C1-C3 alkyl or H. E19. The compound of embodiment 18, wherein X3 is CH2 and X4 is CH. E20. The compound of embodiment 12, wherein R10 has the structure:
Figure imgf000517_0002
. E21. The compound of embodiment 12, wherein the CBP binding moiety has the structure:
Figure imgf000517_0003
. E22. The compound of embodiment 1, wherein the CBP binding moiety has the structure:
Figure imgf000517_0004
Formula III-B wherein: R1 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C2-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C2-C12 heterocycle of R1 is optionally substituted with A1 and/or one or more groups Rb; R2 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- 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, N(Ra)C(O)ORa)C(O)N(Ra)C(O)N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is C1-C12alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3- 12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)—O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, and C2-C5 heterocycle is optionally substituted with A1 and/or one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)—N(Rh)2, S(O)2N(Rh)2, —O)ORh, C(O—C(O)—Rh, —O—C(O)—O—Rh, —C(O)ORh, N(Rh)2, —N(Rh)2, N(Rh)C(O)—N(Rh)S(O)Rh, —N(Rh)—S(O)—Rh, —N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each 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, halo, amino, hydroxyl, C1–C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1–C6 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a 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; each Rb is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, N(Rc)C(O)Rc)C(O)N(Rc, S(O)Rc, S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(Rc)S(O)2N(Rc)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, and C2-C12 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, C(O)N(Rc)2, N(Rc)C(O)2N(Rc)S(O)Rc, N(Rc)S(O)2Rc and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc 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 A1 and/or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, C(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which C3-C12 carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1- C6 alkyl, cyano, N(Rd)2, ORd, C3-C12 heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd 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 A1 and/or 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 Rd are taken together with the nitrogen to which they are attached to form a 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; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2–C9 aryl, and C2–C10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, carbocycle, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or 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, carbocyclyl, heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, SRg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which C3-C12 carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 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 A1 and/or 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 Rg1 are taken together with the nitrogen to which they are attached to form a 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 A1 and/or one or more groups independently selected from halo; wherein one of R1, R2, R3, or R4 comprises A1. E23. The compound of embodiment 22, wherein: R1 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C3-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C3-C12 heterocycle is optionally substituted with A1 and/or one or more groups Rb; R2 is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), or (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6- 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, N(Ra)C(O)ORa)C(O)N(Ra)C(O)N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C3-C12 heterocycle, wherein each C1–C12 alkyl, C2–C12 alkenyl, C2–C12 alkynyl, C3–C12 carbocycle, and C3–C12 heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups Re; R4 is C1–C4 alkyl, C2–C4 alkenyl, C2–C4 alkynyl, C3–C5 carbocycle, C3–C5 heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, and C3-C5 heterocycle is optionally substituted with A1 and/or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)2, N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C3–C12 heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a 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; each Rb 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(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, N(Rc)C(O)O)N(Rc)2, IRc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)—N(Rc)S(O)N(Rc)2, or N(R)S(O)2N(Rc)2, wherein any C1C-6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, —N(Rc)2, N(Rc)C(O)—N(Rc)S(O)2—N(Rc)S(O)2Rc and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc 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 A1 and/or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, —SRd, C(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl; each Rd 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 A1 and/or 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 Rd are taken together with the nitrogen to which they are attached to form a 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; 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(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, —C(O)—Rf1, C(O)ORf1, S(O)Rf1, S(O)2—Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3–C12 heterocyclyl, C2–C9 aryl, and C2–C10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, carbocycle, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 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 A1 and/or one or more groups independently selected from oxo, C3–C12 carbocyclyl, C3–C12 heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)—N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, SRg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, 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(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 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 A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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 A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1- C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from halo. E24. The compound of embodiment 22 or 23, wherein R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb. E25. The compound of any one of embodiments 22 to 24, wherein R1 is
Figure imgf000522_0001
. E27. The compound of any one of embodiments 22 to 26, wherein R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1 and/or one or more groups Re. E28. The compound of any one of embodiments 22 to 27, wherein R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1 and/or one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring. E29. The compound of any one of embodiments 22 to 28, wherein NR2R3 taken together has the structure:
Figure imgf000522_0002
. E30. The compound of any one of embodiments 22 to 29, wherein R4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. E31. The compound of any one of embodiments 22 to 30, wherein R4 has the structure:
Figure imgf000522_0003
. E32. The compound of any one of embodiments 22 to 31, wherein the CBP binding moiety has the structure:
Figure imgf000523_0001
. E33. The compound of embodiment 1, wherein the CBP binding moiety has the structure:
Figure imgf000523_0002
Formula III-C wherein: X1 is C or N; X2 is C or N; R5 is C1-C12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1- C12alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R5 is optionally substituted with one or more groups Rk1k; R6 is C1-4alkyl, 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), C(O)N(Rh1)2, S(O)N(Rh1)2, S(O)2N(Rh1)2, C(O)Rh1, C(O)ORh1, S(O)Rh1, or S(O)2Rh1, wherein , wherein C1-C4 alkyl, C6-C20 aryl, C1-C20 heteroaryl, (C6- 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 F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh1)2, S(O)N(Rh1)2, S(O)2N(Rh1)2, ORh1, SRh1, OC(O)Rh1, OC(O)ORh1, C(O)Rh1, C(O)ORh1, S(O)Rh1, S(O)2Rh1, OC(O)N(Rh1)2, N(Rh1)C(O)ORh1, N(Rh1)C(O)N(Rh1)2, N(Rh1)C(O)Rh1, N(Rh1)S(O)Rh1, N(Rh1S(O)2Rh1, N(Rh1)S(O)N(Rh1)2, and N(Rh1)S(O)2N(Rh1)2; R7 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- 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 RL1, oxo, F, Cl, Br, I, NO2, N(Ra1)2, CN, C(O)N(Ra1)2, S(O)N(Ra1)2, S(O)2N(Ra1)2, ORa1, SRa1, OC(O)Ra1, OC(O)ORa1, C(O)Ra1, C(O)ORa1, S(O)Ra1, S(O)Ra1, OC(O)N(Ra1)2, N(Ra1)C(OORa1, N(Ra1)C(O)N(Ra1)2, N(Ra1)C(O)Ra1, N(Ra1)S(O)Ra1, N(Ra1)S(O)2Ra1, N(Ra1)S(O)N(Ra1)2, and N(Ra1)S(O)2N(Ra1)2; each Ra1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 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 independently selected from oxo and halo; or two Ra1 are taken together with the nitrogen to which they are attached to form a 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; each Rk1 is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RL1)2, CN, C(O)N(RL1)2, S(O)N(RL1)2, S(O)2N(RL1)2, ORL1, SRL1, OC(O)ORL1, OC(O)ORL1, C(O)RL1, C(O)ORL1, S(O)RL1, S(O)2RL1, OC(O)N(RL1)2, N(RL1)C(O)ORL1, N(RL1)C(O)N(RL1)2, N(RL1)C(O)RL1, N(RL1)S(O)RL1, N(RL1)S(O)RL1, N(RL1)S(O)N(RL1)2, or N(RL1)S(O)2N(RL1)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(RL1)2, CN, C(O)N(RL1)2, S(O)N(RL1)2, S(O)2N(RL1)2, ORL1, SRL1, OC(O)RL1, C(O)RL1, S(O)RL1, S(O)2RL1, C(O)N(RL1)2,N(RL1)C(O)RL1, N(RL1)S(O)RL1, N(RL1)S(O)2RL1 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RL1 is, independently, hydrogen, C1–C6 alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd1)2, CN, C(O)N(Rd1)2, S(O)N(Rd1)2, S(O)2N(Rd1)2, ORd1, SRd1, OC(O)Rd1, C(O)Rd1, C(O)Rd1, S(O)Rd1, S(O)2Rd1, C(O)N(Rd1)2, N(Rd1)C(O)Rd1, N(Rd1)S(O)Rd1, N(Rd1)S(O)2Rd1, 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(Rd1)2, ORd1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd1 are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rh1 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 C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C4 alkyl that is optionally substituted with one or more groups independently selected from halo; and wherein R7 comprises A1. E34. The compound of embodiment 1, wherein the CBP binding moiety has the structure:
Figure imgf000525_0001
Formula IV wherein: R11 is C1-C12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1- C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R11 is optionally substituted with one or more groups RM; R12 is C1–C4 alkyl, C(O)N(Rh3)2, S(O)N(Rh3)2, S(O)N(Rh3)2, C(O)Rh3, C(O)ORh3, S(O)Rh3, or S(O)Rh3, wherein any C1-C4alkyl is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh3)2, S(O)N(Rh3)2, S(O)2N(Rh3)2, ORh3, SRh3, OC(O)Rh3, OC(O)ORh3, C(O)Rh3, C(O)ORh3, S(O)Rh3, S(O)2Rh3, OC(O)N(Rh3)2, N(Rh3)C(O)ORh3, N(Rh3)C(O)N(Rh3)2, N(Rh3)C(O)Rh3, N(Rh3)S(O)Rh3, N(Rh3)S(O)2Rh3, N(Rh3)S(O)N(Rh3)2, and N(Rh3)S(O)2N(Rh3)2; R13 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- 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 RN1, oxo, F, Cl, Br, I, NO2, N(Ra3)2, CN, C(O)N(Ra3)2, S(O)N(Ra3)2, S(O)2N(Ra3)2, ORa3, SRa3, OC(O)Ra3, OC(O)ORa3, C(O)Ra3, C(O)ORa3, S(O)Ra3, S(O)2Ra3, OC(O)N(Ra3)2, N(Ra3)C(O)ORa3, N(Ra3)C(ON(Ra3)2, N(Ra3)C(O)Ra3, N(Ra3)S(O)Ra3, N(Ra3)S(O)2Ra3, N(Ra3)S(O)N(Ra3)2, and N(Ra3)S(O)2N(Ra3)2; each Ra3 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6alkynyl, 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 independently selected from oxo and halo; or two Ra3 are taken together with the nitrogen to which they are attached to form a 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; each RM is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RN1)2, CN, C()N(RN1)2, S(O)N(RN1)2, S(O)2N(Rc)2, ORN1, SRN1, OC(O)ORN1, OC(O)ORN1, C(O)RN1, C(O)ORN1, S(O)RN1, S(O)2RN1, OC(O)N(RN1)2, N(RN1)C(O)ORN1, N(RN1)C(O)N(RN1)2, N(RN1)C(O)RN1, N(RN1)S(O)RN1, N(RN1)S(O)2RN1, N(RN1)S(O)N(RN1)2, or N(RN1)S(O)2N(RN1)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(RN1)2, CN, C(O)N(RN1)2, S(O)N(RN1)2, S(O)2N(RN1)2, ORN1, SRN1, OC(O)RN1, C(O)RN1, S(O)RN1, S(O)2RN1,C(O)N(RN1)2, N(RN1)C(O)RN1, N(RN1)S(O)RN1, N(RN1)S(O)2RN1 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RN1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd3)2, CN, C(O)N(Rd3)2, S(O)N(Rd3)2, S(O)2N(Rd3)2, ORd3, SRd3, OC(O)Rd3, C(O)Rd3, C(O)ORd3, S(O)Rd3, S(O)2Rd3, C(O)N(Rd3)2, N(Rd3)C(O)Rd3, N(Rd3)S(O)Rd3, N(Rd3)S(O)2Rd3, and C1-6alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd3)2, ORd3, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd3 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd3 are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1–3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rh3 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; and wherein R13 comprises A1. E35. The compound of embodiment 1, wherein the CBP binding moiety has the structure of Formula III
Figure imgf000526_0001
Formula III wherein X1a is C or N; R1a and R1b combine with the atoms to which they are attached to form an optionally substituted C3-C10 carbocycle, an optionally substituted C5-C10 aryl, an optionally substituted C3-C9 heteroaryl, or optionally substituted C3-C9 heterocycle, wherein the carbocycle, aryl, heteroaryl or heterocycle is optionally substituted with A1 and/or one or more of the following groups: halogen, C1–C6 alkyl, C5-C10 aryl, C2-C9 heteroaryl, C2-C9 heterocycle, C3-C10 carbocycle, C(O)N(R1e)2, S(O)N(R1e)2, S(O)2N(R1e)2, OR1e, C(O)R1e, C(O)OR1e, S(O)R1e, S(O)2R1e, SR1e, OC(O)R1e, OC(O)OR1e, OC(O)N(R1e)2, N(R1e)C(O)N(R1e)2, N(R1e)C(O)OR1e, N(R1e)C(O)R1e, N(R1e)S(O)R1e, N(R1e)S(O)2R1e, N(R1e)S(O)N(R1e)2, or N(R1e)S(O)N(R1e)2; wherein any C1–C6 alkyl, C5-C10 aryl, C2-C9 heteroaryl, C2-C9 heterocycle, C3-C10 carbocycle is optionally substituted A1 and/or one or more substituent groups independently selected from halogen, C1–C6 alkyl, C2-C9 heteroaryl, C3-C12 carbocycle, C2-C9 heterocycle, C(O)N(R1e)2, S(O)N(R1e)2, S(O)2N(R1e)2, C(O)R1e, C(O)OR1e, S(O)R1e, or S(O)2R1e. R1c is A1, NR2aR3a, C6-C20 aryl, C2-C9 heterocyle, 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-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 R1h, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(R1f)2, CN, C(O)N(R1f)2, S(O)N(R1f)2, S(O)2N(R1f)2, OR1f, SR1f, OC(O)R1f, OC(O)OR1f, C(O)R1f, C(O)OR1f, S(O)R1f, S(O)2R1f, OC(O)N(R1f)2, N(R1f)C(O)OR1f, N(R1f)C(O)N(R1f)2, N(R1a1)C(O)R1f, N(R1f)S(O)R1f, N(R1f)S(O)2R1f, N(R1f)S(O)N(R1f)2, and N(R1f)S(O)2N(R1f)2; R1d is C1-C12 alkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1d is optionally substituted with one or more groups R1g; each R1e 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; R2a is H, C1–C12 alkyl, C5-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-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 R1k, oxo, F, Cl, Br, I, NO2,N(R1j)2, CN, C(O)N(R1j)2, S(O)N(R1j)2, S(O)2N(R1j)2, OR1j, SR1j, OC(O)R1j, OC(O)OR1j, C(O)R1j, C(O)OR1j, S(O)R1j, S(O)2R1j, OC(O)N(R1j)2, N(R1j)C(O)OR1j, N(R1j)C(O)N(R1j)2, N(R1j)C(O)R1j, N(R1j)S(O)R1j, N(R1j)S(O)2R1j, N(R1j)S(O)N(R1j)2, and N(Ra)S(O)2N(R1j)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–C12 alkynyl, 3-12 membered carbocycle, and 3- 12 membered heterocycle of R3a is optionally substituted with A1 and/or one or more groups R1k; or R2a and R3a of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups R1k; each R1f is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C9 carbocyclyl, and C2-C9 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 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 independently selected from oxo and halo; or two R1f are taken together with the nitrogen to which they are attached to form a 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; each R1g is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C9 carbocyclyl, C2-C9 heterocyclyl, C5-C9 aryl, C1-C20 heteroaryl, F, Cl, Br, I, NO2, N(R1L)2, CN, C(O)N(R1L)2, S(O)N(R1L)2, S(O)2N(Rc)2, OR1L, SR1L, OC(O)OR1L, OC(O)OR1L, C(O)R1L, C(O)OR1L, S(O)R1L, S(O)2R1L, OC(O)N(R1L)2, N(R1L)C(O)OR1L, N(R1L)C(O)N(R1L)2, N(R1L)C(O)R1L, N(R1LS(O)R1L, N(R1L)S(O)2R1L, N(R1L)S(O)N(R1L)2, or N(R1L)S(O)2N(R1L)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(R1L)2, CN, C(O)N(R1L)2, S(O)N(R1L)2, S(O)2N(R1L)2, OR1L, SR1L, OC(O)R1L, C(O)R1L, S(O)R1L,S(O)2R1L, C(O)N(R1L)2, N(R1L)C(O)R1L, N(R1L)S(O)R1L, N(R1L)S(O)2R1L and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each R1h is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R1M)2, CN, C(O)N(R1M)2, S(O)N(R1M)2, S(O)2N(R1M)2, OR1M, SR1M, OC(O)R1M, C(O)R1M, C(O)OR1M, S(O)R1M, S(O)R1M, C(O)N(R1M)2, N(R1M)C(O)R1M, N(R1M)S(O)R1M, N(R1M)S(O)2R1M, 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(R1M)2, OR1M, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each R1j is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or 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 independently selected from oxo and halo; or two R1j are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; each R1k is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R1N)2, CN, CHF2, CF3, C(O)N(R1N)2, S(O)N(R1N)2, S(O)2N(R1N)2, OR1N, SR1N, OC(O)R1N, C(O)R1N, C(O)OR1N, S(O)R1N, S(O)2R1Nd, C(O)N(R1N)2, N(R1N)C(O)R1N, N(R1N)S(O)R1N, N(R1N)S(O)2R1N, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(R1N)2, OR1N, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each R1M is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd2 are taken together with the nitrogen to which they are attached to form a 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; each R1N is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C 6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R1N are taken together with the nitrogen to which they are attached to form a 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 R1a, R1b, R1c, or R1d comprises A1. E36. The compound of embodiment 35, wherein the CBP binding moiety of Formula III has the structure:
Figure imgf000529_0001
E37. The compound of embodiment 35, wherein the CBP binding moiety of Formula III has the structure:
Figure imgf000529_0002
Figure imgf000530_0001
E40. The compound of embodiment 35, wherein
Figure imgf000531_0001
. E41. The compound of embodiment 35, wherein the CBP binding moiety of Formula III has the structure: , , ,
Figure imgf000531_0002
, ,
Figure imgf000532_0001
, E42. The compound of embodiment 35, wherein the CBP binding moiety of formula III has the structure: ,
Figure imgf000532_0002
, ,
Figure imgf000533_0001
Figure imgf000534_0001
E43. The compound of embodiment 35, wherein the CBP binding moiety of formula III has the structure:
Figure imgf000534_0002
Formula III-A wherein: R8 is C1-C12 alkyl, C3-C12 carbocycle, or C3-C12 heterocycle, wherein each C1-C12 alkyl, C3-C12 carbocycle, and C3-C12 heterocycle is optionally substituted with one or more groups Ro; R9 is C1-C4 alkyl, C(O)N(Rh2)2, S(O)N(Rh2)2, S(O)2, C(O)Rh2, C(O)—O—Rh2, S(O)2Rh2, C2–C6 heteroaryl, or C2-C9 heterocycle wherein any C1-C4alkyl, C2–C6 heteroaryl, or C2-C9 heterocycle is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)—N(Rh2)2, S(O)2N(Rh2)2, —O— Rh2, S(O)2Rh2, OC(O—Rh2, —C(O)ORh2, N(Rh2)2, — N(Rh2)2, N(Rh2)C(O)—N(Rh2)2, —N(Rh2)S(O)2Rh2, N(Rh2)S(O)N(Rh2)2, and N(Rh2)S(O)2N(Rh2)2; R10 is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), and (C1-20 heteroaryl)(C1-20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6- 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 Rp, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Ra2)2, CN, C(O)N(Ra2)2, S(O)N(Ra2)2, S(O)2—N(Ra2)2, N(Ra2)C(O)—O—Ra2)C(O)N(Ra2)—C(O)—N(Ra2)S(O)2Ra2, N(Ra2)S(O)N(Ra2)2, and N(Ra2)S(O)2N(Ra2)2; each Ra2 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C2–C12 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C12 carbocyclyl, and C2-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, or C1–C6 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; or two Ra2 are taken together with the nitrogen to which they are attached to form a 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; each RO is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6–C10 aryl, C2–C9 heteroaryl, F, Cl, Br, I, NO2, N(RP)2, CN, C(O)N(RP)2, S(O)N(RP)2, S(O)2N(RP)2, ORP, SRP, OC(O)ORP, OC(O)ORP, C(O)RP, C(O)ORP, S(O)RP, S(O)2RP, OC(O)N(RP)2, N(RP)C(O)ORP, N(RP)C(O)N(RP)2, N(RP)C(O)RP, N(RP)S(O)RP, N(RP)S(O)2RP, N(RP)S(O)N(RP)2, or N(RP)S(O)2N(RP)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6–C10 aryl, and C2–C9 heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(RP)2, CN, C(O)N(RP)2, S(O)N(RP)2, S(O)2N(RP)2, ORP, SRP, OC(O)RP, C(O)RP, S(O)RP, S(O)2RP, C(O)N(RP)2, N(RP)C(O)RP, N(RP)S(O)RP, N(Rc2)S(O)2Rc2 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RP 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, carbocyclyl, heterocyclyl, halo, NO2, N(Rd2)2, CN, C(O)N(Rd2)2, S(O)N(Rd2)2, S(O)2—N(Rd2)2, —O—Rd2, — S—Rd2, C(O)—Rd2, S(O)2Rd2, C(O)N(Rd2)2, N(Rd2)2, —N(Rd2)S(O)Rd2, N(Rd2)S(O)2Rd2, and C1–C6 alkyl, which C3-C12 carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd2)2, ORd2, C3-C12 heterocyclyl, and C3-12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6 alkyl; each Rd2 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1C-6 alkoxy, carbocyclyl, or 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, C1C-6 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 Rd2 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; each Rh2 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; and wherein R10 comprises A1. E44. The compound of embodiment 43, wherein R8 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R8 is optionally substituted with one or more groups RO. E45. The compound of embodiment 43, wherein R8 is , , , , , , , , , , , or . E46. The compound of embodiment 43, wherein R8 is . E47. The compound of embodiment 43, wherein R9 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. E48. The compound of embodiment 43, wherein R9 has the structure: . E49. The compound of embodiment 43, wherein the CBP binding moiety has the structure: . E50. The compound of embodiment 43, wherein R10 has the structure: or , wherein X3 is NRN2, CH2, or O; X4 is N, CH; X5 is N, CH; X6 is NRN2, CH2, or O; R14 is CHF2, CHCl2, CH3, Cl, F, or H, and each RN2 is independently, C1-C3 alkyl or H. E51. The compound of embodiment 50, wherein X3 is CH2 and X4 is CH. E52. The compound of embodiment 43, wherein R10 has the structure: , , , , , , , , , , , , , , , , , , , , , , , , or . E53. The compound of embodiment 43, wherein R10 has the structure: . E54. The compound of embodiment 43, wherein the CBP binding moiety has the structure: , , , ,
, , , , , , or . E55. The compound of embodiment 35, wherein the CBP binding moiety of Formula III has the structure: wherein: R1 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C2-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C2-C12 heterocycle of R1 is optionally substituted with A1 and/or one or more groups Rb; R2 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- 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)2—N(Ra)2, N(Ra)C(O)—O—Ra)C(O)N(Ra)—C(O)— N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is C1-C12alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3- 12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)—O)Rh, or S(O)2Rh, wherein any C1–C4 alkyl, C2–C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, and C2-C5 heterocycle is optionally substituted with A1 and/or one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)—N(Rh)2, S(O)2N(Rh)2, —O)ORh, C(O—C(O)—Rh, —O—C(O)—O—Rh, —C(O)ORh, N(Rh)2, —N(Rh)2, N(Rh)C(O)—N(Rh)S(O)Rh, —N(Rh)—S(O)—Rh, —N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each 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, halo, amino, hydroxyl, C1–C6 alkoxy, C3–C12 carbocyclyl, C3–C12 heterocyclyl, or C1-C6 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a 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; each Rb is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2— N(Rc)2, N(Rc)C(O)—Rc)C(O)N(Rc, —S(O)Rc, —S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(Rc)S(O)2N(Rc)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, and C2-C12 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, —C(O)—N(Rc)2, N(Rc)C(O)2—N(Rc)S(O)Rc, N(Rc)S(O)2Rc and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc 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 A1 and/or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, —N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2—N(Rd)2, —O—Rd, — S—Rd, C(O)—Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, —N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which C3-C12 carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, C3-C12 heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd 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 A1 and/or 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 Rd are taken together with the nitrogen to which they are attached to form a 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; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, carbocycle, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or 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, carbocyclyl, heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, SRg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which C3-C12 carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 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 A1 and/or 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 Rg1 are taken together with the nitrogen to which they are attached to form a 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 A1 and/or one or more groups independently selected from halo; wherein one of R1, R2, R3, or R4 comprises A1. E56. The compound of embodiment 55, wherein: R1 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C3-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C3-C12 heterocycle is optionally substituted with A1 and/or one or more groups Rb; R2 is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), or (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6- 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)2—N(Ra)2, N(Ra)C(O)—O—Ra)C(O)N(Ra)—C(O)— N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C3-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C3-C12 heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups Re; R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, C3-C5 heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)—O)Rh, or S(O)2Rh, wherein any C1–C4 alkyl, C2–C4 alkenyl, C2–C4 alkynyl, C3-C5 carbocycle, and C3-C5 heterocycle is optionally substituted with A1 and/or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)—N(Rh)2, —S(O)— N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)2, —N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a 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; each Rb 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(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2— N(Rc)2, N(Rc)C(O)—O)N(Rc)2, IRc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)—N(Rc)S(O)N(Rc)2, or N(R)S(O)2N(Rc)2, wherein any C1C-6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, —N(Rc)2, N(Rc)C(O)—N(Rc)S(O)2—N(Rc)S(O)2Rc and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc 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 A1 and/or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2—N(Rd)2, —O—Rd, —S— Rd, C(O)—Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, —N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–6alkyl; each Rd 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 A1 and/or 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 Rd are taken together with the nitrogen to which they are attached to form a 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; 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(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, —C(O)—Rf1, C(O)ORf1, S(O)Rf1, S(O)2—Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-9 aryl, and C2-10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)—Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, carbocycle, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 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 C3C-12 heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)—N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, SRg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, —S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 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 A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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 A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C3 alkoxy, and C1- C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from halo. E57. The compound of embodiment 55, wherein R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb. E58. The compound of embodiment 55, wherein R1 is , , , , , , , or . E59. The compound of embodiment 55, wherein R1 is or . E60. The compound of embodiment 55, wherein R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1 and/or one or more groups Re. E61. The compound of embodiment 55, wherein R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1 and/or one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring. E62. The compound of embodiment 55, wherein NR2R3 taken together has the structure:
Figure imgf000545_0001
, , . E63. The compound of embodiment 55, wherein R4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. E64. The compound of embodiment 55, wherein R4 has the structure:
Figure imgf000545_0002
.
E65. The compound of embodiment 55, wherein the CBP binding moiety has the structure: ,
Figure imgf000546_0001
, ,
Figure imgf000547_0001
,
Figure imgf000548_0001
Figure imgf000549_0001
E66. The compound of embodiment 35, wherein the CBP binding moiety has the structure:
Figure imgf000549_0002
Formula III-C wherein: X1 is C or N; X2 is C or N; R5 is C1-C12alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1- C12alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R5 is optionally substituted with one or more groups Rk1k; R6 is C1-4alkyl, 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), C(O)N(Rh1)2, S(O)N(Rh1)2, S(O)2N(Rh1)2, C(O)Rh1, C(O)ORh1, S(O)Rh1, or S(O)2Rh1, wherein , wherein C1-C4 alkyl, C6-C20 aryl, C1-C20 heteroaryl, (C6- 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 F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh1)2, S(O)N(Rh1)2, S(O)2N(Rh1)2, ORh1, SRh1, OC(O)Rh1, OC(O)ORh1, C(O)Rh1, C(O)ORh1, S(O)Rh1, S(O)2Rh1, OC(O)N(Rh1)2, N(Rh1)C(O)ORh1, N(Rh1)C(O)N(Rh1)2, N(Rh1)C(O)Rh1, N(Rh1)S(O)Rh1, N(Rh1S(O)2Rh1, N(Rh1)S(O)N(Rh1)2, and N(Rh1)S(O)2N(Rh1)2; R7 is NR2R3, 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- 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 RL1, oxo, F, Cl, Br, I, NO2, N(Ra1)2, CN, C(O)N(Ra1)2, S(O)N(Ra1)2, S(O)2N(Ra1)2, ORa1, SRa1, OC(O)Ra1, OC(O)ORa1, C(O)Ra1, C(O)ORa1, S(O)Ra1, S(O)Ra1, OC(O)N(Ra1)2, N(Ra1)C(OORa1, N(Ra1)C(O)N(Ra1)2, N(Ra1)C(O)Ra1, N(Ra1)S(O)Ra1, N(Ra1)S(O)2Ra1, N(Ra1)S(O)N(Ra1)2, and N(Ra1)S(O)2N(Ra1)2; R2 is C6-C20 aryl, C1-C20 heteroaryl, (C6-20 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-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, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 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-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or 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 independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; each Rc is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6a lkyl; each Rd is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a 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; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)—N(Rf1)2,S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1S(O)2Rf1, carbocycle, and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, Rg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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; each Ra1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 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 independently selected from oxo and halo; or two Ra1 are taken together with the nitrogen to which they are attached to form a 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; each Rk1 is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RL1)2, CN, C(O)N(RL1)2, S(O)N(RL1)2, S(O)2N(RL1)2, ORL1, SRL1, OC(O)ORL1, OC(O)ORL1, C(O)RL1, C(O)ORL1, S(O)RL1, S(O)2RL1, OC(O)N(RL1)2, N(RL1)C(O)ORL1, N(RL1)C(O)N(RL1)2, N(RL1)C(O)RL1, N(RL1)S(O)RL1, N(RL1)S(O)RL1, N(RL1)S(O)N(RL1)2, or N(RL1)S(O)2N(RL1)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(RL1)2, CN, C(O)N(RL1)2, S(O)N(RL1)2, S(O)2N(RL1)2, ORL1, SRL1, OC(O)RL1, C(O)RL1, S(O)RL1, S(O)2RL1, C(O)N(RL1)2,N(RL1)C(O)RL1, N(RL1)S(O)RL1, N(RL1)S(O)2RL1 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RL1 is, independently, hydrogen, C1–C6 alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd1)2, CN, C(O)N(Rd1)2, S(O)N(Rd1)2, S(O)2N(Rd1)2, ORd1, SRd1, OC(O)Rd1, C(O)Rd1, C(O)Rd1, S(O)Rd1, S(O)2Rd1, C(O)N(Rd1)2, N(Rd1)C(O)Rd1, N(Rd1)S(O)Rd1, N(Rd1)S(O)2Rd1, 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(Rd1)2, ORd1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd1 are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rh1 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 C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C4 alkyl that is optionally substituted with one or more groups independently selected from halo; and wherein R7 comprises A1. E67. The compound of embodiment 65, wherein R5 is , , , , , , , , , , , or . E68. The compound of embodiment 65, wherein R7 is , , , , , , , , , , , , , , , , , , , , , , , or . E69. The compound of embodiment 1, wherein the CBP binding moiety has the structure:
Figure imgf000554_0001
Formula IV wherein: R11 is C1-C12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1- C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R11 is optionally substituted with one or more groups RM; R12 is C1–C4 alkyl, C(O)N(Rh3)2, S(O)N(Rh3)2, S(O)N(Rh3)2, C(O)Rh3, C(O)ORh3, S(O)Rh3, or S(O)Rh3, wherein any C1-C4alkyl is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh3)2, S(O)N(Rh3)2, S(O)2N(Rh3)2, ORh3, SRh3, OC(O)Rh3, OC(O)ORh3, C(O)Rh3, C(O)ORh3, S(O)Rh3, S(O)2Rh3, OC(O)N(Rh3)2, N(Rh3)C(O)ORh3, N(Rh3)C(O)N(Rh3)2, N(Rh3)C(O)Rh3, N(Rh3)S(O)Rh3, N(Rh3)S(O)2Rh3, N(Rh3)S(O)N(Rh3)2, and N(Rh3)S(O)2N(Rh3)2; R13 is NR2R3, 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-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 RN1, oxo, F, Cl, Br, I, NO2, N(Ra3)2, CN, C(O)N(Ra3)2, S(O)N(Ra3)2, S(O)2N(Ra3)2, ORa3, SRa3, OC(O)Ra3, OC(O)ORa3, C(O)Ra3, C(O)ORa3, S(O)Ra3, S(O)2Ra3, OC(O)N(Ra3)2, N(Ra3)C(O)ORa3, N(Ra3)C(ON(Ra3)2, N(Ra3)C(O)Ra3, N(Ra3)S(O)Ra3, N(Ra3)S(O)2Ra3, N(Ra3)S(O)N(Ra3)2, and N(Ra3)S(O)2N(Ra3)2; R2 is C6-C20 aryl, C1-C20 heteroaryl, (C6-20 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-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, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 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-C12 alkynyl, 3-12 membered carbocycle, and 3- 12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or 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 independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; each Rc is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6a lkyl; each Rd is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a 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; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)—N(Rf1)2,S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1S(O)2Rf1, carbocycle, and C1–6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, Rg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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; each Ra3 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6alkynyl, 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 independently selected from oxo and halo; or two Ra3 are taken together with the nitrogen to which they are attached to form a 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; each RM is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RN1)2, CN, C()N(RN1)2, S(O)N(RN1)2, S(O)2N(Rc)2, ORN1, SRN1, OC(O)ORN1, OC(O)ORN1, C(O)RN1, C(O)ORN1, S(O)RN1, S(O)2RN1, OC(O)N(RN1)2, N(RN1)C(O)ORN1, N(RN1)C(O)N(RN1)2, N(RN1)C(O)RN1, N(RN1)S(O)RN1, N(RN1)S(O)2RN1, N(RN1)S(O)N(RN1)2, or N(RN1)S(O)2N(RN1)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(RN1)2, CN, C(O)N(RN1)2, S(O)N(RN1)2, S(O)2N(RN1)2, ORN1, SRN1, OC(O)RN1, C(O)RN1, S(O)RN1, S(O)2RN1,C(O)N(RN1)2, N(RN1)C(O)RN1, N(RN1)S(O)RN1, N(RN1)S(O)2RN1 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RN1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd3)2, CN, C(O)N(Rd3)2, S(O)N(Rd3)2, S(O)2N(Rd3)2, ORd3, SRd3, OC(O)Rd3, C(O)Rd3, C(O)ORd3, S(O)Rd3, S(O)2Rd3, C(O)N(Rd3)2, N(Rd3)C(O)Rd3, N(Rd3)S(O)Rd3, N(Rd3)S(O)2Rd3, and C1-6alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd3)2, ORd3, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd3 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd3 are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rh3 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; and wherein R13 comprises A1. E70. The compound of embodiment 69, wherein R12 is . E71. The compound of embodiment 69, wherein the CBP binding moiety of Formula IV has the structure: . E72. The compound of embodiment 69, wherein R11 is , , , , , or . E73. The compound of embodiment 69, wherein R13 C1-C20 heteroaryl. E74. The compound of embodiment 69, wherein R13 is , , , , , , , , , , , , , , or . E75. The compound of embodiment 69, wherein R13 is NR2R3. E76. The compound of embodiment 69, wherein NR2R3 is , , , , , , , , or . E77. The compound of embodiment 69, wherein R13 is . E78. The compound of embodiment 69, wherein the CBP binding moiety of Formula IV has the structure:
Figure imgf000559_0001
. E79. The compound of any one of embodiments 1 to 79, wherein the degradation moiety is a ubiquitin ligase binding moiety. E80. The compound of embodiment 12, 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. E81. The compound of any one of embodiments 1 to 80, wherein the degradation moiety comprises the structure of Formula IV:
Figure imgf000560_0001
Formula IV, wherein RB1 is H, A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1–C6 alkyl C6-C10 aryl; RB4 is H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl C3-C10 carbocyclyl, or optionally substituted C1–C6 alkyl C6- C10 aryl; RB5 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, 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, hydroxy, thiol, or optionally substituted amino; and each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl, RB9 and RB10 are, independently, H, or optionally substituted C1–C6 alkyl, wherein one of RB1 and RB3 is A2, or a pharmaceutically acceptable salt thereof. E82. The compound of embodiment 81, wherein the structure of Formula IV is
Figure imgf000561_0001
E83. The compound of embodiment 82, wherein the degradation moiety has the structure:
Figure imgf000561_0002
. E84. The compound of embodiment 82, wherein the degradation moiety has the structure:
Figure imgf000561_0003
. E85. The compound of any one of embodiments 1 to 80, wherein the degradation moiety has the structure of Formula V-C:
Figure imgf000562_0001
Formula V-C, RB1 is H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl, C3-C10 carbocyclyl, or optionally substituted C1–C6 alkyl wherein the C1–C6 alkyl, C1–C6 heteroalkyl, C3-C10 carbocyclyl, C6-C10 aryl, C1–C6 alkyl, C3-C10 carbocyclyl, or C6-C10 aryl is substituted with A2 and/or one of more groups of RJ2; RB4 is H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl; RB5 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, halogen, optionally substituted C1–C6 alkyl, optionally substituted C1-6 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol, RB9 is H, or optionally substituted C1–C6 alkyl; wherein one of RB1 and RB3 is A2 or C(O)A2, each RJ2 is, independently, hydrogen, optionally substituted C1–C6 alkyl, optionally substituted C3-C12 carbocyclyl, and optionally substituted C3-C12 heterocyclyl, wherein each C1–C6 alkyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, thio, C1–C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1–C6 alkyl that is optionally substituted with A2 and/or one or more groups independently selected from oxo and haloor a pharmaceutically acceptable salt thereof. E86. The compound of embodiment 85, wherein RB6 is optionally substituted C2-C9 heteroaryl. E87. The compound of embodiment 85, wherein RB6 is:
Figure imgf000562_0002
ucture of Formula V-C is
Figure imgf000563_0001
E89. The compound of embodiment 85, wherein RB6 is halogen or optionally substituted C2-C6 alkynyl. E90. The compound of embodiment 85, wherein RB6 is optionally substituted C1–C6 heteroalkyl. E91. The compound of embodiment 90, wherein the optionally substituted C1–C6 heteroalkyl is methoxy. E92. The compound of embodiment 85, wherein the structure of Formula V-C is
Figure imgf000564_0001
, , or a derivative or analog thereof. E93. The compound of any one of embodiments 1 to 80, wherein the degradation moiety (B)has the structure of Formula V-D:
Figure imgf000564_0002
Formula V-D, wherein RB1 is H, A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4 is H, optionally substituted C1-6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, 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, hydroxy, thiol, or optionally substituted amino; and each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl, RB9 and RB10 are, independently, H, or optionally substituted C1–C6 alkyl, wherein one of RB1 and RB3 is A2, or a pharmaceutically acceptable salt thereof E94. The compound of embodiment 93, wherein the structure of Formula V-D is
Figure imgf000565_0001
E95. The compound of embodiment 93, wherein the degradation moiety has the structure: Attorney Docket No.51121-086WO3 PATENT
Figure imgf000566_0001
. E96. The compound of embodiment 93, wherein the degradation moiety has the structure:
Figure imgf000566_0002
. E97. The compound of any one of embodiments 1 to 80, wherein the degradation moiety (B) has the structure of Formula V-E:
Figure imgf000566_0003
Formula V-E RC1 is optionally substituted C1-C6 alkyl; RC2 is A2, or optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, wherein each C1-C6 alkyl, C3-10 carbocyclyl, C1-C6 heteroalkyl, C6-C10 aryl, or C2-C9 heteroaryl is optionally substituted with A2 and/or one or more groups RJ; RC3 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RC4 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each of RC5 and RC6 is, independently, H, or optionally substituted C1-C6 alkyl each RC7 is, independently, 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 C2-9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and each of RC8 and RC9 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl, each RJ is, independently, hydrogen, C1–C6 alkyl, C3-C6 carbocyclyl, and C2–C6 heterocyclyl, wherein each C1–C6 alkyl, C3-C6 carbocyclyl, and C2–C6 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, C1–C6 alkoxy, C3-C6 carbocyclyl, C2–C6 heterocyclyl, or C1–C6 alkyl that is optionally substituted with A2 and/or one or more groups independently selected from oxo and halo; or a pharmaceutically acceptable salt thereof. E98. The compound of embodiment 97, wherein the linker-degradation moiety has the structure:
Figure imgf000567_0001
E99. The compound of any one of embodiments 1 to 80, wherein the degradation moiety (B) has the structure of Formula V-F:
Figure imgf000567_0002
Formula V-F, wherein RB1 is H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4 is H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one of RB1 and RB3 is A2 or C(O)A2, or a pharmaceutically acceptable salt thereof. E100. The compound of any one of embodiments 1 to 80, wherein the degradation moiety has the structure of Formula V-F:
Figure imgf000568_0001
or a derivative or analog thereof. E101. The compound of any one of embodiments 1 to 80, wherein the degradation moiety comprises the structure of Formula V:
Figure imgf000568_0002
Formula V, wherein RB1a is H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2a is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3a is A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4a is H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5a is H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; RB6a is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one of RB1a and RB3a is A2 or C(O)A2. E102. The compound of embodiment 129, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-A):
Figure imgf000569_0001
Formula V-A, wherein RB1a is H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2a is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3a is A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4a is H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5a is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB6a is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one of RB1a and RB3a is A2 or C(O)A2. E103. The compound of embodiment 129, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-B):
Figure imgf000569_0002
Formula V-B, wherein RB1a is H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2a is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3a is A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4a is H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5a is H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; RB6a is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; E104. The compound of embodiment 129, wherein
Figure imgf000570_0001
, wherein each RB6 is, independently, 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol; RB9 is, independently, H, or optionally substituted C1–C6 alkyl; RB10 is, independently, H, or optionally substituted C1–C6 alkyl, and v2 is 0, 1, 2, 3, or 4. E105. The compound of embodiment 129,, wherein RB6a is
Figure imgf000570_0002
.
Figure imgf000570_0003
wherein each RB6 is, independently, 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol; RB11 is optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl; RB9 is, independently, H, or optionally substituted C1–C6 alkyl; RB10 is, independently, H, or optionally substituted C1–C6 alkyl, and
Figure imgf000571_0004
E112. The compound of embodiment 129, wherein
Figure imgf000571_0001
, wherein v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, 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, hydroxy, thiol, or optionally substituted amino; each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl; and RB9 and RB10 are, independently, H, or optionally substituted C1–C6 alkyl. E113. The compound of embodiment 129, wherein
Figure imgf000571_0002
, ,
Figure imgf000571_0003
E114. The compound of embodiment 129, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula V-C:
Figure imgf000572_0001
Formula V-C, RB1 is H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl, C3-C10 carbocyclyl, or optionally substituted C1–C6 alkyl wherein the C1–C6 alkyl, C1–C6 heteroalkyl, C3-C10 carbocyclyl, C6-C10 aryl, C1–C6 alkyl, C3-C10 carbocyclyl, or C6-C10 aryl is substituted with A2 and/or one of more groups of RJ2; RB4 is H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl; RB5 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, halogen, optionally substituted C1–C6 alkyl, optionally substituted C1-6 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol, RB9 is H, or optionally substituted C1–C6 alkyl; and wherein one of RB1 and RB3 is A2 or C(O)A2, each RJ2 is, independently, hydrogen, optionally substituted C1–C6 alkyl, optionally substituted C3-C12 carbocyclyl, and optionally substituted C3-C12 heterocyclyl, wherein each C1–C6 alkyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, thio, C1–C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1–C6 alkyl that is optionally substituted with A2 and/or one or more groups independently selected from oxo and haloor a pharmaceutically acceptable salt thereof. E114. The compound of embodiment 115, wherein RB6 is optionally substituted C2-C9 heteroaryl. E115. The compound of embodiment 115, wherein RB6 is:
Figure imgf000572_0002
E116. The compound of embodiment 115, wherein the structure of Formula V-C is
Figure imgf000573_0001
E117. The compound of embodiment 115, wherein RB6 is halogen or optionally substituted C2-C6 alkynyl. E118. The compound of embodiment 115, wherein RB6 is optionally substituted C1–C6 heteroalkyl. E119. The compound of embodiment 115, wherein the optionally substituted C1–C6 heteroalkyl is methoxy. E120. The compound of embodiment 115, wherein the structure of Formula V-C is
Figure imgf000573_0002
, , or a derivative or analog thereof. E121. The compound of embodiment 129, wherein the degradation moiety (B) of Formula (V) comprises
Figure imgf000574_0001
Formula V-D, wherein RB1 is H, A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4 is H, optionally substituted C1-6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, 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, hydroxy, thiol, or optionally substituted amino; and each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl, RB9 and RB10 are, independently, H, or optionally substituted C1–C6 alkyl, wherein one of RB1 and RB3 is A2, or a pharmaceutically acceptable salt thereof. E122. The compound of embodiment 121, wherein the structure of Formula V-D is
Figure imgf000574_0002
,
Figure imgf000575_0001
, or derivative or analog thereof. E123. The compound of embodiment 121, wherein the degradation moiety has the structure:
Figure imgf000575_0002
. E124. The compound of embodiment 121, wherein the degradation moiety has the structure:
Figure imgf000576_0001
. E125. The compound of embodiment 129, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula V-E:
Figure imgf000576_0002
Formula V-E RC1 is optionally substituted C1–C6 alkyl; RC2 is A2, or optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, wherein each C1–C6 alkyl, C3-10 carbocyclyl, C1–C6 heteroalkyl, C6-C10 aryl, or C2-C9 heteroaryl is optionally substituted with A2 and/or one or more groups RJ; RC3 is H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RC4 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each of RC5 and RC6 is, independently, H, or optionally substituted C1–C6 alkyl each RC7 is, independently, 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 C2-9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and each of RC8 and RC9 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl, each RJ is, independently, hydrogen, C1–C6 alkyl, C3-C6 carbocyclyl, and C2–C6 heterocyclyl, wherein each C1–C6 alkyl, C3-C6 carbocyclyl, and C2–C6 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, C1–C6 alkoxy, C3-C6 carbocyclyl, C2–C6 heterocyclyl, or C1–C6 alkyl that is optionally substituted with A2 and/or one or more groups independently selected from oxo and halo; or a pharmaceutically acceptable salt thereof. E126. The compound of embodiment 125, wherein the linker-degradation moiety has the structure:
Figure imgf000577_0001
E127. The compound of embodiment 125, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula V-F:
Figure imgf000577_0002
Formula V-F, wherein RB1 is H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4 is H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5 is H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one of RB1 and RB3 is A2 or C(O)A2, or a pharmaceutically acceptable salt thereof. E128. The compound of embodiment 127, wherein the degradation moiety has the structure of Formula V-F:
Figure imgf000577_0003
or a derivative or analog thereof. E129. The compound of any one of embodiments 1 to 128, wherein L has the structure of Formula II: A1–(F)–(E)m–C-A2, Formula II wherein A1 is a bond between the linker and A; A2 is a bond between B and the linker; m is 0 or 1; C is absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; E is absent, optionally substituted C1–10 alkylene; and F is optionally substituted C2–10 heterocyclylene or optionally substituted C2-C9 heteroarylene. E130. The compound of embodiment 129, wherein m is 0. E131. The compound of embodiment 129, wherein m is 1. E132. The compound of any one of embodiments 1 to 129, wherein E is methylene or ethylene. E133. The compound of any one of embodiments 1 to 129, wherein E is methylene, ethylene,
Figure imgf000578_0001
,
Figure imgf000578_0002
E134. The compound of any one of embodiments 1 to 129, wherein C is carbonyl. E135. The compound of any one of embodiments 1 to 129, wherein C is absent. E136. The compound of any one of embodiments 1 to 129, wherein F is optionally substituted C2–10 heterocyclylene. E137. The compound of any one of embodiments 1 to 129, wherein F is:
Figure imgf000578_0003
E139. The compound of any one of embodiments 1 to 129, wherein F is optionally substituted C2-C9 heteroarylene. E140. The compound of any one of embodiments 1 to 129, wherein F is:
Figure imgf000579_0001
E141. The compound of any one of embodiments 1 to 129, wherein F is the structure:
Figure imgf000579_0002
, wherein X7 and X8 are each independently -CH or -NH; R17 is H, optionally substituted C1-6 alkyl or A1; and R15 and R16 combine with the atoms to which they are attached to form an optionally substituted C3-12 heteroaryl, wherein the C3-12 heteroaryl is optionally substituted with A1 and/or one or more of the following groups: halogen or C1-6 alkyl.
Figure imgf000579_0003
E143. The compound of any one of embodiments 1 to 129, wherein F is
Figure imgf000579_0004
Figure imgf000580_0001
E144. The compound of any one of embodiments 1 to 143, wherein the compound structure is
Figure imgf000580_0002
Figure imgf000581_0001
Figure imgf000582_0001
Figure imgf000583_0001
Figure imgf000583_0002
pharmaceutically acceptable salt thereof. E145. The compound of any one of embodiments 1 to 143, wherein the compound structure is
Figure imgf000584_0001
Figure imgf000585_0001
,
Figure imgf000586_0001
Figure imgf000587_0001
Figure imgf000588_0001
, or a pharmaceutically acceptable salt thereof. E146. The compound of any one of embodiments 1 to 143, wherein the compound is any one of compounds 1 to 536, or a pharmaceutically acceptable salt thereof. E147. The compound of any one of embodiments 1 to 143, wherein the compound is any one of compounds 1A to 28A of Table 2, or a pharmaceutically acceptable salt thereof. E148. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 147 and a pharmaceutically acceptable excipient. E149. 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 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. E150. The method of embodiment 149, wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophogeal, stomach, or lung cancer. E151. The method of embodiment 150, wherein the cancer is gastric cancer. E152. A method of treating gastric 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 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. E153. The method of any one of embodiments 149 to 152, wherein the cancer is metastatic. E154. The method of any one of embodiments 149 to 153, wherein the subject or cancer has a EP300 loss of function mutation. E155. The method of any one of embodiments 149 to 154, wherein the method further comprises administering to the subject an anticancer therapy. E156. The method of embodiment 155, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof. E157. A method of treating inflammatory and/or autoimmune disorders 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 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. E158. The method of embodiment 157, wherein the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis. E159. The method of embodiment 157 or 158, wherein the method further comprises administering to the subject a JAK inhibitor. E160. The method of embodiment 159, wherein the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib. E161. A method of treating a disease, disorder, or medical condition mediated by member of the JAK- STAT pathway, the method including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. E162. The method of embodiment 161, wherein the member of the JAK-STAT pathway is a janus kinase (JAK). E163. The method of embodiment 162, wherein the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT). E164. The method of embodiment 163, wherein the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis. E165. A method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. E166. A method for inhibiting an inflammatory or autoimmune response in a subject in need thereof, including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. E167. A method of suppressing a memory CD8+ T cell response in a subject in a subject having or at risk of developing an inflammatory response, including administering to the subject an effective amount of a compound of any one of embodiments 1 to 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. E168. A method of treating an infection 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 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. E169. The method of embodiment 109, wherein the infection is Herpesvirus K*. E170. A method of treating rubinstein taybi syndrome 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 147, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 148. Other Embodiments While the invention has been described in connection with specific embodiments thereof, it will be 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. Other embodiments are in the claims.

Claims

CLAIMS 1. A compound having the structure of Formula I: A-L-B Formula I, wherein A is a CBP binding moiety; B is a degradation moiety; and L has the structure of Formula II: A1–(F)–(E)m–C-A2, Formula II wherein A1 is a bond between the linker and A; A2 is a bond between B and the linker; m is 0 or 1; C is, independently, absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; E is, independently, absent, O, S, NRN, optionally substituted C1–C10 alkylene, optionally substituted C2– C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene; each RN is, independently, H, optionally substituted C1–C4 alkyl, optionally substituted C2–C4 alkenyl, optionally substituted C2–C4 alkynyl, optionally substituted C2–C6 heterocyclyl, optionally substituted C6– C12 aryl, or optionally substituted C1–C7 heteroalkyl; F is, independently, optionally substituted C3-C10 carbocyclylene, optionally substituted C2-C10 heterocyclylene, optionally substituted C6-C10 arylene, or optionally substituted C2-C9 heteroarylene, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein the CBP binding moiety has the structure of Formula III
Figure imgf000591_0001
Formula III wherein X1a is, independently, C or N; R1a and R1b, independently, combine with the atoms to which they are attached to form an optionally substituted C3-C10 carbocycle, an optionally substituted C5-C10 aryl, an optionally substituted C3-C9 heteroaryl, or optionally substituted C3-C9 heterocycle, wherein the carbocycle, aryl, heteroaryl or heterocycle is optionally substituted with A1 and/or one or more of the following groups: halogen, C1–C6 alkyl, C5-C10 aryl, C2-C9 heteroaryl, C2-C9 heterocycle, C3-C10 carbocycle, C(O)N(R1e)2, S(O)N(R1e)2, S(O)2N(R1e)2, OR1e, C(O)R1e, C(O)OR1e, S(O)R1e, S(O)2R1e, SR1e, OC(O)R1e, OC(O)OR1e, OC(O)N(R1e)2, N(R1e)C(O)N(R1e)2, N(R1e)C(O)OR1e, N(R1e)C(O)R1e, N(R1e)S(O)R1e, N(R1e)S(O)2R1e, N(R1e)S(O)N(R1e)2, or N(R1e)S(O)N(R1e)2; wherein any C1–C6 alkyl, C5-C10 aryl, C2-C9 heteroaryl, C2-C9 heterocycle, C3-C10 carbocycle is optionally substituted A1 and/or one or more substituent groups independently selected from halogen, C1–C6 alkyl, C2-C9 heteroaryl, C3-C12 carbocycle, C2-C9 heterocycle, C(O)N(R1e)2, S(O)N(R1e)2, S(O)2N(R1e)2, C(O)R1e, C(O)OR1e, S(O)R1e, or S(O)2R1e. R1c is, independently, A1, NR2aR3a, C6-C20 aryl, C2-C9 heterocyle, 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-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 R1h, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(R1f)2, CN, C(O)N(R1f)2, S(O)N(R1f)2, S(O)2N(R1f)2, OR1f, SR1f, OC(O)R1f, OC(O)OR1f, C(O)R1f, C(O)OR1f, S(O)R1f, S(O)2R1f, OC(O)N(R1f)2, N(R1f)C(O)OR1f, N(R1f)C(O)N(R1f)2, N(R1a1)C(O)R1f, N(R1f)S(O)R1f, N(R1f)S(O)2R1f, N(R1f)S(O)N(R1f)2, and N(R1f)S(O)2N(R1f)2; R1d is, independently, C1-C12 alkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1d is optionally substituted with one or more groups R1g; each R1e 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; R2a is, independently, H, C1-C12 alkyl, C5-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-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 R1k, oxo, F, Cl, Br, I, NO2,N(R1j)2, CN, C(O)N(R1j)2, S(O)N(R1j)2, S(O)2N(R1j)2, OR1j, SR1j, OC(O)R1j, OC(O)OR1j, C(O)R1j, C(O)OR1j, S(O)R1j, S(O)2R1j, OC(O)N(R1j)2, N(R1j)C(O)OR1j, N(R1j)C(O)N(R1j)2, N(R1j)C(O)R1j, N(R1j)S(O)R1j, N(R1j)S(O)2R1j, N(R1j)S(O)N(R1j)2, and N(Ra)S(O)2N(R1j)2; R3a is, independently, 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-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3a is optionally substituted with A1 and/or one or more groups R1k; or R2a and R3a of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups R1k; each R1f is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C9 carbocyclyl, and C2-C9 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 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 independently selected from oxo and halo; or two R1f are taken together with the nitrogen to which they are attached to form a 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; each R1g is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C9 carbocyclyl, C2-C9 heterocyclyl, C5-C9 aryl, C1-C20 heteroaryl, F, Cl, Br, I, NO2, N(R1L)2, CN, C(O)N(R1L)2, S(O)N(R1L)2, S(O)2N(Rc)2, OR1L, SR1L, OC(O)OR1L, OC(O)OR1L, C(O)R1L, C(O)OR1L, S(O)R1L, S(O)2R1L, OC(O)N(R1L)2, N(R1L)C(O)OR1L, N(R1L)C(O)N(R1L)2, N(R1L)C(O)R1L, N(R1LS(O)R1L, N(R1L)S(O)2R1L, N(R1L)S(O)N(R1L)2, or N(R1L)S(O)2N(R1L)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(R1L)2, CN, C(O)N(R1L)2, S(O)N(R1L)2, S(O)2N(R1L)2, OR1L, SR1L, OC(O)R1L, C(O)R1L, S(O)R1L,S(O)2R1L, C(O)N(R1L)2, N(R1L)C(O)R1L, N(R1L)S(O)R1L, N(R1L)S(O)2R1L and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each R1h is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R1M)2, CN, C(O)N(R1M)2, S(O)N(R1M)2, S(O)2N(R1M)2, OR1M, SR1M, OC(O)R1M, C(O)R1M, C(O)OR1M, S(O)R1M, S(O)R1M, C(O)N(R1M)2, N(R1M)C(O)R1M, N(R1M)S(O)R1M, N(R1M)S(O)2R1M, 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(R1M)2, OR1M, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each R1j is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or 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 independently selected from oxo and halo; or two R1j are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo and C1–C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; each R1k is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(R1N)2, CN, CHF2, CF3, C(O)N(R1N)2, S(O)N(R1N)2, S(O)2N(R1N)2, OR1N, SR1N, OC(O)R1N, C(O)R1N, C(O)OR1N, S(O)R1N, S(O)2R1Nd, C(O)N(R1N)2, N(R1N)C(O)R1N, N(R1N)S(O)R1N, N(R1N)S(O)2R1N, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(R1N)2, OR1N, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each R1M is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected 589 from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd2 are taken together with the nitrogen to which they are attached to form a 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; each R1N is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C 6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R1N are taken together with the nitrogen to which they are attached to form a 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 one and only one of R1a, R1b, R1c, or R1d comprises A1. 3. The compound of claim 2, wherein the CBP binding moiety of Formula III has the structure:
Figure imgf000594_0001
4. The compound of claim 2 or 3, wherein the CBP binding moiety of Formula III has the structure:
Figure imgf000595_0001
6. The compound of any one of claims 2 to 4, wherein
Figure imgf000596_0001
,
Figure imgf000596_0002
8. The compound of claim 2, wherein the CBP binding moiety of Formula III has the structure:
Figure imgf000597_0001
9. The compound of claim 2, wherein the CBP binding moiety of formula III has the structure:
Figure imgf000598_0001
, , or
Figure imgf000599_0001
. 10. The compound of claim 2, wherein the CBP binding moiety of formula III has the structure:
Figure imgf000599_0002
Formula III-A wherein: R8 is, independently, C1–C12 alkyl, C3–C12 carbocycle, or C3–C12 heterocycle, wherein each C1–C12 alkyl, C3-C12 carbocycle, and C3-C12 heterocycle is optionally substituted with one or more groups Ro; R9 is, independently, C1-C4 alkyl, C(O)N(Rh2)2, S(O)N(Rh2)2, S(O)2, C(O)Rh2, C(O)ORh2, S(O)2Rh2, C2–C6 heteroaryl, or C2-C9 heterocycle wherein any C1-C4alkyl, C2–C6 heteroaryl, or C2-C9 heterocycle is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, C3–C5 carbocycle, C(O)N(Rh2)2, S(O)2N(Rh2)2, ORh2, S(O)2Rh2, OC(O)Rh2, C(O)ORh2, N(Rh2)2, N(Rh2)2, N(Rh2)C(O)N(Rh2)2, N(Rh2)S(O)2Rh2, N(Rh2)S(O)N(Rh2)2, and N(Rh2)S(O)2N(Rh2)2; R10 is, independently, C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1- C20 heteroaryl)(C6-C20 aryl), and (C1-20 heteroaryl)(C1-20 heteroaryl), wherein each C6-C20 aryl, C1- C20 heteroaryl, (C6-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 Rp, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Ra2)2, CN, C(O)N(Ra2)2, S(O)N(Ra2)2, S(O)2N(Ra2)2, N(Ra2)C(O)ORa2)C(O)N(Ra2), C(O)N(Ra2), S(O)2Ra2, N(Ra2)S(O)N(Ra2)2, and N(Ra2)S(O)2N(Ra2)2; each Ra2 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C2-C12 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C2-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, or C1–C6 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; or two Ra2 are taken together with the nitrogen to which they are attached to form a 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; each RO is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, C2-C9 heteroaryl, F, Cl, Br, I, NO2, N(RP)2, CN, C(O)N(RP)2, S(O)N(RP)2, S(O)2N(RP)2, ORP, SRP, OC(O)ORP, OC(O)ORP, C(O)RP, C(O)ORP, S(O)RP, S(O)2RP, OC(O)N(RP)2, N(RP)C(O)ORP, N(RP)C(O)N(RP)2, N(RP)C(O)RP, N(RP)S(O)RP, N(RP)S(O)2RP, N(RP)S(O)N(RP)2, or N(RP)S(O)2N(RP)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, and C2-C9 heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, NO2, N(RP)2, CN, C(O)N(RP)2, S(O)N(RP)2, S(O)2N(RP)2, ORP, SRP, OC(O)RP, C(O)RP, S(O)RP, S(O)2RP, C(O)N(RP)2, N(RP)C(O)RP, N(RP)S(O)RP, N(Rc2)S(O)2Rc2 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RP 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, carbocyclyl, heterocyclyl, halo, NO2, N(Rd2)2, CN, C(O)N(Rd2)2, S(O)N(Rd2)2, S(O)2N(Rd2)2, ORd2, SRd2, C(O)Rd2, S(O)2Rd2, C(O)N(Rd2)2, N(Rd2)2, N(Rd2)S(O)Rd2, N(Rd2)S(O)2Rd2, and C1–C6 alkyl, which C3–C12 carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd2)2, ORd2, C3-C12 heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6 alkyl; each Rd2 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1C–6 alkoxy, carbocyclyl, or 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, C1C-6 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 Rd2 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; each Rh2 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; and wherein R10 comprises A1.
11. The compound of claim 10, wherein R8 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R8 is optionally substituted with one or more groups RO.
Figure imgf000601_0001
14. The compound of any one of claims 10 to 13, wherein R9 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. 15. The compound of any one of claims 10 to 14, wherein R9 has the structure:
Figure imgf000601_0002
. 16. The compound of any one of claims 10 to 15, wherein the CBP binding moiety has the structure:
Figure imgf000602_0001
. 17. The compound of any one of claims 10 to 16, wherein R10 has the structure:
Figure imgf000602_0002
, wherein X3 is NRN2, CH2, or O; X4 is N, CH; X5 is N, CH; X6 is NRN2, CH2, or O; R14 is CHF2, CHCl2, CH3, Cl, F, or H, and each RN2 is independently, C1-C3 alkyl or H. 18. The compound of claim 17, wherein X3 is CH2 and X4 is CH. 19. The compound of any one of claims 10 to 18, wherein R10 has the structure:
Figure imgf000602_0003
,
Figure imgf000602_0004
,
Figure imgf000603_0001
21. The compound of any one of claims 10 to 20, wherein the CBP binding moiety has the structure:
Figure imgf000603_0002
,
Figure imgf000604_0001
22. The compound of claim 2, wherein the CBP binding moiety of Formula III has the structure:
Figure imgf000604_0002
Formula III-B wherein: R1 is, independently, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C2-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C2-C12 heterocycle of R1 is optionally substituted with A1 and/or one or more groups Rb; R2 is, independently, 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-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)2—N(Ra)2, N(Ra)C(O)—O—Ra)C(O)N(Ra)— C(O)—N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is, independently, C1-C12alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3- 12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; R4 is, independently, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)—O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, and C2-C5 heterocycle is optionally substituted with A1 and/or one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)— N(Rh)2, S(O)2N(Rh)2, —O)ORh, C(O—C(O)—Rh, —O—C(O)—O—Rh, —C(O)ORh, N(Rh)2, —N(Rh)2, N(Rh)C(O)—N(Rh)S(O)Rh, —N(Rh)—S(O)—Rh, —N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each 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, halo, amino, hydroxyl, C1–C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1–C6 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a 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; each Rb is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2— N(Rc)2, N(Rc)C(O)—Rc)C(O)N(Rc, —S(O)Rc, —S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(Rc)S(O)2N(Rc)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, and C2-C12 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, —C(O)—N(Rc)2, N(Rc)C(O)2—N(Rc)S(O)Rc, N(Rc)S(O)2Rc and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc 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 A1 and/or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, —N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2—N(Rd)2, —O—Rd, — S—Rd, C(O)—Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, —N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which C3–C12 carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, C3-C12 heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd 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 A1 and/or 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 Rd are taken together with the nitrogen to which they are attached to form a 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; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C12 carbocyclyl, C3–C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, carbocycle, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or 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, carbocyclyl, heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, SRg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which C3-C12 carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 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 A1 and/or 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 Rg1 are taken together with the nitrogen to which they are attached to form a 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 A1 and/or one or more groups independently selected from halo; wherein one and only one of R1, R2, R3, or R4 comprises A1. 23. The compound of claim 22, wherein: R1 is, independently, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C3-C12 heterocycle, wherein each C1–C12 alkyl, C2–C12 alkenyl, C2–C12 alkynyl, C3–C12 carbocycle, and C3–C12 heterocycle is optionally substituted with A1 and/or one or more groups Rb; R2 is, independently, C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1- C20 heteroaryl)(C6-C20 aryl), or (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1- C20 heteroaryl, (C6-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, N(Ra)C(O)ORa)C(O)N(Ra)C(O)N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is, independently, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C3-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C3-C12 heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups Re; R4 is, independently, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, C3-C5 heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2, C(O)Rh, C(O)—O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, and C3-C5 heterocycle is optionally substituted with A1 and/or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)—N(Rh)2, — S(O)—N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)2, —N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a 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; each Rb 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(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2— N(Rc)2, N(Rc)C(O)—O)N(Rc)2, IRc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)—N(Rc)S(O)N(Rc)2, or N(R)S(O)2N(Rc)2, wherein any C1C-6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, —N(Rc)2, N(Rc)C(O)—N(Rc)S(O)2—N(Rc)S(O)2Rc and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc 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 A1 and/or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2—N(Rd)2, —O—Rd, —S— Rd, C(O)—Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)2, —N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl; each Rd 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 A1 and/or 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 Rd are taken together with the nitrogen to which they are attached to form a 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; 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(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, —C(O)—Rf1, C(O)ORf1, S(O)Rf1, S(O)2—Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-9 aryl, and C2-10 heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)—Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, carbocycle, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 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 C3C-12 heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)—N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, SRg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, —S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 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 A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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 A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C3 alkoxy, and C1- C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from halo. 24. The compound of claim 22 or 23, wherein R1 is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1 is optionally substituted with one or more groups Rb.
Figure imgf000609_0003
The compound of any one of claims 22 to 24, wherein
Figure imgf000609_0001
. 27. The compound of any one of claims 22 to 26, wherein R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1 and/or one or more groups Re. 28. The compound of any one of claims 22 to 27, wherein R2 and R3 taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1 and/or one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring. 29. The compound of any one of claims 22 to 28, wherein NR2R3 taken together has the structure:
Figure imgf000609_0002
Figure imgf000610_0001
. 30. The compound of any one of claims 22 to 29, wherein R4 is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. 31. The compound of any one of claims 22 to 30, wherein R4 has the structure:
Figure imgf000610_0002
. 32.
Figure imgf000610_0003
of claims 22 to 31, wherein the CBP binding moiety has the structure:
Figure imgf000610_0004
,
Figure imgf000611_0001
Figure imgf000612_0001
33. The compound of claim 2, wherein the CBP binding moiety has the structure:
Figure imgf000612_0002
Formula III-C wherein: X1 is C or N; X2 is C or N; R5 is, independently, C1-C12alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R5 is optionally substituted with one or more groups Rk1k; R6 is, independently, C1-4alkyl, 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), C(O)N(Rh1)2, S(O)N(Rh1)2, S(O)2N(Rh1)2, C(O)Rh1, C(O)ORh1, S(O)Rh1, or S(O)2Rh1, wherein , wherein C1-C4 alkyl, C6-C20 aryl, C1- C20 heteroaryl, (C6-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 F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh1)2, S(O)N(Rh1)2, S(O)2N(Rh1)2, ORh1, SRh1, OC(O)Rh1, OC(O)ORh1, C(O)Rh1, C(O)ORh1, S(O)Rh1, S(O)2Rh1, OC(O)N(Rh1)2, N(Rh1)C(O)ORh1, N(Rh1)C(O)N(Rh1)2, N(Rh1)C(O)Rh1, N(Rh1)S(O)Rh1, N(Rh1S(O)2Rh1, N(Rh1)S(O)N(Rh1)2, and N(Rh1)S(O)2N(Rh1)2; R7 is, independently, NR2R3, 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-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 RL1, oxo, F, Cl, Br, I, NO2, N(Ra1)2, CN, C(O)N(Ra1)2, S(O)N(Ra1)2, S(O)2N(Ra1)2, ORa1, SRa1, OC(O)Ra1, OC(O)ORa1, C(O)Ra1, C(O)ORa1, S(O)Ra1, S(O)Ra1, OC(O)N(Ra1)2, N(Ra1)C(OORa1, N(Ra1)C(O)N(Ra1)2, N(Ra1)C(O)Ra1, N(Ra1)S(O)Ra1, N(Ra1)S(O)2Ra1, N(Ra1)S(O)N(Ra1)2, and N(Ra1)S(O)2N(Ra1)2; R2 is, independently, C6-C20 aryl, C1-C20 heteroaryl, (C6-20 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-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, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is, independently, 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–C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or 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 independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; each Rc is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6a lkyl; each Rd is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a 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; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)—N(Rf1)2,S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1S(O)2Rf1, carbocycle, and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, Rg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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; each Ra1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 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 independently selected from oxo and halo; or two Ra1 are taken together with the nitrogen to which they are attached to form a 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; each Rk1 is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RL1)2, CN, C(O)N(RL1)2, S(O)N(RL1)2, S(O)2N(RL1)2, ORL1, SRL1, OC(O)ORL1, OC(O)ORL1, C(O)RL1, C(O)ORL1, S(O)RL1, S(O)2RL1, OC(O)N(RL1)2, N(RL1)C(O)ORL1, N(RL1)C(O)N(RL1)2, N(RL1)C(O)RL1, N(RL1)S(O)RL1, N(RL1)S(O)RL1, N(RL1)S(O)N(RL1)2, or N(RL1)S(O)2N(RL1)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(RL1)2, CN, C(O)N(RL1)2, S(O)N(RL1)2, S(O)2N(RL1)2, ORL1, SRL1, OC(O)RL1, C(O)RL1, S(O)RL1, S(O)2RL1, C(O)N(RL1)2,N(RL1)C(O)RL1, N(RL1)S(O)RL1, N(RL1)S(O)2RL1 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RL1 is, independently, hydrogen, C1–C6 alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd1)2, CN, C(O)N(Rd1)2, S(O)N(Rd1)2, S(O)2N(Rd1)2, ORd1, SRd1, OC(O)Rd1, C(O)Rd1, C(O)Rd1, S(O)Rd1, S(O)2Rd1, C(O)N(Rd1)2, N(Rd1)C(O)Rd1, N(Rd1)S(O)Rd1, N(Rd1)S(O)2Rd1, 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(Rd1)2, ORd1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd1 are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rh1 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 C2–5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C4 alkyl that is optionally substituted with one or more groups independently selected from halo; and wherein R7 comprises A1.
Figure imgf000616_0001
36. The compound of claim 1, wherein the CBP binding moiety has the structure:
Figure imgf000617_0001
Formula IV wherein: R11 is, independently, C1-C12 alkyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R11 is optionally substituted with one or more groups RM; R12 is, independently, C1-C4 alkyl, C(O)N(Rh3)2, S(O)N(Rh3)2, S(O)N(Rh3)2, C(O)Rh3, C(O)ORh3, S(O)Rh3, or S(O)Rh3, wherein any C1-C4alkyl is optionally substituted one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh3)2, S(O)N(Rh3)2, S(O)2N(Rh3)2, ORh3, SRh3, OC(O)Rh3, OC(O)ORh3, C(O)Rh3, C(O)ORh3, S(O)Rh3, S(O)2Rh3, OC(O)N(Rh3)2, N(Rh3)C(O)ORh3, N(Rh3)C(O)N(Rh3)2, N(Rh3)C(O)Rh3, N(Rh3)S(O)Rh3, N(Rh3)S(O)2Rh3, N(Rh3)S(O)N(Rh3)2, and N(Rh3)S(O)2N(Rh3)2; R13 is, independently, NR2R3, 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-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 RN1, oxo, F, Cl, Br, I, NO2, N(Ra3)2, CN, C(O)N(Ra3)2, S(O)N(Ra3)2, S(O)2N(Ra3)2, ORa3, SRa3, OC(O)Ra3, OC(O)ORa3, C(O)Ra3, C(O)ORa3, S(O)Ra3, S(O)2Ra3, OC(O)N(Ra3)2, N(Ra3)C(O)ORa3, N(Ra3)C(ON(Ra3)2, N(Ra3)C(O)Ra3, N(Ra3)S(O)Ra3, N(Ra3)S(O)2Ra3, N(Ra3)S(O)N(Ra3)2, and N(Ra3)S(O)2N(Ra3)2; R2 is, independently, C6-C20 aryl, C1-C20 heteroaryl, (C6-20 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-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, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3 is, independently, 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-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with A1 and/or one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and/or one or more groups Re; each Ra is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or 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 independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with A1 and/or one or more groups independently selected from oxo and halo; each Rc is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6a lkyl; each Rd is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1–C 3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Re is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rf1)2, CN, C(O)N(Rf1)2, S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, OC(O)ORf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, OC(O)N(Rf1)2, N(Rf1)C(O)ORf1, N(Rf1)C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1)S(O)2Rf1, N(Rf1)S(O)N(Rf1)2, or N(Rf1)S(O)2N(Rf1)2, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, NO2, N(Rf1)2, CN, C(O)—N(Rf1)2,S(O)N(Rf1)2, S(O)2N(Rf1)2, ORf1, SRf1, OC(O)Rf1, C(O)Rf1, C(O)ORf1, S(O)Rf1, S(O)2Rf1, C(O)N(Rf1)2, N(Rf1)C(O)Rf1, N(Rf1)S(O)Rf1, N(Rf1S(O)2Rf1, carbocycle, and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rg1)2, CN, C(O)N(Rg1)2, S(O)N(Rg1)2, S(O)2N(Rg1)2, ORg1, Rg1, OC(O)Rg1, C(O)Rg1, C(O)ORg1, S(O)Rg1, S(O)2Rg1, C(O)N(Rg1)2, N(Rg1)C(O)Rg1, N(Rg1)S(O)Rg1, N(Rg1)S(O)2Rg1, and C1–C6 alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rg1)2, ORg1, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rg1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1 and/or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg1 are taken together with the nitrogen to which they are attached to form a 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; each Ra3 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6alkynyl, 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 independently selected from oxo and halo; or two Ra3 are taken together with the nitrogen to which they are attached to form a 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; each RM is, independently, oxo, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(RN1)2, CN, C()N(RN1)2, S(O)N(RN1)2, S(O)2N(Rc)2, ORN1, SRN1, OC(O)ORN1, OC(O)ORN1, C(O)RN1, C(O)ORN1, S(O)RN1, S(O)2RN1, OC(O)N(RN1)2, N(RN1)C(O)ORN1, N(RN1)C(O)N(RN1)2, N(RN1)C(O)RN1, N(RN1)S(O)RN1, N(RN1)S(O)2RN1, N(RN1)S(O)N(RN1)2, or N(RN1)S(O)2N(RN1)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(RN1)2, CN, C(O)N(RN1)2, S(O)N(RN1)2, S(O)2N(RN1)2, ORN1, SRN1, OC(O)RN1, C(O)RN1, S(O)RN1, S(O)2RN1,C(O)N(RN1)2, N(RN1)C(O)RN1, N(RN1)S(O)RN1, N(RN1)S(O)2RN1 and C1–C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RN1 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd3)2, CN, C(O)N(Rd3)2, S(O)N(Rd3)2, S(O)2N(Rd3)2, ORd3, SRd3, OC(O)Rd3, C(O)Rd3, C(O)ORd3, S(O)Rd3, S(O)2Rd3, C(O)N(Rd3)2, N(Rd3)C(O)Rd3, N(Rd3)S(O)Rd3, N(Rd3)S(O)2Rd3, and C1-6alkyl, which carbocyclyl and C1–C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1–C6 alkyl, cyano, N(Rd3)2, ORd3, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1–C6 alkyl; each Rd3 is, independently, hydrogen, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, or heterocyclyl, wherein each C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1–C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd3 are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rh3 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; and wherein R13 comprises A1. 37. The compound of claim 36, wherein
Figure imgf000620_0001
. 38. The compound of claim 37, wherein the CBP binding moiety of Formula IV has the structure:
Figure imgf000620_0002
40. The compound of any one of claims 36 to 39, wherein R13 C1-C20 heteroaryl.
Figure imgf000621_0001
. The compound of any one of claims 36 to 40, wherein
Figure imgf000621_0002
, ,
Figure imgf000621_0003
43. The compound of any one of claims 36 to 40, wherein
Figure imgf000621_0004
.
44. The compound of claim 36, wherein the CBP binding moiety of Formula IV has the structure:
Figure imgf000622_0001
45. The compound of any one of claims 1 to 44, wherein the degradation moiety is a ubiquitin ligase binding moiety. 46. The compound of claim 45, 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. 47. The compound of any one of claims 1 to 46, wherein the degradation moiety comprises the structure of Formula V:
Figure imgf000623_0001
Formula V, wherein RB1a is, independently, H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3a is, independently, A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4a is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5a is, independently, H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; RB6a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one and only one of RB1a and RB3a is A2 or C(O)A2. 48. The compound of claim 47, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-A):
Figure imgf000623_0002
Formula V-A, wherein RB1a is, independently, H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3a is, independently, A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4a is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB6a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one and only one of RB1a and RB3a is A2 or C(O)A2. 49. The compound of claim 47, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-B):
Figure imgf000624_0001
Formula V-B, wherein RB1a is, independently, H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3a is, independently, A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4a is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5a is, independently, H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; RB6a is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one and only one of RB1a and RB3a is A2 or C(O)A2. 50. The compound of any one of claims 47 to 49, wherein
Figure imgf000624_0002
, wherein each RB6 is, independently, 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol; RB9 is, independently, H, or optionally substituted C1–C6 alkyl; RB10 is, independently, H, or optionally substituted C1–C6 alkyl, and v2 is 0, 1, 2, 3, or 4. 51. The compound of any one of claims 47 to 50, wherein RB6a is
Figure imgf000625_0001
. 52. The compound of any one of claims 47 to 50, wherein
Figure imgf000625_0002
. 53. The compound of any one of claims 47 to 50, wherein
Figure imgf000625_0003
54. The compound of any one of claims 47 to 50, wherein RB6 is
Figure imgf000625_0004
, . 55. The compound of any one of claims 47 to 50, wherein
Figure imgf000625_0005
, wherein each RB6 is, independently, 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol; RB11 is, independently, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl; RB9 is, independently, H, or optionally substituted C1-C6 alkyl; RB10 is, independently, H, or optionally substituted C1–C6 alkyl, and v2 is 0, 1, 2, 3, or 4. 56. The compound of any one of claims 47 to 55, wherein
Figure imgf000625_0006
57. The compound of any one of claims 47 to 55, wherein RB11 is
Figure imgf000625_0007
, .
58. The compound of any one of claims 47 to 55, wherein
Figure imgf000626_0001
, wherein v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, 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, hydroxy, thiol, or optionally substituted amino; each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl; and RB9 and RB10 are, independently, H, or optionally substituted C1–C6 alkyl. 59. The compound of any one of claims 47 to 58, wherein
Figure imgf000626_0002
,
Figure imgf000626_0003
60. The compound of claim 47, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula V-C:
Figure imgf000627_0001
Formula V-C, RB1 is, independently, H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is, independently, A2, C(O)A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl, C3-C10 carbocyclyl, or optionally substituted C1–C6 alkyl wherein the C1–C6 alkyl, C1–C6 heteroalkyl, C3-C10 carbocyclyl, C6-C10 aryl, C1–C6 alkyl, C3-C10 carbocyclyl, or C6-C10 aryl is substituted with A2 and/or one of more groups of RJ2; RB4 is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C1–C6 alkyl, optionally substituted C3- C10 carbocyclyl, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl; RB5 is, independently, H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, halogen, optionally substituted C1–C6 alkyl, optionally substituted C1-6 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, optionally substituted C2-C6 alkynyl, hydroxy, thiol, RB9 is, independently, H, or optionally substituted C1–C6 alkyl; each RJ2 is, independently, hydrogen, optionally substituted C1–C6 alkyl, optionally substituted C3-C12 carbocyclyl, and optionally substituted C3-C12 heterocyclyl, wherein each C1–C6 alkyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, thio, C1–C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1–C6 alkyl that is optionally substituted with A2 and/or one or more groups independently selected from oxo and halo; wherein one and only one of RB1 and RB3 is A2 or C(O)A2, or a pharmaceutically acceptable salt thereof. 61. The compound of claim 60, wherein RB6 is optionally substituted C2-C9 heteroaryl. 62. The compound of claim 60 or 61, wherein RB6 is:
Figure imgf000628_0001
63. The compound of any one of claims 60 to 62, wherein the structure of Formula V-C is
Figure imgf000628_0002
,
Figure imgf000628_0003
, or a derivative or analog thereof. 64. The compound of claim 60, wherein RB6 is halogen or optionally substituted C2-C6 alkynyl. 65. The compound of claim 60, wherein RB6 is optionally substituted C1–C6 heteroalkyl. 66. The compound of claim 65, wherein the optionally substituted C1–C6 heteroalkyl is methoxy. 67. The compound of claim 65 or 66, wherein the structure of Formula V-C is
Figure imgf000628_0004
, , or a derivative or analog thereof.
68. The compound of claim 48, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula V-D:
Figure imgf000629_0001
Formula V-D, wherein RB1 is, independently, H, A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB2 is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is, independently, A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4 is, independently, H, optionally substituted C1-6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5 is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each RB6 is, independently, 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, hydroxy, thiol, or optionally substituted amino; and each of RB7 and RB8 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl, RB9 and RB10 are, independently, H, or optionally substituted C1–C6 alkyl, wherein one and only one of RB1 and RB3 is A2, or a pharmaceutically acceptable salt thereof. 69. The compound of claim 68, wherein the structure of Formula V-D is
Figure imgf000629_0002
,
Figure imgf000630_0001
, or derivative or analog thereof. 70. The compound of claim 69, wherein the degradation moiety has the structure:
Figure imgf000630_0002
. 71. The compound of claim 69, wherein the degradation moiety has the structure:
Figure imgf000631_0001
. 72. The compound of claim 48, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula V-E:
Figure imgf000631_0002
Formula V-E RC1 is, independently, optionally substituted C1–C6 alkyl; RC2 is, independently, A2, or optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, wherein each C1–C6 alkyl, C3-10 carbocyclyl, C1–C6 heteroalkyl, C6-C10 aryl, or C2-C9 heteroaryl is optionally substituted with A2 and/or one or more groups RJ; RC3 is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RC4 is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each of RC5 and RC6 is, independently, H, or optionally substituted C1–C6 alkyl each RC7 is, independently, 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 C2-9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and each of RC8 and RC9 is, independently, H, halogen, optionally substituted C1–C6 alkyl, or optionally substituted C6-C10 aryl, each RJ is, independently, hydrogen, C1–C6 alkyl, C3-C6 carbocyclyl, and C2–C6 heterocyclyl, wherein each C1–C6 alkyl, C3-C6 carbocyclyl, and C2–C6 heterocyclyl is optionally substituted with one or more groups independently selected from amino, hydroxyl, C1–C6 alkoxy, C3-C6 carbocyclyl, C2–C6 heterocyclyl, or C1–C6 alkyl that is optionally substituted with A2 and/or one or more groups independently selected from oxo and halo; or a pharmaceutically acceptable salt thereof. 73. The compound of claim 72, wherein the linker-degradation moiety has the structure:
Figure imgf000632_0001
74. The compound of claim 48, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula V-F:
Figure imgf000632_0002
Formula V-F, wherein RB1 is, independently, H, A2, C(O)A2, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl; RB3 is, independently, A2, C(O)A2, optionally substituted C1–C6 alkyl, optionally substituted C1–C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB4 is, independently, H, optionally substituted C1–C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; RB5 is, independently, H, optionally substituted C1–C6 alkyl, or optionally substituted C1–C6 heteroalkyl or arylalkyl; wherein one and only one of RB1 and RB3 is A2 or C(O)A2, or a pharmaceutically acceptable salt thereof.
75. The compound of claim 74, wherein the degradation moiety has the structure of Formula V-F is
Figure imgf000633_0001
or a derivative or analog thereof. 76. The compound of any one of claims 1 to 75, wherein L has the structure of Formula II: A1–(F)–(E)m–C-A2, Formula II wherein A1 is a bond between the linker and A; A2 is a bond between B and the linker; m is 0 or 1; C is, independently, absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; E is, independently, absent, optionally substituted C1–C10 alkylene; and F is, independently, optionally substituted C2–C10 heterocyclylene or optionally substituted C2-C9 heteroarylene. 77. The compound of any one of claims 1-76, wherein m is 0. 78. The compound of any one of claims 1-76, wherein m is 1. 79. The compound of any one of claims 1 to 77 or 79, wherein E is methylene, ethylene,
Figure imgf000633_0002
,
Figure imgf000633_0003
80. The compound of any one of claims 1 to 79, wherein C is carbonyl. 81. The compound of any one of claims 1 to 79, wherein C is absent. 82. The compound of any one of claims 1 to 81, wherein F is optionally substituted C2-C10 heterocyclylene.
83. The compound of claim 82, wherein F is:
Figure imgf000634_0001
84. The compound of any one of claims 1 to 81, wherein F is optionally substituted C2-C9 heteroarylene. 85. The compound of claim 84, wherein F is the structure:
Figure imgf000634_0002
, wherein X7 and X8 are each independently C or N; R17 is, independently, H, optionally substituted C1–C6 alkyl or A1; and R15 and R16 combine with the atoms to which they are attached to form an optionally substituted C3-C12 heteroaryl, wherein the C3-C12 heteroaryl is optionally substituted with A1 and/or one or more of the following groups: halogen or C1–C6 alkyl. 86. The compound of claim 84, wherein F is
Figure imgf000634_0003
,
Figure imgf000635_0001
87. The compounds of any one of claims 1 to 86, wherein the compound is any one of compounds 1 to 536 of Table 1, or a pharmaceutically acceptable salt thereof. 88. The compound of any one of claims 1 to 86, wherein the compound is any one of compounds 1A to 28A of Table 2, or a pharmaceutically acceptable salt thereof. 89. A pharmaceutical composition comprising a compound of any one of claims 1 to 88 and a pharmaceutically acceptable excipient. 90. 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 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 89. 91. The method of claim 90, wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophogeal, stomach, or lung cancer. 92. The method of claim 91, wherein the cancer is gastric cancer. 93. A method of treating gastric 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 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 89. 94. The method of any one of claims 90 to 93, wherein the cancer is metastatic. 95. The method of any one of claims 90 to 94, wherein the subject or cancer has a EP300 loss of function mutation. 96. The method of any one of claims 90 to 95, wherein the method further comprises administering to the subject an anticancer therapy. 97. The method of claim 96, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof.
98. A method of treating inflammatory and/or autoimmune disorders 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 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 89. 99. The method of claim 98, wherein the inflammatory and/or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non- anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis. 100. The method of claim 98 or 99, wherein the method further comprises administering to the subject a JAK inhibitor. 101. The method of claim 100, wherein the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib. 102. A method of treating a disease, disorder, or medical condition mediated by member of the JAK- STAT pathway, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 89. 103. The method of claim 102, wherein the member of the JAK-STAT pathway is a janus kinase (JAK). 104. The method of claim 102, wherein the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT). 105. The method of claim 102, wherein the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, aicardi goutieres syndrome, sjogren's syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis. 106. A method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound of any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 89.
107. A method for inhibiting an inflammatory or autoimmune response in a subject in need thereof, including administering to the subject an effective amount of a compound of any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 89. 108. A method of suppressing a memory CD8+ T cell response in a subject in a subject having or at risk of developing an inflammatory response, including administering to the subject an effective amount of a compound of any one of claims 1 to 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 89. 109. A method of treating an infection 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. 110. The method of claim 109, wherein the infection is Herpesvirus K*. 111. A method of treating rubinstein taybi syndrome 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 88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 89.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180327419A1 (en) * 2016-09-29 2018-11-15 Dana-Farber Cancer Institute, Inc. Targeted protein degradation using a mutant e3 ubiquitin ligase
WO2022081928A1 (en) * 2020-10-14 2022-04-21 C4 Therapeutics, Inc. Tricyclic heterobifunctional compounds for degradation of targeted proteins

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180327419A1 (en) * 2016-09-29 2018-11-15 Dana-Farber Cancer Institute, Inc. Targeted protein degradation using a mutant e3 ubiquitin ligase
WO2022081928A1 (en) * 2020-10-14 2022-04-21 C4 Therapeutics, Inc. Tricyclic heterobifunctional compounds for degradation of targeted proteins

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