Compounds and uses thereof

Abstract

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

Description

[0001]PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 COMPOUNDS AND USES THEREOF BACKGROUND OF THE INVENTION CREB-binging protein (CBP) is a transcriptional co-activator that maintains gene expression 5 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. 10 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 15 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). 20 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 A1is a bond between the linker and A; A2is a bond between B and the linker; m is 0 or 1; C is absent, or carbonyl; 25 E is 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, 30 OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, 1 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; F is 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 5 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo, 10 each Rais, 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 Raare taken 15 together with the atom to which they are attached to form a carbocyclyl or 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; the CBP binding moiety has the structure of Formula IIIa: 20 Formula IIIa wherein Y is CR4, or N; Z is C or N; R1is, independently, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 25 3-12 membered heterocycle, wherein each C1-C12 alkyl, C1-C9 heteroalkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rb; R2is, 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 is optionally substituted with one or more groups Rb; 30 R3is, independently, ORf, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3- C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)- (C6-C20aryl), and (C1-C20heteroaryl)(C1-C20heteroaryl), wherein each C1-C12alkyl, C1-C9heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6- C20 aryl)(C1-C20 heteroaryl) and (C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally 35 substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, 2 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, and N(Rf)S(O)2N(Rf)2; R4is, independently, ORf, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3- 5 C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)- (C6-C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2- C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6- C20 aryl)(C1-C20 heteroaryl) and (C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, 10 I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, and N(Rf)S(O)2N(Rf)2; each Rbis, 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 15 carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Re; Rcis, 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 is optionally substituted with A1and / or one or more groups 20 Re; Rdis, 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 is optionally substituted with A1and / or one or more groups Re; 25 or Rcand Rdof Formula (III) taken together with the nitrogen to which they are attached form a 3- 12 membered heterocycle that is optionally substituted with A1and / or one or more groups Re; each Reis, independently, H, 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 is optionally substituted with one or more groups 30 independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; each Rfis, independently, H, 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 is optionally substituted with one or more groups 35 independently selected from oxo, halo, amino, hydroxyl, C(O)OH, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; or a pharmaceutically acceptable salt thereof. In some embodiments, C is absent. In some embodiments, C is carbonyl. 40 In some embodiments, m is 0. 3 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 In some embodiments, E is absent. In some embodiments, m is 1. In some embodiments, E is optionally substituted C1–C10 alkylene. In some embodiments, E is methylene or ethylene. In some embodiments, F is optionally substituted C2-C9 heteroarylene. 5 In some embodiments, F is optionally substituted C2–C10 heterocyclylene. 10 . In some embodiments, the CBP binding moiety has the structure of Formula IIIb: Formula IIIb 15 wherein Y is CR4or N; 4 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 R1is, independently, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C1-C9 heteroalkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rb; R2is, independently, C1-C12 alkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered 5 heterocycle, wherein each C1-C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rb; R3is, independently, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)-(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C1210 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1- C20 heteroaryl) and (C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, OC(O)ORf, 15 N(Rf)C(O)R R4is, independently, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1- 20 C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, and N(Rf)S(O)2N(Rf)2; 25 each Rbis, 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 is optionally substituted with A1and / or one or more groups Re; Rcis, 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 30 carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Re; Rdis, 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 is optionally substituted with A1and / or one or more groups Re; or Rcand Rdof Formula (III) taken together with the nitrogen to which they are attached form a 3-12 35 membered heterocycle that is optionally substituted with A1and / or one or more groups Re; each Reis, independently, H, 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 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 40 substituted with one or more groups independently selected from halo; 5 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 each Rfis, independently, H, 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 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 5 substituted with one or more groups independently selected from halo; or a pharmaceutically acceptable salt thereof. In some embodiments, the CBP binding moiety of Formula IIIb has the structure:10 6 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 , In some embodiments, R3is C1-C12 alkyl. 5 In some embodiments, R3is methyl. In some embodiments, R3is C1-C9 heteroalkyl. In some embodiments, R3is OMe. In some embodiments, R3is C2-C9 heterocycle. 10 7 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 In some embodiments, R4is C1-C12 alkyl. 5 In some embodiments, R4is methyl. In some embodiments, R4is C1-C9 heteroalkyl. In some embodiments, R4is OMe. In some embodiments, R4is C2-C9 heterocycle. 10 In some embodiments, the CBP binding moiety has the structure: , 8 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 In some embodiments, the CBP binding moiety has the structure: 5 9 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 10 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 , , 11 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 5 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. 12 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 In some embodiments, the degradation moiety (B) comprises the structure of Formula V: wherein 5 R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R7is 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; R8is H, optionally substituted C1-C6alkyl, optionally substituted C3-C10carbocyclyl, or optionally 10 substituted C6-C10 aryl; R9is H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; R10is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or optionally substituted arylalkyl; wherein one of R5and R7is A2or C(O)A2. 15 In some embodiments, the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-A): wherein 20 R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R7is 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; R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally 25 substituted C6-C10 aryl; R9is H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; R10is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or optionally substituted arylalkyl; wherein one of R5and R7is A2or C(O)A2. 13 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 In some embodiments, the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-B): 5 wherein R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R7is A2, C(O)A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10carbocyclyl, or optionally substituted C6-C10aryl; 10 R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-6 alkyl, or optionally substituted C1-C6 heteroalkyl; R10is H, optionally substituted C1-C6alkyl, or optionally substituted C1-C6heteroalkyl or optionally substituted arylalkyl; 15 wherein one of R5and R7is A2or C(O)A2. 20 14 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 5 R11and R12are, independently, H, or optionally substituted C1-C6 alkyl; each R13is, 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; 10 n is 0, 1, 2, 3, or 4; and each of R15and R16is, independently, H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl. 15 15 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 In some embodiments, the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-C): 5 wherein R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R7is 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; 10 R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; R11and R12are, independently, H, or optionally substituted C1-C6 alkyl; each R13is, independently, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1- 15 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; R14is optionally substituted C3-C10carbocyclyl, optionally substituted C2-C9heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl; 20 n is 0, 1, 2, 3, or 4; and wherein one of R5and R7is is A2or C(O)A2. In some embodiments, the degradation moiety of formula V has the structure: 25 , 16 PATENT ATTORNEY-DOCKET NO.: 51121-101WO35 17 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 derivative or analog thereof. In some embodiments, the degradation moiety comprises the structure of Formula VI: Formula VI R6ais, independently, optionally substituted C1-C6 alkyl; R7ais, independently, A2, or optionally substituted C1-C6alkyl, optionally substituted C1-C65 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl, that is substituted with A2and / or one or more groups Rg; R8ais H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10aryl; R9ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 10 n1 is 0, 1, 2, 3, or 4; each of R11aand R12ais, independently, H, or optionally substituted C1-C6 alkyl; each R13ais, independently, halogen, optionally substituted C1-C6alkyl, 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 15 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; R14ais optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl; and each Rgis, 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 20 selected from amino, hydroxyl, C1-C6 alkoxy, carbocyclyl, heterocyclyl, or C1-C6 alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; or a pharmaceutically acceptable salt thereof. In some embodiments, the degradation moiety comprises the structure of Formula VI: 18 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Formula VI R6ais, independently, optionally substituted C1-C6 alkyl; R7ais, 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 A2and / or one or more groups Rg; 5 R8ais H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; n1 is 0, 1, 2, 3, or 4; each of R11aand R12ais, independently, H, or optionally substituted C1-C6 alkyl; 10 each R13ais, 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 R15aand R16ais, independently, H, halogen, optionally substituted C1-C6 alkyl, or 15 optionally substituted C6-C10 aryl; and each Rgis, 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 A2and / or one or more groups independently selected from oxo and halo; 20 or a pharmaceutically acceptable salt thereof. In some embodiments, the degradation moiety has the structure: derivative or analog thereof. In some embodiments, L has the structure of Formula II: A1–(F)–(E)m–C-A2, Formula II wherein A1is a bond between the linker and A; 19 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 A2is 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–C10 alkylene; and F is optionally substituted C2–C10 heterocyclylene or optionally substituted C2-C9 heteroarylene. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, E is methylene or ethylene. In some embodiments, C is carbonyl. In some embodiments, C is absent. In some embodiments, F is optionally substituted C2–C10 heterocyclylene. 5 In some embodiments, F is: In some embodiments, F is optionally substituted C2-C9 heteroarylene. In some embodiments, F is 10 In some embodiments, the compound is any one of compounds 1 to 48, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a pharmaceutical composition and a pharmaceutically acceptable excipient. In an 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 a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, 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. In some embodiments, the cancer is gastric cancer. 20 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 In an aspect, the invention features 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 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, the cancer is metastatic. In some embodiments, the subject or cancer has a EP300 loss of function mutation. In some embodiments, the method includes administering to the subject an anticancer therapy. In some embodiments, the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof. In some embodiments, the anticancer agent is a CDK4 / 6 inhibitor. 5 In some embodiments, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib. In some embodiments, the method further comprises administering hormone therapy. In an aspect, the invention features 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, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. 10 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-Goutières syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis. 15 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 an aspect, the invention features 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 20 effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. 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). 25 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-Goutières syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque 30 psoriasis, or myelofibrosis. In an aspect, the invention features a method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. 21 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 In an aspect, the invention features 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, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In an aspect, the invention features a method of suppressing a memory CD8+T cell response in a 5 subject in a subject having or at risk of developing an inflammatory response, including administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In an aspect, the invention features 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, or a 10 pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, the infection is Herpesvirus K*. In an aspect, the invention features 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, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. 15 Table 1. Compounds of the Invention 22 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 23 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 24 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 25 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 26 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 27 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 In some embodiments, the compound is any one of compounds 1-48 of table 1. In another aspect, the disclosure features a pharmaceutical composition including any of the foregoing compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable 5 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 10 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. 15 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. 20 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. 28 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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, 15 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, 20 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 25 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., 30 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, 35 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 40 estrogen receptors. 29 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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. 5 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. 10 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 15 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, 20 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 25 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 30 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 35 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 40 cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma 30 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 (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, 5 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 10 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 15 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 20 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- 25 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, 30 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, 35 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 31 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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, 5 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). 10 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 15 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, 20 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 25 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 30 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 35 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 40 cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma 32 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 (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, 5 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 10 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 15 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 20 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, 25 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 30 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, 35 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 33 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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, 5 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, 10 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 15 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 20 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 25 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., 30 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 35 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 40 virus and BK virus), Paramyxoviridae family (e.g., Measles virus), Togaviridae family (e.g., Rubella virus). 34 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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, 10 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-Goutières 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 15 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 × 20 109 / 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, 25 palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, Sjogren’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 30 erythematosus, Aicardi-Goutières 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. 35 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 40 activator of transcription (STAT). 35 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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-Goutières syndrome, 5 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 10 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 15 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 20 plaque psoriasis, alopecia areata, Sjogren’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-Goutières syndrome, 25 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. 30 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 35 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 40 more, three or more, four or more of): (a) reduced T cell (e.g., CD8+memory T cells) activity, (b) reduced 36 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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- 15 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 20 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 25 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). 30 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 35 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 37 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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, esophageal, stomach, or hematologic cell is in a subject. 15 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 20 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 25 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. 30 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 35 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 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In 38 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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%). 5 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 10 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 15 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 20 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 25 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 30 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 35 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 a40 chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparagine- 39 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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 15 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., 20 sotrastaurin or IDE196). Chemical terms The terminology employed herein is for the purpose of describing particular embodiments and is 25 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 30 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 35 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). 40 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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, 5 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). 10 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, 15 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 20 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, 25 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 30 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 35 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 40 one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some 41 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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 15 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. 20 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), 25 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 30 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 35 (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 40 the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral 42 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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. 5 "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 10 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 15 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 20 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 25 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 30 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 35 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 40 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or 43 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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 15 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 20 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. 25 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. 30 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. 35 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, 40 and vitreal. 44 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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%, 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 15 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, 20 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, 25 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 30 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, 35 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 45 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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 15 “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 20 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 25 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%, 30 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, 35 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 40 the art, e.g., HiBit assay. 46 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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. 10 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, 15 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, 20 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 25 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 30 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 35 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 40 well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases 47 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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, 5 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, 10 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. 15 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 20 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”), 25 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 30 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 35 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 40 measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or 48 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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. 15 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 20 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. 25 BRIEF DESCRIPTION OF THE DRAWINGS Fig.1A are a series of images illustrating the effect of the combination of abemaciclib, fulvestrant, and DMSO over 14 days as described in Example 867 in MCF7 cells. Fig.1B are a series of images illustrating the effect of the combination of abemaciclib (e.g, 0 nM, 12.5nM, 30 25nM, or 50nM), fulvestrant (e.g.0 nM, 0.05nM, 0.1nM), and 1 nM Compound A over 14 days as described in Example 867 in MCF7 cells. Fig.2A are a series of images illustrating the effect of the combination of abemaciclib, fulvestrant, and DMSO over 14 days as described in Example 867 in T47D cells. Fig.2B are a series of images illustrating the effect of the combination of abemaciclib (e.g, 0 nM, 12.5nM, 35 25nM, or 50nM), fulvestrant (e.g.0 nM, 0.05nM, 0.1nM), and 1 nM Compound A over 14 days as described in Example 867 in T47D cells. DETAILED DESCRIPTION OF THE INVENTION The present disclosure features compositions and methods useful for the treatment of CBP- 40 related disorders (e.g., cancer and infection). The disclosure further features compositions and methods 49 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 A1is a bond between the linker and A; A2is a bond between B and the linker; m is 0 or 1; 10 C is absent, or carbonyl; E is 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 15 independently selected from oxo, halo, 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, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; F is optionally substituted C3-C10 carbocyclylene, optionally substituted C2–C10 heterocyclylene, 20 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with 25 one or more groups independently selected from oxo and halo, each Rais, 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 50 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 substituted with one or more groups independently selected from oxo and halo; or two Raare taken together with the atom to which they are attached to form a carbocyclyl or 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; 5 the CBP binding moiety has the structure of Formula IIIb: Formula IIIb wherein Y is CR4or N; 10 R1is, independently, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C1-C9 heteroalkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rb; R2is, 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 is 15 optionally substituted with one or more groups Rb; R3is, independently, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)-(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1- 20 C20 heteroaryl) and (C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, and N(Rf)S(O)2N(Rf)2; 25 R4is, independently, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)-(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1- C20 heteroaryl) and (C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with A130 and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, OC(O)ORf, N(Rf)C(O)R 51 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 each Rbis, 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 is optionally substituted with A1and / or one or more groups Re; 5 Rcis, 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 is optionally substituted with A1and / or one or more groups Re; Rdis, independently, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3- 10 12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Re; or Rcand Rdof Formula (III) taken together with the nitrogen to which they are attached form a 3- 12 membered heterocycle that is optionally substituted with A1and / or one or more groups Re; 15 each Reis, independently, H, 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 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; 20 each Rfis, independently, H, 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 is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; or a pharmaceutically acceptable 25 salt thereof. CBP and Janus Kinase (JAK) Pathway 30 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, 35 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 52 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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- 5 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, 10 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, 15 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. 20 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, 25 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 30 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 35 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 40 intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential 53 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 × 10 109 / 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 15 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-Goutières 20 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, intermediate25 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 30 atopic dermatitis, Aicardi-Goutières 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 35 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 54 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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- 15 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, Sjogren’s syndrome, and systemic lupus erythematosus, 20 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- 25 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, 30 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 35 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- 40 to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or 55 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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. 5 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 10 vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, Sjogren’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, 15 alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutières 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 20 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 25 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-Goutières syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, 30 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 35 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-Goutières syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior 40 uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis. 56 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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-Goutières syndrome, 10 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. 15 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 20 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 25 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 30 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 35 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 40 some embodiments, the myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV 57 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 MF). In some embodiments, the myeloproliferative disorder is post- essential thrombocythemia myelofibrosis (Post-ET MF). CDK4 / 6 Inhibitors CDK4 / 6 inhibitors are a class of drugs that target cyclin-dependent kinases 4 and 6 (CDK4 and 5 CDK6), enzymes crucial for cell division and proliferation. By inhibiting these kinases, CDK4 / 6 inhibitors disrupt the cell cycle, preventing cancer cells from growing and dividing. These inhibitors are primarily used in the treatment of hormone receptor-positive (HR+), HER2-negative breast cancer, both in early and metastatic stages. Common CDK4 / 6 inhibitors include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). 10 CDK4 / 6 inhibitors are often administered in combination with hormone therapy, such as aromatase inhibitors or fulvestrant, to enhance their effectiveness. This combination therapy has been shown to improve progression-free survival and overall survival in patients. Side effects of CDK4 / 6 inhibitors can include fatigue, gastrointestinal disturbances, and bone marrow suppression, but they are generally less severe than those associated with traditional chemotherapy. 15 These inhibitors represent a significant advancement in targeted cancer therapy, offering a more precise approach to treating certain types of breast cancer and improving patient outcomes. The dosing of CDK4 / 6 inhibitors varies depending on the specific drug and clinical setting. Palbociclib is typically administered at a dose of 125 mg once daily for 21 days, followed by a 7-day break. Ribociclib is given at 600 mg once daily for 21 days, with a 7-day off period. Abemaciclib is dosed 20 continuously at 200 mg twice daily. Dose adjustments are often necessary based on the patient's tolerance and side effects, such as neutropenia or diarrhea. For instance, abemaciclib may be reduced to 150 mg or 100 mg twice daily if adverse reactions occur. These dosing schedules are designed to maximize therapeutic efficacy while managing potential side effects, ensuring that patients receive the most effective treatment with minimal discomfort. 25 In another aspect, the present disclosure provides a method of treating cancer the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof (see e.g., Figs.1A and 1B and Example 50). In some embodiments, the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast 30 cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophogeal, stomach, or lung cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is metastatic. In some embodiments, the subject or cancer has a EP300 loss of function mutation. In another aspect, the present disclosure provides a method of treating gastric cancer the method 35 including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof (see e.g., Figs.1A and 1B and Example 50). In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is metastatic. In some embodiments, the subject or cancer has a EP300 loss of function mutation. 40 58 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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. 5 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 10 tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject. Treating cancer can result in a reduction in size or volume of a tumor. For example, after 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 15 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 20 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 25 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 30 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 35 (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 40 inflammation. For example, after treatment, inflammation is reduced by 5% or greater (e.g., 10%, 20%, 59 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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, 5 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 10 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, 15 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 20 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 25 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 30 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, 35 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. 60 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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, 5 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 10 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 15 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, 20 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, 25 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, 30 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; 35 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; 40 phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® 61 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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; 5 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 10 (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 15 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 20 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); 25 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); 30 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. 35 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 40 may be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion 62 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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; 10 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 15 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 20 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 25 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. 30 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 35 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 40 the second therapeutic agent. 63 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 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 10 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 15 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 20 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 25 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 30 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 35 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 40 can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration 64 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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. 5 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 10 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 15 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 20 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 25 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 30 range from 0.1-50 mg / kg (e.g., 0.25-25 mg / kg). Kits 35 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 40 package insert with instructions to perform any of the methods described herein. 65 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Examples Abbreviations ACN or MeCN acetonitrile 5 Ac2O acetic anhydride tBuOK potassium tert-butoxide DAST diethylaminosulfur trifluoride DCM dichloromethane DIEA N,N-diisopropylethylamine 10 DMF N,N-dimethylformamide DMSO dimethylsulfoxide dppf bis(diphenylphosphino)ferrocene ESI electrospray ionization Et3N or TEA triethylamine 15 EtOAc ethyl acetate EtOH ethyl alcohol FA formic acid FCC flash column chromatography h hours 20 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 25 LCMS liquid chromatography / mass spectrometry LiHMDS lithium hexamethyldisilazide MeOH methyl alcohol mL milliliter mmol millimole 30 mg milligrams MHz megahertz MS mass spectrometry MTBE methyl t-butylether m / z mass / charge ratio 35 NBS N-bromosuccinimide nm nanometer NMR nuclear magnetic resonance ppm parts per million rt room temperature 40 RT retention time Ruphos Pd 3G (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′- biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II) methanesulfonate SFC supercritical fluid chromatography 45 TFA trifluoroacetic acid THF tetrahydrofuran XPhos Pd 3G (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate 50 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. 55 66 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Preparation of Intermediates Intermediate 1: 1-bromo-3-cyclopropylimidazo[1,5-a]pyrazine Step 1: 1-chloro-2-(difluoromethyl)-5-fluoro-4-nitrobenzene 5 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 (3 x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by 10 silica gel column chromatography (Eluent: CH2Cl2 / MeOH (20:10) 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- 15 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 (3 x 50 mL). 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), 20 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- 25 (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 (Eluent: PE / EtOAc 30 (10:1)) to afford the title compound (1.1 g) as a yellow solid. LCMS (ESI) m / z [M+H]+= 234.0. 67 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel 5 column chromatography (Eluent: 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) ppm. LCMS (ESI) m / z [M+H]+=220.0. Intermediate 2: 6-chloro-7-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine 10 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. 15 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 (Eluent: 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) ppm. 20 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 25 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 the next step directly without further purification. LCMS (ESI) m / z [M+H]+= 342.95. 30 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 68 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 (Eluent: PE / EtOAc (5:1)) to afford the title compound (9.4 5 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) ppm. Step 4: 2-bromo-6-chloro-5-(difluoromethyl)pyridin-3-amine To a stirred solution of 6-chloro-5-(difluoromethyl)pyridin-3-amine (9.4 g, 52.640 mmol) in ACN (100 10 mL) was added NBS (9.37 g, 52.640 mmol) in ACN (50 mL) dropwise at 0 °C. 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 15 chromatography (Eluent: PE / EtOAc (10:1)) to afford the title compound (11.8 g) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 256.80 & 258.85.1H NMR (300 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.08 (t, J = 54.0 Hz, 1H), 6.06 (s, 2H) ppm. Step 5: ethyl (E)-3-(3-amino-6-chloro-5-(difluoromethyl)pyridin-2-yl)acrylate 20 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 25 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 (Eluent: PE / EtOAc (10:1)) to afford the title compound (9.1 g) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 276.80. 30 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 35 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- 40 (difluoromethyl)pyridin-2-yl)propanoate (9.2 g, 33.0 mmol) in EtOH (90 mL) at room temperature. The 69 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 5 purified by silica gel column chromatography (Eluent: PE / EtOAc (1:1)) to afford the title compound (5.5 g) as a white solid. LCMS (ESI) m / z [M+H]+ = 233.15.1H 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) ppm. Step 8: 6-chloro-7-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine 10 BH3-THF (70.93 mL, 70.935 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, 23.645 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 (Eluent: PE / 15 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) ppm. Intermediate 3: 7-fluoro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine. 20 Step 1: methyl 2-[(5-fluoro-3-nitropyridin-2-yl)oxy]acetate Methyl 2-hydroxyacetate (4.39 g, 48.726 mmol) was added to a solution of 2,5-difluoro-3-nitropyridine (3.9 g, 24.363 mmol) and K2CO3 (6.73 g, 48.726 mmol) in DMF (50 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water (500 mL) and extracted with 25 EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (Eluent: 0 to 100% EA in PE) to afford the title compound (5.3 g) as a yellow oil. LCMS (ESI) m / z [M+H]+= 231.0. 30 Step 2: 7-fluoro-1H,3H-pyrido[2,3-b][1,4]oxazin-2-one Fe (6.31 g, 112.970 mmol) was added to a stirred solution of methyl 2-[(5-fluoro-3-nitropyridin-2- yl)oxy]acetate (5.2 g, 22.594 mmol) and AcOH (4.07 mL, 71.028 mmol) in EtOH (40 mL) and H2O (10 mL). The resulting mixture was stirred for 2 h at 80°C. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to afford intermediate 3 (1.9 g, crude) as a white solid that was used 35 in the next step directly without further purification. LCMS (ESI) m / z [M+H]+=169.0. 70 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 3: 7-fluoro-1H,2H,3H-pyrido[2,3-b][1,4]oxazine Borane-tetrahydrofuran complex (15 mL, 1.0M in THF) was added dropwise to a solution of 7-fluoro-1H,3H- pyrido[2,3-b][1,4]oxazin-2-one (1.3 g, 7.732 mmol) in THF (15 mL) at 0°C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was quenched with MeOH (50 mL) at 0°C and 5 concentrated under reduced pressure. The residue was diluted with water (300 mL) and extracted with EtOAc (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. The crude product was purified by FCC (Eluent: 0 to 100% EA in PE) to afford the title compound (1 g) as a white solid. LCMS (ESI) m / z [M+H]+= 155.1. 10 Intermediate 4: 5-bromo-1,3-dimethylquinolin-2-one. Step 1. N-(3-bromo-2-formylphenyl)propionamide Pyridine (1.19 g, 1.21 mL, 15.0 mmol) and propionyl chloride (1.85 g, 1.74 mL, 20.0 mmol) were added to 15 a solution of 2-amino-6-bromobenzaldehyde (2.00 g, 10.0 mmol) in DCM (20.0 mL) at 0 °C. The resulting mixture was gradually warmed to rt and allowed to stir for 4 h. The reaction mixture was cooled to 0 °C and quenched with ice water (30 mL). The resulting solution was extracted with DCM (20 mL x 3) and the combined organic layers were washed with brine (35 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (2.5 g) as a yellow solid. LCMS (ESI) m / z [M+H]+20 = 257.9 Step 2.5-bromo-3-methyl-4a,8a-dihydroquinolin-2(1H)-one Cesium carbonate (6.51 g, 20.0 mmol) was added to a solution of N-(3-bromo-2- formylphenyl)propionamide (2.56 g, 10.0 mmol) in DMF (10.0 mL). The reaction mixture was stirred at 50 25 °C overnight. The mixture was cooled to rt and poured into ice water. The resulting precipitate was collected with filtration and washed with water to obtain the title compound (2.30 g) as a yellow solid. LCMS (ESI) m / z [M+H]+= 238.0 Step 3.5-bromo-1,3-dimethylquinolin-2-one 30 Cesium carbonate (6.51 g, 20.0 mmol) and methyl iodide (71.5 mg, 31.5 μL, 504 μmol) were added to a solution of 5-bromo-3-methyl-4a,8a-dihydroquinolin-2(1H)-one (2.40 g, 10.0 mmol) in DMF (40.0 mL). The resulting mixture was stirred at rt for 1.5 h. The reaction mixture was poured into ice water and the solid precipitate was collected with filtration and washed with water to provide crude product. The residue was purified by FCC (Eluent: 0 to 100% EA in heptane) to afford the title compound (1.30 g) as a yellow solid. 35 LCMS (ESI) m / z [M+H]+= 252.0 71 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Intermediates 5 and 6: 7-bromo-5-methoxy-1,3-dimethylquinolin-2(1H)-one and 5-bromo-7-methoxy- 1,3-dimethylquinolin-2(1H)-one. Step 1. N-(3-bromo-5-methoxyphenyl)propionamide 5 Pyridine (10.6 g, 10.8 mL, 134 mmol) was added to a solution of 3-bromo-5-methoxyaniline (9.0 g, 44.5 mmol) in DCM (90.0 mL) at 0 °C. To the resulting mixture was added propionyl chloride (6.18 g, 5.83 mL, 66.8 mmol) dropwise at 0 °C. The reaction mixture was gradually warmed to rt with stirring. After 3 h the reaction was complete, and the resulting mixture was cooled to 0 °C, quenched with ice water (50 mL) and extracted with DCM (40 mL x 3). The combined organic layers were washed with water (80 mL x 2), brine 10 (80 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide title compound (10.4 g) as a brown solid. LCMS (ESI) m / z [M+H]+= 252.0 Step 2.5-bromo-2-chloro-7-methoxy-3-methylquinoline and 7-bromo-2-chloro-5-methoxy-3- methylquinoline 15 DMF (5.06 g, 5.36 mL, 69.2 mmol) was added to a flask and cooled to 0 °C. POCl3 (29.5 g, 17.9 mL, 192 mmol) was then added dropwise to the reaction flask over 30 min at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. A solution of methyl (3-bromo-5-methoxyphenyl)carbamate (10.0 g, 38.4 mmol) in DMF (15.0 mL) was added to the reaction mixture at 0 °C and the resulting mixture was warmed to 90 °C with stirring overnight. After completion, the reaction was cooled to 0 °C and slowly quenched with ice water. 20 The precipitate was collected via filtration with copious water washes to yield a mixture of regioisomers (7.00 g) as an off white solid. LCMS (ESI) m / z [M+H]+= 287.9 Step 3.5-bromo-7-methoxy-3-methylquinolin-2(1H)-one and 7-bromo-5-methoxy-3-methylquinolin- 2(1H)-one 25 Acetic acid (73.3 g, 69.9 mL, 1.22 mol) was added to a solution of 7-bromo-2-chloro-5-methoxy-3- methylquinoline and 5-bromo-2-chloro-7-methoxy-3-methylquinoline (7.00 g, 24.4 mmol) in water (11.0 g, 11.0 mL, 611 mmol). The reaction mixture was stirred at 100 °C for 48 h. Upon reaction completion, the mixture was poured into ice water and the white precipitate was collected with filtration and copious water washes to provide a mixture of regioisomers (4.90 g). LCMS (ESI) m / z [M+H]+= 268.0 30 72 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 4.5-bromo-7-methoxy-1,3-dimethylquinolin-2(1H)-one and 7-bromo-5-methoxy-1,3- dimethylquinolin-2(1H)-one Cesium carbonate (2.92 g, 8.95 mmol) and iodomethane (1.06 g, 466 μL, 7.46 mmol) was added to a solution of 5-bromo-7-methoxy-3-methylquinolin-2(1H)-one and 7-bromo-5-methoxy-3-methylquinolin- 5 2(1H)-one (2.00 g, 7.46 mmol) in DMF (25.0 mL). The resulting mixture was stirred at rt for 4 h at which time the reaction mixture was quenched with ice water and extracted with DCM (35 mL x 3). The combined organic layers were washed with water (75 mL x 1), brine (75 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: 0 to 60% EA in heptane) to afford intermediate 5 (0.950 g). LCMS (ESI) m / z [M+]+= 282.01H NMR (400 MHz, Chloroform-d) δ 7.95 10 – 7.89 (m, 1H), 7.14 – 7.09 (m, 1H), 6.80 (d, J = 1.5 Hz, 1H), 3.94 (d, J = 0.7 Hz, 3H), 3.69 (d, J = 0.7 Hz, 3H), 2.23 (d, J = 1.2 Hz, 3H) ppm. and intermediate 6 (0.440 g). LCMS (ESI) m / z [M+]+= 282.01H NMR (400 MHz, Chloroform-d) δ 7.88 (q, J = 1.2 Hz, 1H), 7.09 (t, J = 1.9 Hz, 1H), 6.74 (t, J = 1.9 Hz, 1H), 3.89 (d, J = 1.5 Hz, 3H), 3.70 (d, J = 1.5 Hz, 3H), 2.26 (t, J = 1.4 Hz, 3H) ppm. 15 Intermediate 7: 1,3-dimethyl-7-morpholino-2-oxo-1,2-dihydroquinolin-5-yl trifluoromethanesulfonate. Step 1.5-methoxy-1,3-dimethyl-7-morpholinoquinolin-2(1H)-one Pd2(dba)3 (97.4 mg, 106 μmol), rac BINAP (265 mg, 425 μmol), and cesium carbonate (1.39 g, 4.25 mmol) 20 was added to a degassed solution of 7-bromo-5-methoxy-1,3-dimethylquinolin-2(1H)-one (600 mg, 2.13 mmol) and morpholine (185 mg, 2.13 mmol) in 1,4-Dioxane (15.0 mL). The resulting mixture was stirred at 90 °C overnight under nitrogen atmosphere. The reaction mixture was cooled to rt, quenched with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with water (30 mL x 1), brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The 25 residue was purified by FCC (Eluent: 0 to 90% EA in heptane) to afford the title compound (570 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+= 289.1 Step 2.5-hydroxy-1,3-dimethyl-7-morpholinoquinolin-2(1H)-one Sodium ethanethiolate (1.46 g, 17.3 mmol) was added to a solution of 5-methoxy-1,3-dimethyl-7- 30 morpholinoquinolin-2(1H)-one (500 mg, 1.73 mmol) in DMF (15.0 mL). The reaction mixture was stirred at 100 °C overnight. The mixture was allowed to cool to rt, quenched with ice water, saturated ammonium chloride, and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with water (20 73 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 mL x 2), brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (300 mg). LCMS (ESI) m / z [M+H]+= 275.1 Step 3.1,3-dimethyl-7-morpholino-2-oxo-1,2-dihydroquinolin-5-yl trifluoromethanesulfonate 5 Pyridine (155 mg, 158 μL, 1.96 mmol) and trifluoromethanesulfonic anhydride (368 mg, 219 μL, 1.30 mmol) were added to a solution of 5-bromo-1,3-dimethyl-7-morpholinoquinolin-2(1H)-one (220 mg, 652 μmol) in DCM (10.0 mL) was added at 0 °C. The reaction mixture was allowed to gradually warm to rt and stirred for 3 h. After completion, the reaction was cooled to 0 °C, quenched with ice water (3 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with dilute 1N HCl (30 mL x 1), water 10 (30 mL x 1), brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: 0 to 75% EA in heptane) to afford the title compound (200 mg) as an off white solid. LCMS (ESI) m / z [M+H]+= 407.2 Intermediate 8: 1,3-dimethyl-2-oxo-7-(tetrahydro-2H-pyran-4-yl)-1,2-dihydroquinolin-5-yl 15 trifluoromethanesulfonate Step 1.7-(3,6-dihydro-2H-pyran-4-yl)-5-methoxy-1,3-dimethylquinolin-2(1H)-one K2CO3 (946 mg, 6.84 mmol) and Pd(amphos)Cl2 (161 mg, 228 μmol) was added to a degassed solution of 7-hydroxy-5-methoxy-1,3-dimethylquinolin-2(1H)-one (500 mg, 2.28 mmol) and 2-(3,6-dihydro-2H-pyran-4- 20 yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (575 mg, 2.74 mmol) in 1,4-Dioxane (15.0 mL) and water (3.75 mL). The reaction mixture was warmed to 80 °C and stirred overnight. The resulting mixture was cooled to rt, quenched with water, and extracted with EtOAc (15mL x 3). The combined organic layers were washed with water (30 mL x 1), brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: 0 to 70% EA in heptane) to afford the title compound 25 (400 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+= 286.1 Step 2.5-methoxy-1,3-dimethyl-7-(tetrahydro-2H-pyran-4-yl)quinolin-2(1H)-one Palladium on carbon (149 mg, 10% Wt, 140 μmol) was added to a degassed solution of 7-(3,6-dihydro-2H- pyran-4-yl)-5-methoxy-1,3-dimethylquinolin-2(1H)-one (400 mg, 1.40 mmol) in EtOH (12.0 mL). The 30 reaction mixture was fitted with a hydrogen gas balloon and stirred at rt overnight. Upon reaction completion, the mixture was filtered over a Celite® bed with EtOH washes. The resulting filtrate was 74 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 concentrated under reduced pressure to provide the title compound (390 mg) as a white solid. LCMS (ESI) m / z [M+H]+= 288.1 Step 3.5-hydroxy-1,3-dimethyl-7-(tetrahydro-2H-pyran-4-yl)quinolin-2(1H)-one 5 Sodium ethanethiolate (1.14 g, 13.6 mmol) was added to a solution of 5-methoxy-1,3-dimethyl-7- (tetrahydro-2H-pyran-4-yl)quinolin-2(1H)-one (390 mg, 1.36 mmol) in DMF (1.50 mL). The reaction mixture was stirred at 110 °C overnight. Upon reaction completion, the mixture was allowed to cool to rt, quenched with ice water, saturated ammonium chloride, and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with water (20 mL x 2), brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, 10 and concentrated in vacuo to provide crude title compound (350 mg) which was taken forward without additional purification. LCMS (ESI) m / z [M+H]+= 274.2 Step 4.1,3-dimethyl-2-oxo-7-(tetrahydro-2H-pyran-4-yl)-1,2-dihydroquinolin-5-yl trifluoromethanesulfonate 15 Pyridine (506 mg, 518 μL, 6.40 mmol) and trifluoromethanesulfonic anhydride (723 mg, 429 μL, 2.56 mmol) were added to a solution of 5-hydroxy-1,3-dimethyl-7-(tetrahydro-2H-pyran-4-yl)quinolin-2(1H)-one (350 mg, 1.28 mmol) in DCM (15.0 mL) at 0 °C. The resulting reaction mixture was gradually warmed to rt and stirred for 5 h. Upon reaction completion, the mixture was quenched with ice water and extracted with DCM (10 mL x 3). The organic layers were combined, washed with DI water (30 mL x 1), brine (30 mL x 1), dried 20 over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: 0 to 50% EA in heptane) to afford the title compound (285 mg) as an orange solid. LCMS (ESI) m / z [M+H]+= 406.1 Intermediate 9: 6-chloro-7-(difluoromethyl)-1',3'-dimethyl-3,4-dihydro-2H-[1,5'-biquinolin]-2'-one. 25 Step 1.6-chloro-7-(difluoromethyl)-1',3'-dimethyl-3,4-dihydro-2H-[1,5'-biquinolin]-2'-one XPhos Pd G3 (67.15 mg, 0.079 mmol) and Cs2CO3 (516.95 mg, 1.586 mmol) was added to a stirred mixture of 5-bromo-1,3-dimethylquinolin-2-one (200 mg, 0.793 mmol) and 6-chloro-7-(difluoromethyl)-1,2,3,4- tetrahydroquinoline (172.65 mg, 0.793 mmol) in dioxane (5 mL). The resulting mixture was stirred for 2 h 30 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 (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), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (135 mg) as a yellow solid. LCMS 35 (ESI) m / z [M+H]+= 388.8. 75 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Intermediate 10: 5-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-1,3- dimethylquinolin-2-one. Step 1.5-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-1,3-dimethylquinolin-2-one 5 K3PO4 (252.59 mg, 1.190 mmol) and XPhos Pd G3 (50.36 mg, 0.059 mmol) was added to a stirred solution of 5-bromo-1,3-dimethylquinolin-2-one (150 mg, 0.595 mmol) and 7-chloro-6-(difluoromethyl)-3,4-dihydro- 2H-1,4-benzoxazine (130.67 mg, 0.595 mmol) in dioxane (1 mL) at room temperature. The resulting mixture was stirred for an additional 1 h at 80 °C. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over 10 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 (230 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+= 391.1. 15 Intermediate 11: 5-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-1,3- dimethylquinolin-2-one. Step 1.5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-1,3-dimethylquinoin-2- one 20 XantPhos Pd G4 (38.17 mg, 0.040 mmol) and Cs2CO3 (387.71 mg, 1.191 mmol) was added to a stirred solution of 5-bromo-1,3-dimethylquinolin-2-one (100 mg, 0.397 mmol) and 2-chloro-3-(difluoromethyl)- 5,6,7,8-tetrahydro-1,5-naphthyridine (86.72 mg, 0.397 mmol) in dioxane (2 mL). 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 DCM (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried 25 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 (0.05% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (117 mg) as a yellow solid. LCMS (ESI) m / z [M+H+= 390.1. 76 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Intermediate 12: 5-{6-bromo-7-fluoro-2H,3H-pyrido[2,3-b][1,4]oxazin-1-yl}-1,3-dimethylquinolin-2- one Step 1: 5-{7-fluoro-2H,3H-pyrido[2,3-b][1,4]oxazin-1-yl}-1,3-dimethylquinolin-2-one 5 XPhos Pd G3 (54.91 mg, 0.065 mmol) was added to a stirred solution of 7-fluoro-1H,2H,3H-pyrido[2,3- b][1,4]oxazine (100 mg, 0.649 mmol), 5-bromo-1,3-dimethylquinolin-2-one (163.56 mg, 0.649 mmol) and Cs2CO3 (422.75 mg, 1.298 mmol) in dioxane (3.0 mL). The mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (40 mL) and dried over anhydrous 10 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatograph (elution gradient 0 to 100% MeCN in water (containing 10mmol / L NH4HCO3)) to afford the title compound (77 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=326.1. Step 2: 5-{6-bromo-7-fluoro-2H,3H-pyrido[2,3-b][1,4]oxazin-1-yl}-1,3-dimethylquinolin-2-one NBS (42.12 mg, 0.237 mmol) was added to a solution of 5-{7-fluoro-2H,3H-pyrido[2,3-b][1,4]oxazin-1-yl}- 15 1,3-dimethylquinolin-2-one (70 mg, 0.215 mmol) in ACN (1 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was quenched with sat. Na2S2O3 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (Eluent: 0 to 10% MeOH in DCM) to afford the title compound (83 mg) as a light yellow 20 solid. LCMS (ESI) m / z [M+H]+= 404.1. Intermediate 13: ethyl 5-(6-chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-7- methoxy-1,3-dimethylquinolin-2(1H)-one 25 Step 1: ethyl 5-(6-chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-7-methoxy-1,3- dimethylquinolin-2(1H)-one Xantphos Pd G4 (30.70 mg, 0.032 mmol) and XantPhos (36.92 mg, 0.064 mmol) was added to a stirred solution of 5-bromo-7-methoxy-1,3-dimethylquinolin-2(1H)-one (90 mg, 0.319 mmol), 2-chloro-3- (difluoromethyl)-5,6,7,8-tetrahydro-1,5-naphthyridine (69.74 mg, 0.319 mmol) and Cs2CO3 (311.80 mg, 30 0.957 mmol) in dioxane (2 mL). The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over 77 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 (86 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+ =419.9. 5 Intermediate 14: 5-[(6-chloropyridin-3-yl)(methyl)amino]-1,3-dimethylquinolin-2-one. Step 1.5-[(6-chloropyridin-3-yl)(methyl)amino]-1,3-dimethylquinolin-2-one t-BuONa (674.30 mg, 0.714 mmol) was added to a solution of 5-bromo-1,3-dimethylquinolin-2-one (90 mg, 10 0.357 mmol), 6-chloro-N-methylpyridin-3-amine (55.99 mg, 0.393 mmol) and XPhos Pd G3 (30.22 mg, 0.036 mmol,) in dioxane (3 mL). The resulting mixture was stirred for 1 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 15 (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 60% gradient in 15 min; detector, UV 254 nm) affording the title compound (63 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=314.0. Intermediate 15: 7-[(6-chloropyridin-3-yl)(methyl)amino]-5-methoxy-1,3-dimethylquinolin-2-one. 20 Step 1.7-[(6-chloropyridin-3-yl)(methyl)amino]-5-methoxy-1,3-dimethylquinolin-2-one XPhos Pd G3 (17.89 mg, 0.021 mmol) was added to a stirred solution of 7-bromo-5-methoxy-1,3- dimethylquinolin-2-one (60 mg, 0.213 mmol), 6-chloro-N-methylpyridin-3-amine (30.32 mg, 0.213 mmol) and Cs2CO3 (40.88 mg, 0.426 mmol) in dioxane (2 mL). The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with 25 EtOAc (30 mL x 3). The combined organic layers were washed with brine (15 mL) and dried over anhydrous sodium sulfate. 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 100% gradient in 25 min; detector, UV 254 nm) affording the title compound (42 mg,) as a brown- yellow solid. LCMS (ESI) m / z [M+H]+= 344.1. 30 78 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Intermediate 16: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(1-methyl-1H- pyrazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; hydrogen chloride. Step 1: tert-butyl N-[(1S)-1-[4-(2-methylpyrazol-3-yl)phenyl]ethyl]carbamate 5 XPhos Pd G3 (5.64 g, 6.662 mmol) was added to a stirred solution of tert-butyl N-[(1S)-1-(4- bromophenyl)ethyl]carbamate (20 g, 66.623 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole (20.79 g, 99.935 mmol) and Cs2CO3 (65.12 g, 199.869 mmol) in dioxane (200 mL) and H2O (50 mL). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (600 mL) and extracted with EtOAc (600 mL x 3). The combined organic layers were 10 washed with brine (600 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by FCC (Eluent: 0 to 100% EA in PE) to provide the desired product (21.1 g) as a white solid. LCMS (ESI) m / z [M+H]+=302.10. Step 2: (1S)-1-[4-(2-methylpyrazol-3-yl)phenyl]ethanamine hydrochloride 15 HCl (gas) in 1,4-dioxane (80 mL) was added dropwise to a solution of tert-butyl N-[(1S)-1-[4-(2- methylpyrazol-3-yl)phenyl]ethyl]carbamate (15 g, 49.769 mmol) in DCM (80 mL) at room temperature. The resulting mixture was stirred for 1h at room temperature. The reaction mixture was concentrated under reduced pressure to give the desired intermediate (15.3 g, crude) as a brown solid that was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+= 202.80. 20 Step 3: tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1S)-1-[4-(2-methylpyrazol-3-yl)phenyl] ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate HATU (34.00 g, 89.418 mmol) was added to a stirred solution of (1S)-1-[4-(2-methylpyrazol-3- yl)phenyl]ethanamine hydrochloride (15 g, 49.769 mmol), (2S,4R)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]- 25 3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (17.20 g, 49.941 mmol) and DIEA (28.95 g, 223.552 mmol) in DMF (150 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was dilute with water (400 mL) and extracted with EtOAc (400 mL x3). The combined organic layers were washed with brine (800 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Eluent: 30 0 to 10% MeOH in DCM) to afford the title compound (16.2 g) as a white solid. LCMS (ESI) m / z [M+H]+=528.45. 79 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 4: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(1-methyl-1H- pyrazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide; hydrogen chloride HCl (gas) in 1,4-dioxane (50 mL) was added to a solution of tert-butyl N-[(2S)-1-[(2S,4R)-4-hydroxy-2- {[(1S)-1-[4-(2-methylpyrazol-3-yl)phenyl] ethyl]carbamoyl}pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2- 5 yl]carbamate (5 g, 9.476 mmol) in DCM (50 mL) dropwise at room temperature. The resulting mixture was stirred for 1h at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (5.1 g, crude) as a brown solid that was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+= 428.20. 10 Intermediate 17: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-fluoro-1-methyl-1H- pyrazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride. Step 1: tert-butyl N-[(1S)-1-[4-(4-fluoro-2-methylpyrazol-3-yl)phenyl]ethyl]carbamate Selectfluor (3526.26 mg, 9.954 mmol) was added to a solution of tert-butyl N-[(1S)-1-[4-(2-methylpyrazol- 15 3-yl)phenyl]ethyl]carbamate (2 g, 6.636 mmol) in DMF (24 mL). The resulting mixture was stirred for 2 h at 50 °C. The resulting mixture was diluted with water (250 mL) and extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (Eluent: 0 to 100% EA in PE) to afford the title compound (417 mg) as a light yellow solid. LCMS (ESI) m / z 20 [M+H]+=320.17. Step 2: (S)-1-(4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)phenyl)ethan-1-amine hydrochloride HCl (gas) in 1,4-dioxane (4 mL) was added to a stirred solution of tert-butyl N-[(1S)-1-[4-(4-fluoro-2- methylpyrazol-3-yl)phenyl]ethyl]carbamate (400 mg, 1.252 mmol) in DCM (4 mL). The resulting mixture 25 was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford the desired product (397 mg, crude) as a yellow solid that was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+=220.12 80 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 3: tert-butyl N-[(2S)-1-[(2S,4R)-2-{[(1S)-1-[4-(4-fluoro-2-methylpyrazol-3-yl)phenyl]ethyl] carbamoyl}-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate HATU (815.74 mg, 2.146 mmol) was added to a stirred solution of (S)-1-(4-(4-fluoro-1-methyl-1H-pyrazol- 5-yl)phenyl)ethan-1-amine hydrochloride (392 mg, 1.788 mmol), (2S,4R)-1-[(2S)-2-[(tert- 5 butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (527.95 mg, 1.533 mmol) and DIEA (693.21 mg, 5.364 mmol) in DMF (6 mL). The resulting mixture was stirred for 1 h at room temperature. Without any additional work-up, the resulting mixture was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% TFA))to afford the title compound (443 mg) a s an off-white solid. LCMS (ESI) m / z [M+H]+= 546.30 10 Step 4: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-fluoro-1-methyl-1H-pyrazol-5- yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride HCl (gas) in 1,4-dioxane (1 mL) was added to a stirred solution of tert-butyl N-[(2S)-1-[(2S,4R)-2-{[(1S)-1- [4-(4-fluoro-2-methylpyrazol-3-yl)phenyl]ethyl] carbamoyl}-4-hydroxypyrrolidin-1-yl]-3,3-dimethyl-1- 15 oxobutan-2-yl]carbamate (35 mg, 0.064 mmol) in DCM (1 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford the title compound (41 mg, crude) as an off-white solid that was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+= 446.25. 20 Intermediate 18: 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-1,3-dimethyl- 7 -(oxetan-3-yloxy)quinolin-2-one Step 1: 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-7-methoxy-1,3- dimethylquinolin-2-one 25 XantPhos Pd G4 (170.55 mg, 0.177 mmol) was added to a stirred solution of 5-bromo-7-methoxy-1,3- dimethylquinolin-2-one (500 mg, 1.772 mmol), 2-chloro-3-(difluoromethyl)-5,6,7,8-tetrahydro-1,5- naphthyridine (387.45 mg, 1.772 mmol), Cs2CO3 (1.73 g, 5.316 mmol) and XantPhos (205.09 mg, 0.354 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred for 1 h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). 30 The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (Eluent: 0 to 50% EA in PE) to afford the desired product (630 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=420.12. 81 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 2: 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-7-hydroxy-1,3- dimethylquinolin-2-one A solution of 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-7-methoxy-1,3- dimethylquinolin-2-one (600 mg, 1.905 mmol) in hydrogen bromide-acetic acid solution (10 mL) was 5 stirred for 2 h at 80°C. The resulting mixture was diluted with water (50 mL) and extracted with CH2Cl2 (50 mL x 3). The combined organic layers were washed with brine (150 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 0.1% FA)) to afford 5- [6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-7-methoxy-1,3-dimethylquinolin-2-one 10 (379 mg) as a white solid. LCMS (ESI) m / z [M+H]+=406.11. Step 3: 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-1,3-dimethyl-7 -(oxetan-3- yloxy)quinolin-2-one K2CO3 (47.68 mg, 0.344 mmol) was added to a solution of 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H- 15 1,5-naphthyridin-1-yl] -7-hydroxy-1,3-dimethylquinolin-2-one (70 mg, 0.172 mmol) and 3-iodooxetane (95.20 mg, 0.516 mmol) in DMF (1 mL). The resulting mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (30 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 20 C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% NH4HCO3)) to afford the title compound (58 mg) as an orange oil. LCMS (ESI) m / z [M+H]+=462.15 Intermediate 19: 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-1,3-dimethyl- 1,6-naphthyridin-2-one 25 Step 1: 5-chloro-3-methyl-1H-1,6-naphthyridin-2-oneEt3N (11.63 g, 114.964 mmol) was added to a stirred solution of 4-amino-2-chloropyridine-3-carbaldehyde (9 g, 57.482 mmol) and DMAP (7.02 g, 57.482 mmol) in THF (30 mL). The resulting mixture was stirred for 10 min at room temperature. To the above mixture was added propanoyl chloride (10.64 g, 114.964 30 mmol) dropwise over 3 min at 0°C. The resulting mixture was stirred for additional 1 h at 80°C. The 82 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 precipitated solids were collected by filtration and washed with DCM (30 mL x 3) and water (30 mL x 3) to afford the desired product (4.9 g) as an off-white solid. LCMS (ESI) m / z [M+H]+=195.1. Step 2: 5-iodo-3-methyl-1H-1,6-naphthyridin-2-one 5 NaI (69.16 mL, 0.684 mmol) was added to a solution of 5-chloro-3-methyl-1H-1,6-naphthyridin-2-one (504 mg, 2.590 mmol) and chlorotrimethylsilane (1406.70 mg, 12.950 mmol) in MeCN (6 mL). The resulting mixture was stirred for 1 h at 120°C under nitrogen atmosphere. The precipitated solids were collected by filtration and washed with DCM (30 mL x 3) and water (30 mL x 3) to afford the desired intermediate (534.4 mg) as a black solid. LCMS (ESI) m / z [M+H]+=287.1. 10 Step 3: 5-iodo-1,3-dimethyl-1,6-naphthyridin-2-one CH3I (193.11 mg, 1.360 mmol) was added to a stirred solution of 5-iodo-3-methyl-1H-1,6-naphthyridin-2- one (194.6 mg, 0.680 mmol) and Cs2CO3 (443.28 mg, 1.360 mmol) in DMF (3 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (30 mL) and 15 washed with of water (30 mL x 3), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure to afford the title compound (157.3 mg) as a brown solid. LCMS (ESI) m / z [M+H]+=301.1. Step 4: 5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-1,3-dimethyl-1,6-naphthyridin- 20 2-one XantPhos Pd G4 (48.10 mg, 0.050 mmol) was added to a stirred solution of 5-iodo-1,3-dimethyl-1,6- naphthyridin-2-one (150 mg, 0.500 mmol), Cs2CO3 (325.71 mg, 1.000 mmol), XantPhos (28.92 mg, 0.050 mmol) and 2-chloro-3-(difluoromethyl)-5,6,7,8-tetrahydro-1,5-naphthyridine hydrochloride (127.50 mg, 0.500 mmol) in DMSO (3 mL). The resulting mixture was stirred for 1 h at 100°C under nitrogen 25 atmosphere. 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 (90 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 Pre-TLC (EA) to afford the title compound (69.9 mg) as a light yellow solid. LCMS (ESI) m / z [M+H]+=391.1. 30 83 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Intermediate 20: 5-((6-chloro-5-(difluoromethyl)pyridin-3-yl)(methyl)amino)-7-(2-hydroxyethoxy)- 1,3-dimethylquinolin-2(1H)-one Step 1: 5-bromo-2-chloro-3-(difluoromethyl)pyridine 5 DAST (25.71 mL, 194.601 mmol) was added dropwise to a stirred solution of 5-bromo-2-chloropyridine-3- carbaldehyde (14.3 g, 64.867 mmol) in DCM (140 mL) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was quenched by the addition of sat. NaHCO3 (aq.) (600 mL) at 0 °C and extracted with EtOAc (600 mL x 3). The combined organic layers were washed with brine (700 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under 10 reduced pressure. The residue was purified by FCC (Eluent: 0 to 10% MeOH in DCM) to afford the title compound (12.52 g) as a yellow oil. LCMS (ESI) m / z [M+H]+ =241.91. Step 2: N-(6-chloro-5-(difluoromethyl)pyridin-3-yl)-1,1-diphenylmethanimine Pd2(dba)3 (3.78 g, 4.125 mmol) was added to a solution of 5-bromo-2-chloro-3-(difluoromethyl)pyridine 15 (10 g, 41.246 mmol), diphenylmethanimine (7.48 g, 41.246 mmol), t-BuONa (5.15 g, 53.620 mmol,) and XantPhos (4.77 g, 8.249 mmol) in toluene (100 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) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the 20 desired intermediate (19.62 g, crude) as a brown oil that was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+=343.07. 84 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 3: 6-chloro-5-(difluoromethyl)pyridin-3-amine 1M solution of HCl (aq.) (100 mL) was added to a stirred solution of N-(6-chloro-5-(difluoromethyl)pyridin- 3-yl)-1,1-diphenylmethanimine (19.62 g, crude) in THF (100 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was basified to pH 7 with NaHCO3 (aq.) and extracted 5 with EtOAc (700 mL x 3). The combined organic layers were washed with brine (700 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% NH4HCO3)) to afford the desired product (6.34 g) as a light yellow solid. LCMS (ESI) m / z [M+H]+=179.01. 10 Step 4: 5-((6-chloro-5-(difluoromethyl)pyridin-3-yl)amino)-7-methoxy-1,3-dimethylquinolin-2(1H)-one XantPhos Pd G4 (204.66 mg, 0.213 mmol) was added to a stirred mixture of 5-bromo-7-methoxy-1,3- dimethylquinolin-2-one (600 mg, 2.127 mmol), 6-chloro-5-(difluoromethyl)pyridin-3-amine (379.75 mg, 2.127 mmol), XantPhos (123.05 mg, 0.213 mmol) and Cs2CO3 (1385.79 mg, 4.254 mmol) in toluene (5 15 mL). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. 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), 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% NH4HCO3)) to afford the desired product (261 mg) as a white 20 solid. LCMS (ESI) m / z [M+H]+=380.1. Step 5: 5-((6-chloro-5-(difluoromethyl)pyridin-3-yl)(methyl)amino)-7-methoxy-1,3-dimethylqui nolin-2(1H)- one NaH (23.70 mg, 0.987 mmol) was added to a stirred solution of 5-((6-chloro-5-(difluoromethyl)pyridin-3- 25 yl)amino)-7-methoxy-1,3-dimethylquinolin-2(1H)-one (250 mg, 0.658 mmol) in DMF (2 mL). The resulting mixture was stirred for 0.5 h. To the above resulting mixture was added CH3I (140.15 mg, 0.987 mmol). 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced 30 pressure. The resulting mixture was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% NH4HCO3)) to afford the title compound (198 mg) as a white solid. LCMS (ESI) m / z [M+H]+=394.1. Step 6: 5-((6-chloro-5-(difluoromethyl)pyridin-3-yl)(methyl)amino)-7-hydroxy-1,3-dimethylqu inolin-2(1H)- 35 one Hydrogen bromide-acetic acid solution (4 mL) was added to 5-((6-chloro-5-(difluoromethyl)pyridin-3- yl)(methyl)amino)-7-methoxy-1,3-dimethylqui nolin-2(1H)-one (180 mg, 0.457 mmol) and the resulting mixture was stirred for 2 days at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (60 mL) and extracted with CH2Cl2 (60 mL x 3). The combined organic layers were washed with 40 brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced 85 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 pressure to afford the desired intermediate (178 mg, crude) as a brown solid that was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+=380.2. Step 7: 5-((6-chloro-5-(difluoromethyl)pyridin-3-yl)(methyl)amino)-7-(2-hydroxyethoxy)-1,3- 5 dimethylquinolin-2(1H)-one K2CO3 (123.73 mg, 0.896 mmol) was added to a stirred solution of 5-((6-chloro-5-(difluoromethyl)pyridin- 3-yl)(methyl)amino)-7-hydroxy-1,3-dimethylqu inolin-2(1H)-one (170 mg, 0.448 mmol) and 2- bromoethanol (55.94 mg, 0.448 mmol) in DMF (5 mL). The resulting mixture was stirred for 2 h at 80°C. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The 10 combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by flash C18- flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% NH4HCO3)) to afford the title compound (71 mg) as a white solid. LCMS (ESI) m / z [M+H]+=424.1. 15 Intermediate 21: Preparation of tert-butyl 6-bromobenzo[e][1,2,4]triazine-3-carboxylic acid. Step 1. Ethyl (Z)-2-(2-(4-bromo-2-nitrophenyl)hydrazineylidene)-2-chloroacetate 12 N hydrochloric acid (13.5 mL) was added to a stirred solution of 4-bromo-2-nitroaniline (50 g, 230 mmol) in methanol (50 mL). The mixture was cooled in an ice-water bath and a solution of sodium nitrite 20 (17.5 g, 253 mmol) in water (10 mL) was added dropwise with stirring over a 15 minute period. The cold suspension was filtered, the solid was filtered out, and ethyl-2-chloroacetoacetate (1.4 mL, 10.1 mmol) was immediately added to the filtrate with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The suspension was filtered, and the filtered solid was collected, and washed with water (200 mL x 4). The yellow solid was dried under vacuum to afford the title compound 25 (57 g, crude) as a yellow solid. LCMS (ESI) m / z [M+H]+= 349.9 Step 2. Ethyl (Z)-2-amino-2-(2-(4-bromo-2-nitrophenyl)hydrazineylidene)acetate NH3(g) 7N in MeOH (25 mL) was added to a stirred solution of ethyl (Z)-2-(2-(4-bromo-2- nitrophenyl)hydrazineylidene)-2-chloroacetate (57 g, 0.014 mmol) in EtOH (50 mL). The resulting mixture 30 was stirred for 1 h at room temperature. The reaction mixture was poured into water (200 mL) and the 86 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 mixture was filtered. The filtered red solid was collected and washed with water (200 mL x4) and dried under vacuum to afford the title compound (42 g, crude) as a red solid. LCMS (ESI) m / z [M+H]+= 331.1 Step 3. Ethyl 6-bromobenzo[e][1,2,4]triazine-3-carboxylate 5 A solution of ethyl (Z)-2-amino-2-(2-(4-bromo-2-nitrophenyl)hydrazineylidene)acetate (25 g, 75.5 mmol) in a mixture of acetic acid (280 mL) and concentrated hydrochloric acid (40 mL) was added dropwise to a stirred mixture of iron powder (16.9 g, 302 mmol), water (120 mL), and concentrated hydrochloric acid (70 mL). The reaction mixture was stirred at room temperature for 2 h. The precipitated solids were collected by filtration and then dissolved with EA (1 L), filtered, the filtrate was concentrated and the crude product 10 was purified by flash chromatography over silica gel column chromatography (Eluent: PE / THF (3:1) to afford the title compound (7.2 g, 25.5 mmol) as a yellow solid. LCMS (ESI) m / z [M+H]+= 282.1 Step 4.6-Bromobenzo[e][1,2,4]triazine-3-carboxylic acid K2CO3 (4.41 g, 31.9 mmol) was added to a stirred solution of ethyl 6-bromobenzo[e][1,2,4]triazine-3- 15 carboxylate (3 g, 10.6 mmol) in MeCN (20 mL) and H2O (20 mL). The resulting mixture was stirred for 1 h at 60oC. The mixture was acidified to pH 5 with 1N HCl (aq.). The reaction mixture was diluted with EtOAc (300 mL x 2), the resulting mixture was washed with water (300 mL x 2) and saturated brine (300 mL x 2). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product (1.9 g) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; 20 Mobile Phase A: Water(0.05% HCl), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 11% B to 127% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.68) to afford the title compound (1.2 g, 4.72 mmols) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ = 8.67 – 8.59 (m, 2H), 8.35 – 8.27 (m, 1H). LCMS (ESI) m / z [M+H]+= 254.0. 25 Intermediate 22: 5-bromo-1,3-dimethyl-1,7-naphthyridin-2(1H)-one Step 1: 3,5-dibromo-4-(dimethoxymethyl)pyridine A catalytic amount of H2SO4 (185 mg, 101 μL, 1.89 mmol) was added to a solution of 3,5-Dibromo-4- pyridine carboxaldehyde (10.0 g, 37.8 mmol) and trimethyl orthoformate (8.01 g, 8.3 mL, 75.5 mmol) in 30 MeOH (30.0 mL). The resulting mixture was stirred at 60 °C for 1.5 h. The reaction mixture was quenched with iced DI water and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with saturated NaHCO3 (1 x 50 mL), brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered, and 87 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 concentrated to provide 3,5-dibromo-4-(dimethoxymethyl)pyridine (11.5 g, 37.0 mmol) as a light brown oil. Step 2: N-(5-bromo-4-(dimethoxymethyl)pyridin-3-yl)propionamide 5 Pd2(dba)3 (736 mg, 804 μmol), Xantphos (930 mg, 1.61 mmol) and cesium carbonate (15.7 g, 48.2 mmol) was added to a degassed solution of 3,5-Dibromo-4-(dimethoxymethyl)pyridine (5.00 g,16.1 mmol) and propionamide (1.18 g, 1.13 mL, 16.1 mmol) in 1,4-Dioxane (30.0 mL). The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The reaction mixture was allowed to cool to rt, quenched with DI water, and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined 10 organic layers were washed with brine (1 x 35 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide crude product as a dark yellow oil. The crude product was purified by FCC (Eluent: 0 to 50% EA in heptane) to provide pure N-(5-bromo-4-(dimethoxymethyl)pyridin-3- yl)propionamide (2.45 g, 8.08 mmol) as a yellow oil. 15 Steps 3 and 4: N-(5-bromo-4-formylpyridin-3-yl)-N-propionylpropionamide A mixture of hydrogen chloride (365 mg, 10.0 mL, 1.00 molar, 10.0 mmol) and water (25.0 mL) was added to N-(5-bromo-4-(dimethoxymethyl)pyridin-3-yl)propionamide (3.00 g, 9.90 mmol). The resulting mixture was stirred at 50 °C overnight. The reaction was cooled to rt and extracted with EtOAC (3 x 15 mL). The combined organic layers were washed with sat sodium bicarbonate (1 x 35 mL), water (1 x 35 20 mL), brine (1 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide a crude product. Pyridine (1.57 g, 19.9 mmol) and propionyl chloride (3.68 g, 39.8 mmol) was added to a solution of 3-amino-5-bromoisonicotinaldehyde (500 mg, 2.49 mmol) in DCM (15.0 mL) at 0 °C. The resulting mixture was allowed to warm to rt and stirred for 3 h. The reaction mixture was cooled to 0 °C and quenched with DI water. The mixture was extracted with DCM (3 x 15 mL) and the organic layers 25 were combined, washed with water (2 x 30 mL), brine (1 x 45 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken forward without further purification. Step 5: 5-bromo-3-methyl-1,7-naphthyridin-2(1H)-one Cesium carbonate (2.43 g, 7.46 mmol) was added to a solution of N-(5-bromo-4-formylpyridin-3-yl)-N- 30 propionylpropionamide (779 mg, 2.49 mmol) in DMF (10.0 mL). The resulting mixture was heated to 60 °C for 2 h with stirring. The reaction was cooled to 0 °C and quenched with DI water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (1 x 30 mL), brine (1 x 45 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide crude product. The crude product was purified by FCC (Eluent: 0 to 60% EA in heptane) to provide 5-bromo-3-methyl-1,7- 35 naphthyridin-2(1H)-one (450 mg, 1.88 mmol) as a yellow solid. Step 6: 5-bromo-1,3-dimethyl-1,7-naphthyridin-2(1H)-one Cesium carbonate (1.84 g, 5.65 mmol) and iodomethane (534 mg, 3.76 mmol) was added to a solution of 5-bromo-3-methyl-1,7-naphthyridin-2(1H)-one (450 mg, 1.88 mmol) in DMF (10.0 mL). The resulting 40 mixture was stirred at rt for 3 h. The reaction mixture was quenched with DI water and extracted with 88 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 DCM (3 x 15 mL). The combined organic layers were washed with water (2 x 25 mL), brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide crude product. The crude material was purified by FCC (Eluent: 0 to 50% EA in heptane) to provide pure 5-bromo-1,3- dimethyl-1,7-naphthyridin-2(1H)-one (198 mg, 782 μmol) as a light yellow solid. 5 Intermediate 23: 7-bromo-5-methoxy-1,3-dimethylquinoxalin-2(1H)-one Step 1: 5-bromo-3-methoxybenzene-1,2-diamine Ammonium chloride (6.50 g, 121.430 mmol) was added to a stirred solution of 4-bromo-2-methoxy-6- 10 nitroaniline (3 g, 12.143 mmol) and Fe (3.39 g, 60.715 mmol) in EtOH (30 mL) and H2O (6 mL). After the reaction was completed, filtered while hot and concentrated under reduced pressure to give crude product. The crude product was diluted with water (200 mL) and extracted with EtOAc (200 mL x 2). The organic layers were combined and washed with brine (200 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give crude product. The crude product was purified by FCC (Eluent: 0 to 60% EA in 15 heptane) to afford the title compound (2.6 g) as a white solid. LCMS (ESI) m / z [M+H]+=216.99 Step 2: 7-bromo-5-methoxy-3-methylquinoxalin-2(1H)-one Methyl-pyruvate (1467.38 mg, 14.374 mmol) was added to a stirred solution of 5-bromo-3- methoxybenzene-1,2-diamine (2.6 g, 11.978 mmol) in EtOH (32 mL) and HOAc (1.6 mL). The resulting 20 mixture was stirred at 80 °C for 1 h. The precipitated solids were collected by filtration and washed with H2O (80 mL) to afford the desired intermediate (1.4 g, crude) as a white solid that was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+=268.98. Step 3: 7-bromo-5-methoxy-1,3-dimethylquinoxalin-2(1H)-one 25 Methyl iodide (348.12 mg, 2.453 mmol) was added to a stirred solution of 7-bromo-5-methoxy-3- methylquinoxalin-2(1H)-one (600 mg, 2.230 mmol) and Cs2CO3 (871.76 mg, 2.676 mmol) in DMF (8 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL x 2). The organic layers were combined and washed with brine (80 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give crude product. The crude product 30 was purified by FCC (Eluent: 0 to 100% EA in PE) to afford the title compound (456 mg) as a white solid. LCMS (ESI) m / z [M+H]+=383.00. 89 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Intermediate 24: 5-{[5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino}-7-(2-hydroxyethoxy)- 1,3-dimethylquinolin-2-one Step 1: 7-methoxy-1,3-dimethyl-2-oxoquinolin-5-ylboronic acid 5 Pd(dppf)Cl2 (0.52 g, 0.709 mmol) was added to a stirred solution of 5-bromo-7-methoxy-1,3- dimethylquinolin-2-one (2 g, 7.089 mmol), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2- dioxaborinane (2.08 g, 9.216 mmol) and KOAc (1.39 g, 14.178 mmol) in dioxane (40 mL). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction mixture was diluted with water (200 mL) and extracted with MTBE (200 mL x 3). The combined organic layers were washed with 10 brine (400 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the desired intermediate (1.96 g, crude) as a brown solid that was used directly without further purification. LCMS (ESI) m / z [M+H]+=248.10. Step 2: 7-methoxy-1,3-dimethyl-5-(methylamino)quinolin-2-one 15 NaOH (485.68 mg, 12.144 mmol) was added to a stirred solution of 7-methoxy-1,3-dimethyl-2- oxoquinolin-5-ylboronic acid (1 g, 4.048 mmol) and 1-(methylamino)-1lambda3,2-benziodaoxol-3-one (1.24 g, 4.453 mmol) in THF (20 mL) at 0°C. The resulting mixture was stirred for 2 h at 60 °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 20 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Eluent: 0 to 100% EA in PE) to afford the title compound (375 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=233.12. Step 3: 5-{[5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino}-7-methoxy-1,3-dimethylquinolin-2-one25 XPhos Pd G3 (145.76 mg, 0.172 mmol) was added to a stirred solution of 7-methoxy-1,3-dimethyl-5- (methylamino)quinolin-2-one (200 mg, 0.861 mmol), 2,5-dichloro-4-(difluoromethyl)pyridine (511.42 mg, 2.583 mmol) and t-BuONa (248.24 mg, 2.583 mmol) in toluene (6 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 (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried 30 over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by 90 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 10mmol / L NH4HCO3)) to afford the desired product (58 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=394.11. Step 4: 5-{[5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino}-7-hydroxy-1,3-dimethylquinolin-2-one 5 TBAB (4.26 mg, 0.013 mmol) was added to a stirred solution of 5-{[5-chloro-4-(difluoromethyl)pyridin-2- yl](methyl)amino}-7-methoxy-1,3-dimethylquinolin-2-one (52 mg, 0.132 mmol) in hydrogen bromide-acetic acid solution (2 mL). The resulting mixture was stirred for overnight at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and 10 concentrated to afford the desired intermediate (73 mg, crude) as a yellow oil that was used directly without further purification. LCMS (ESI) m / z [M+H]+=380.09. Step 5: 5-{[5-chloro-4-(difluoromethyl)pyridin-2-yl](methyl)amino}-7-(2-hydroxyethoxy)-1,3- dimethylquinolin-2-one 15 K2CO3 (98.98 mg, 0.716 mmol) was added to a stirred solution of 5-{[5-chloro-4-(difluoromethyl)pyridin-2- yl](methyl)amino}-7-hydroxy-1,3-dimethylquinolin-2-one (68 mg, 0.179 mmol) and 2-bromoethanol (26.85 mg, 0.215 mmol) in DMF (2 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. After20 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% TFA)) to afford the title compound (38 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=424.12. Intermediate 25: 5-(6-chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-7-methoxy- 25 1,3-dimethyl-1,6-naphthyridin-2(1H)-one Step 1: 7-chloro-5-hydroxy-1,3-dimethyl-1,6-naphthyridin-2(1H)-one 7-chloro-5-methoxy-1,3-dimethyl-1,6-naphthyridin-2-one (5 g, 20.949 mmol) was dissolved in a solution of hydrogen bromide (20% in Methanol) (60 mL) and stirred at 60 °C for 1 h. The residue was purified by 30 trituration with H2O (100 mL). The precipitated solids were collected by filtration and washed with H2O (30 mL x 3) to afford the desired product (4.1 g) as a white solid. LCMS (ESI) m / z [M+H]+=225.04 91 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 2: 5-hydroxy-7-methoxy-1,3-dimethyl-1,6-naphthyridin-2(1H)-one di-tert-butyl[3-methoxy-6-methyl-2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane; {2'-amino-[1,1'- biphenyl]-2-yl}palladio methanesulfonate (279.93 mg, 0.334 mmol) was added to a stirred solution of 7- 5 chloro-5-hydroxy-1,3-dimethyl-1,6-naphthyridin-2(1H)-one (750 mg, 3.339 mmol), methanol (320.93 mg, 10.017 mmol), di-tert-butyl[3-methoxy-6-methyl-2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (156.49 mg, 0.334 mmol) and Cs2CO3 (2175.61 mg, 6.678 mmol) in 1,4-dioxane (9 mL). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, diluted with water (200 mL) and extracted with CH2Cl2 (200 mL x 2). The organic 10 layers were combined and washed with brine (200 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by FCC (Eluent: 0 to 10% MeOH in DCM) to afford the title compound (554 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=221.08. Step 3: 7-methoxy-1,3-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl trifluoromethanesulfonate 15 To a stirred solution of 5-hydroxy-7-methoxy-1,3-dimethyl-1,6-naphthyridin-2(1H)-one (535 mg, 2.429 mmol, 1 equiv) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (1301.76 mg, 3.643 mmol, 1.5 equiv) in DMF (8 mL) was added Et3N (737.48 mg, 7.287 mmol, 3 equiv).The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 2). The organic layers were combined and washed 20 with brine (200 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford the desired product (847 mg, 98.97%) as a white solid. LCMS (ESI) m / z [M+H]+=353.03. 25 Step 4: 5-(6-chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-7-methoxy-1,3-dimethyl-1,6- naphthyridin-2(1H)-one XantPhos Pd G4 (76.49 mg, 0.080 mmol) was added to a stirred solution of 7-methoxy-1,3-dimethyl-2- oxo-1,2-dihydro-1,6-naphthyridin-5-yl trifluoromethanesulfonate (280 mg, 0.795 mmol), 2-chloro-3- (difluoromethyl)-5,6,7,8-tetrahydro-1,5-naphthyridine hydrochloride (223.03 mg, 0.875 mmol) and Cs2CO3 30 (517.94 mg, 1.590 mmol) in 1,4-dioxane (4 mL). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The organic layers were combined and washed with brine (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by FCC (Eluent: 0 to 60% EA in PE) to afford the title compound (247 mg) as a white solid. LCMS (ESI) m / z 35 [M+H]+=421.12. 92 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Intermediate 26: (S)-5-(6-chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-7-(3- hydroxypyrrolidin-1-yl)-1,3-dimethyl-1,6-naphthyridin-2(1H)-one Step 1: 7-[(3S)-3-hydroxypyrrolidin-1-yl]-5-methoxy-1,3-dimethyl-1,6-naphthyridin-2-one 5 XantPhos Pd G4 (604.85 mg, 0.629 mmol) was added to a stirred solution of 7-chloro-5-methoxy-1,3- dimethyl-1,6-naphthyridin-2-one (500 mg, 2.095 mmol), (3S)-pyrrolidin-3-ol hydrochloride (388.34 mg, 3.143 mmol) and Cs2CO3 (2.05 g, 6.285 mmol) in dioxane (5 mL). The resulting mixture was stirred at 100°C for 1 h under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), then 10 dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by FCC (elution gradient 0 to 100% EtOAc in petroleum ether) to afford the title compound (388 mg) as a light yellow solid. LCMS (ESI) m / z [M+H]+=290.14. Step 2: (3S)-1-(5-methoxy-1,3-dimethyl-2-oxo-1,6-naphthyridin-7-yl)pyrrolidin-3-ylbenzoate 15 Benzoyl chloride (204.05 mg, 1.452 mmol) was added to a stirred solution of 7-[(3S)-3-hydroxypyrrolidin- 1-yl]-5-methoxy-1,3-dimethyl-1,6-naphthyridin-2-one (280 mg, 0.968 mmol), TEA (293.78 mg, 2.904 mmol) and DMAP (59.11 mg, 0.484 mmol) in DCM (5 mL) was added benzoyl chloride (204.05 mg, 1.452 mmol). 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 FCC (elution gradient 0 to 20 100% EtOAc in petroleum ether) to afford the title compound (294 mg) as a white solid. LCMS (ESI) m / z [M+H]+=394.17. Step 3: (3S)-1-(5-methoxy-1,3-dimethyl-2-oxo-1,6-naphthyridin-7-yl)pyrrolidin-3-ylbenzoate NaI (320.02 mg, 2.136 mmol) was added to a stirred solution of (3S)-1-(5-methoxy-1,3-dimethyl-2-oxo- 25 1,6-naphthyridin-7-yl)pyrrolidin-3-ylbenzoate (280 mg, 0.712 mmol) and TMSCl (231.95 mg, 2.136 mmol) in ACN (5 mL) was added. The resulting mixture was stirred at 80°C for 1 h. The resulting mixture was quenched with sat. Na2S2O3(60 mL) and extracted with EtOAc (60 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (243 mg) as a yellow solid that was 30 used directly without further purification. LCMS (ESI) m / z [M+H]+=380.15. 93 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 4: (3S)-1-(5-bromo-1,3-dimethyl-2-oxo-1,6-naphthyridin-7-yl)pyrrolidin-3-yl benzoate Phosphoroyl tribromide (906.71 mg, 3.165 mmol) was added to a stirred solution of (3S)-1-(5-methoxy- 1,3-dimethyl-2-oxo-1,6-naphthyridin-7-yl)pyrrolidin-3-ylbenzoate (240 mg, 0.633 mmol) in ACN (8 mL). The resulting mixture was stirred at 80°C for 6 h. The resulting mixture was quenched with sat. NaHCO3 5 (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with saturated brine (80 mL) and dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (elution gradient 0 to 100% EtOAc in petroleum ether) to afford the title compound (189 mg) as a light yellow solid. LCMS (ESI) m / z [M+H]+=442.07. 10 Step 5: (3S)-1-{5-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1-yl]-1,3-dimethyl-2-oxo- 1,6-naphthyridin-7-yl}pyrrolidin-3-yl benzoate XantPhos Pd G4 (117.49 mg, 0.122 mmol) was added to a stirred mixture of (3S)-1-(5-bromo-1,3- dimethyl-2-oxo-1,6-naphthyridin-7-yl)pyrrolidin-3-yl benzoate (180 mg, 0.407 mmol), 2-chloro-3- 15 (difluoromethyl)-5 ,6,7,8-tetrahydro-1,5-naphthyridine hydrochloride (103.81 mg, 0.407 mmol), Cs2CO3 (398.05 mg, 1.221 mmol) and XantPhos (23.69 mg, 0.041 mmol) in dioxane (5 mL). The resulting mixture was stirred at 80°C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), then dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by FCC 20 (elution gradient 0 to 100% EtOAc in petroleum ether) to afford the title compound (157 mg, 66.43%) as a light yellow solid. LCMS (ESI) m / z [M+H]+=580.18. Step 6: (S)-5-(6-chloro-7-(difluoromethyl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-7-(3-hydroxypyrrolidin-1- yl)-1,3-dimethyl-1,6-naphthyridin-2(1H)-one 25 NaOH (126.06 mg, 3.150 mmol) was added to a stirred solution of (3S)-1-{5-[6-chloro-7-(difluoromethyl)- 3,4-dihydro-2H-1,5-naphthyridin-1-yl]-1,3-dimethyl-2-oxo-1,6-naphthyridin-7-yl}pyrrolidin-3-yl benzoate (150 mg, 0.315 mmol) in MeOH (3 mL) was added. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), then dried over anhydrous sodium sulfate, 30 filtered and concentrated. The crude product was purified by FCC (elution gradient 0 to 10% MeOH in DCM) to afford the title compound (94 mg, 76.39%) as a light yellow solid. LCMS (ESI) m / z [M+H]+=476.16. Intermediate 27: 1,3-dimethyl-2-oxo-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydro-1,6- 35 naphthyridin-5-yl trifluoromethanesulfonate 94 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 1: 7-chloro-1,3-dimethyl-1,6-naphthyridine-2,5(1H,6H)-dione A solution of 7-chloro-5-methoxy-1,3-dimethyl-1,6-naphthyridin-2-one (1 g, 4.190 mmol) in hydrogen bromide (20% in Methanol) (15 mL) was stirred for 12 h at 60°C. The resulting mixture was diluted with water (15 mL). The precipitated solids were collected by filtration and washed with water (10 mL x 3) to 5 afford the title compound (744 mg, crude) as a white solid which was used directly in the next step. LCMS (ESI) m / z [M+H]+=224.90. Step 2: 1,3-dimethyl-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,6-naphthyridine-2,5(1H,6H)-dione DIEA (604.12 mg, 4.674 mmol) was added to a stirred solution of 7-chloro-1,3-dimethyl-1,6- 10 naphthyridine-2,5(1H,6H)-dione (350 mg, 1.558 mmol), bis(2-oxa-6-azaspiro[3.3]heptane) and oxalic acid (898.37 mg, 3.116 mmol) in DMSO (5 mL). The resulting mixture was stirred for 1 h at 120 °C. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash 15 chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% FA)) to afford the title compound (298 mg) as a white solid. LCMS (ESI) m / z [M+H]+=288.15. Step 3: 1,3-dimethyl-2-oxo-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,2-dihydro-1,6-naphthyridin-5-yl trifluoromethanesulfonate 20 Et3N (269.81 mg, 3.654 mmol) was added to a stirred solution of 1,3-dimethyl-7-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-1,6-naphthyridine-2,5(1H,6H)-dione (250 mg, 0.938 mmol) and 1,1,1-trifluoro-N- phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (552.76 mg, 1.227 mmol) in DMF (7 mL) was added The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed 25 with brine (40 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 60% EtOAc in petroleum ether) to afford the title compound (211 mg) as a white solid. LCMS (ESI) m / z [M+H]+=420.05. Intermediate 28: 5-{[6-chloro-5-(difluoromethyl)pyridin-3-yl](methyl)amino}-7-(2-hydroxyethoxy)- 30 1,3-dimethyl-1,6-naphthyridin-2-one 95 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 1: 7-chloro-5-hydroxy-1,3-dimethyl-1,6-naphthyridin-2-one A solution of 7-chloro-5-methoxy-1,3-dimethyl-1,6-naphthyridin-2-one (1 g, 4.190 mmol) in hydrogen bromide-acetic acid solution (15 mL) was stirred for 1 h at 60°C. The resulting mixture was diluted with water (15 mL). The precipitated solids were collected by filtration and washed with acetone (5 mL x 5) to 5 afford the title compound (886 mg) as a white solid. LCMS (ESI) m / z [M+H]+=225.04. Step 2: 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-5-hydroxy-1,3-dimethyl-1,6-naphthyridin-2-one RockPhos Pd G3 (223.94 mg, 0.267 mmol) was added to a stirred solution of 7-chloro-5-hydroxy-1,3- dimethyl-1,6-naphthyridin-2-one (600 mg, 2.671 mmol), 2-[(tert-butyldimethylsilyl)oxy]ethanol (1.88 g, 10 10.684 mmol), RockPhos (125.19 mg, 0.267 mmol) and Cs2CO3 (2.61 g, 8.013 mmol) in 1,4-dioxane (6 mL). The resulting mixture was stirred at 100°C for 3 h 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 (60 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 10% MeOH in 15 CH2Cl2) to afford the title compound (344 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=365.18. Step 3: 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-1,3-dimethyl-2-oxo-1,6-naphthyridin-5-yl trifluoromethanesulfonate 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane) sulfonylmethanesulfonamide (499.82 mg, 1.400 mmol) was20 added to a stirred solution of 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-5-hydroxy-1,3-dimethyl-1,6- naphthyridin-2-one (340 mg, 0.933 mmol) and TEA (283.16 mg, 2.799 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 1 h. 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 25 crude product was purified by FCC (elution gradient 0 to 100% EtOAc in PE) to afford the title compound (345 mg) as a white solid. LCMS (ESI) m / z [M+H]+=497.16. Step 4: 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-5-{[6-chloro-5-(difluoromethyl)pyridin-3-yl]amino}-1,3- dimethyl-1,6-naphthyridin-2-one 30 XantPhos Pd G4 (58.14 mg, 0.060 mmol) was added to a stirred solution of 7-{2-[(tert- butyldimethylsilyl)oxy]ethoxy}-1,3-dimethyl-2-oxo-1,6-naphthyridin-5-yl trifluoromethanesulfonate (300 mg, 0.604 mmol), 6-chloro-5-(difluoromethyl)pyridin-3-amine (118.67 mg, 0.664 mmol), XantPhos (69.92 mg, 0.121 mmol) and Cs2CO3 (590.53 mg, 1.812 mmol) in 1,4-dioxane (3 mL). The resulting mixture was stirred at 80°C for 1 h under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) 35 and extracted with EtOAc (30 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 FCC (elution gradient 0 to 100% EtOAc in PE) to afford the title compound (255 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=525.20. 96 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 5: 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-5-{[6-chloro-5-(difluoromethyl)pyridin-3-yl](methyl)amino}- 1,3-dimethyl-1,6-naphthyridin-2-one NaH (54.85 mg, 2.285 mmol) was added to a stirred solution of 7-{2-[(tert-butyldimethylsilyl)oxy]ethoxy}-5- {[6-chloro-5-(difluoromethyl)pyridin-3-yl]amino}-1,3-dimethyl-1,6-naphthyridin-2-one (240 mg, 0.457 mmol) 5 in DMF (3 mL). The resulting mixture was stirred at 0°C for 30 min under nitrogen atmosphere. To the above mixture was added CH3I (129.76 mg, 0.914 mmol) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched by the addition of sat. NH4Cl (aq.) (30 mL) at 0°C and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under 10 reduced pressure. The crude product was purified by FCC (elution gradient 0 to 100% EtOAc in PE to afford the title compound (192 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=539.20. Step 6: 5-{[6-chloro-5-(difluoromethyl)pyridin-3-yl](methyl)amino}-7-(2-hydroxyethoxy)-1,3-dimethyl-1,6- naphthyridin-2-one 15 Tetra-n-butylammonium fluoride (1.0M in THF) (2 mL) was added dropwise to a stirred solution of 7-{2- [(tert-butyldimethylsilyl)oxy]ethoxy}-5-{[6-chloro-5-(difluoromethyl)pyridin-3-yl](methyl)amino}-1,3- dimethyl-1,6-naphthyridin-2-one (190 mg, 0.352 mmol) in THF (2 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched with MeOH at room temperature and diluted with water (20 mL). The 20 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 FCC (elution gradient 0 to 100% EtOAc in PE) to afford the title compound (82 mg) as a white solid. LCMS (ESI) m / z [M+H]+=425.11. 25 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 30 in the art without departing from the spirit of the present disclosure and / or scope of the appended claims. 97 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Example 1: (2S,4R)-1-[(2S)-2-({6-[7-(difluoromethyl)-1',3'-dimethyl-2'-oxo-3,4-dihydro-2H-[1,5'- biquinolin]-6-yl]pyrazolo[1,5-a]pyrimidin-2-yl}formamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl] pyrrolidine-2-carboxamide 5 Step 1: (2S,4R)-1-[(2S)-2-({6-bromopyrazolo[1,5-a]pyrimidin-2-yl}formamido)-3,3-dimethylbutanoyl]- 4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide HATU (2.37 g, 6.237 mmol) was added to a stirred mixture of (2S,4R)-1-[(2S)-2-amino-3,3- dimethylbutanoyl]-4-hydroxy-N- [(1S)- 1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide hydrochloride (2 g, 4.158 mmol), 6-bromopyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1.01 g, 10 4.158 mmol), and DIEA (1.07 g, 8.316 mmol) in DMF (50 mL). The resulting mixture was stirred for 1h at room temperature. 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 (300 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 15 min; detector, UV 254 nm) affording the title compound (2.35 g) as a light-brown solid. LCMS (ESI) m / z [M+H]+=668.2. Step 2: (2S,4R)-1-[(2S)-3,3-dimethyl-2-{[6-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyrimidin-2-yl]formamido}butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5- 20 yl)phenyl]ethyl]pyrrolidine-2-carboxamide XPhos Pd G3 (0.29 g, 0.344 mmol) was added to a stirred solution of (2S,4R)-1-[(2S)-2-({6- bromopyrazolo[1,5-a]pyrimidin-2-yl}formamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2.3 g, 3.440 mmol), 4,4,5,5-tetraethyl-2-(4,4,5,5- tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.89 g, 5.160 mmol), and KOAc (0.68 g, 6.880 25 mmol) in dioxane (30 mL). The resulting mixture was stirred for 1 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 crude product was purified by silica gel column chromatography (Eluent: CH2Cl2 / MeOH (10:1)) to afford the desired product (1.92 g) as a light brown 30 solid. LCMS (ESI) m / z [M+H]+= 772.4. 98 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Step 3. (2S,4R)-1-[(2S)-2-({6-[7-(difluoromethyl)-1',3'-dimethyl-2'-oxo-3,4-dihydro-2H-[1,5'- biquinolin]-6-yl]pyrazolo[1,5-a]pyrimidin-2-yl}formamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)- 1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl] pyrrolidine-2-carboxamide XPhos Pd G3 (8.71 mg, 0.010 mmol) and Cs2CO3 (67.03 mg, 0.206 mmol) was added to a stirred mixture 5 of 6-chloro-7-(difluoromethyl)-1',3'-dimethyl-3,4-dihydro-2H-[1,5'-biquinolin]-2'-one and (2S,4R)-1-[(2S)- 3,3-dimethyl-2-{[6-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidin-2- yl]formamido}butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide (79.39 mg, 0.103 mmol) in dioxane (2 mL) and H2O (0.5 mL). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) extracted 10 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. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 EXRS 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 51% B to 64% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.65) to afford 15 Example 1 (11.8 mg) as a white solid.1H NMR (300 MHz, DMSO-d6) δ = 9.11 – 9.05 (m, 1H), 8.98 (s, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.77 – 7.73 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.41 – 7.33 (m, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.20 – 7.13 (m, 1H), 6.80 (t, J = 54.6 Hz, 1H), 6.20 (s, 1H), 5.16 (d, J = 3.0 Hz, 1H), 4.93 (t, J = 7.1 Hz, 1H), 4.76 (d, J = 9.5 Hz, 1H), 4.47 (t, J = 8.3 Hz, 1H), 4.37 – 4.22 (m, 1H), 3.72 (s, 3H), 3.68 – 3.53 (m, 3H), 20 3.07 – 2.95 (m, 2H), 2.45 (s, 3H), 2.31 – 2.02 (m, 6H), 1.85 – 1.72 (m, 1H), 1.38 (d, J = 7.0 Hz, 3H), 1.02 (s, 9H) ppm. LCMS (ESI) m / z [M+H]+=942. The following examples in TABLE 1a were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 1. 25 99 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Table 1a 100 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 101 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 102 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 103 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 104 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 105 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 106 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 107 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 108 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 109 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 110 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 111 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 112 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 113 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 114 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 115 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 116 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 117 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Example 40: 6-[6-(difluoromethyl)-4-(1,3-dimethyl-2-oxoquinolin-5-yl)-2,3-dihydro-1,4-benzoxazin-7- yl]-N-[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]-1,2,4-benzotriazine-3- 5 carboxamide Step 1: ethyl 6-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)benzo[e][1,2,4]triazine-3-carboxylate. Pd(dppf)Cl2 (0.39 g, 0.532 mmol) was added to a stirred solution of ethyl 6-bromo-1,2,4-benzotriazine-3- carboxylate (1 g, 3.545 mmol), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- 10 dioxaborolane (2.60 g, 7.090 mmol) and KOAc (1.04 g, 10.635 mmol) in dioxane (10 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 (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 118 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 The residue was purified by silica gel column chromatography (Eluent: 0 to 100% EA in PE) to afford the title compound (1.9 g) as a red solid. LCMS (ESI) m / z [M+H]+=385.3. Step 2.6-[6-(difluoromethyl)-4-(1,3-dimethyl-2-oxoquinolin-5-yl)-2,3-dihydro-1,4-benzoxazin-7-yl]- 5 1,2,4-benzotriazine-3-carboxylic acid K3PO4 (103.20 mg, 0.486 mmol) and XPhos Pd G3 (20.33 mg, 0.024 mmol) was added to a stirred solution of 5-[7-chloro-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-1,3-dimethylquinolin-2-one (95 mg, 0.243 mmol) and ethyl 6-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,2,4-benzotriazine-3-carboxylate (140.48 mg, 0.364 mmol) in dioxane (0.8 mL) and H2O (0.2 mL). The resulting mixture was stirred for 10 additional 1 h at 80 °C under nitrogen atmosphere. The mixture was acidified to pH 5 with HCl (aq.). 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 residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 15 min; detector, 15 UV 254 nm to provide the desired product (97 mg) as a yellow solid. LCMS (ESI) m / z [M+H]+=530.2. Step 3.6-[6-(difluoromethyl)-4-(1,3-dimethyl-2-oxoquinolin-5-yl)-2,3-dihydro-1,4-benzoxazin-7-yl]-N- [(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1- yl]-3,3-dimethyl-1-oxobutan-2-yl]-1,2,4-benzotriazine-3-carboxamide 20 NMI (18.61 mg, 0.226 mmol) and TCFH (38.15 mg, 0.136 mmol) was added to a stirred solution of 6-[6- (difluoromethyl)-4-(1,3-dimethyl-2-oxoquinolin-5-yl)-2,3-dihydro-1,4-benzoxazin-7-yl]-1,2,4-benzotriazine- 3-carboxylic acid (60 mg, 0.113 mmol) and (2R,4S)-1-[(2R)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N- {[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride (52.92 mg, 0.113 mmol) in DMF (3 mL). The resulting mixture was stirred for an additional 1 h at room temperature. Without 25 any additional work-up, the mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5m; Mobile Phase A: Water(0.5%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 38% B to 55% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.52) to afford Example 40 (11.5 mg) as a red solid.1H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.79 (d, J = 9.5 Hz, 1H), 8.69 (d, J = 9.4 Hz, 1H), 8.44 (s, 1H), 8.15 – 8.05 (m, 2H), 7.88 (d, J = 1.5 30 Hz, 1H), 7.77 – 7.68 (m, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.43 (s, 4H), 7.33 (dd, J = 7.8, 1.0 Hz, 1H), 7.09 (s, 1H), 6.71 (t, 1H), 6.47 (s, 1H), 4.91 (d, J = 9.5 Hz, 1H), 4.64 (s, 1H), 4.58 – 4.34 (m, 4H), 4.30 (d, 1H), 3.74 (s, 8H), 2.46 (s, 3H), 2.18 (d, J = 1.3 Hz, 3H), 2.15 – 2.06 (m, 1H), 2.06 – 1.93 (m, 1H), 1.10 (s, 9H). LCMS (ESI) m / z [M+H]+=942.3. 35 The following examples in TABLE 2 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 23. 119 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Table 2 120 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 121 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Example 49: Example: U2OS IF Degradation Assay Procedure: A set of two CRISPR knock-in stable U2OS polyclonal cell lines, each with a HiBiT tag fused 5 to either CREBBP or EP300 were purchased from Promega. On day 0, cells were seeded in 30 μL phenol-free RPMI media supplemented with 10% FBS into each well of 384-well cell culture plates. The seeding density was 5000 cells / well. On day one, cells were treated with 90 nL DMSO or 90 nL of 3-fold serially DMSO-diluted compounds (10 points in duplicates with 30 μM as final top dose). Subsequently plates were incubated for 24 hours in a standard tissue culture incubator. After the 24 hours incubation, 10 medium was removed and cells were fixed with a solution of 4% paraformaldehyde for 20 minutes at room temperature. Subsequently, cells were washed three times with PBS-0.1% Tween20 and permeabilized with a 0.1%Triton X-100 solution for 20 minutes at room temperature. Cells were then washed three times with 15 PBS-0.1% Tween20 and incubated with blocking buffer (5% goat serum PBS-0.1% Tween20) for 1 hour at room temperature. Cells were washed three times with PBS-0.1% Tween20. Subsequently cells were incubated with primary antibody appropriately diluted in blocking buffer. Cells were incubated in primary antibody over night at 4℃. U2OS CREBBP HiBiT line was stained with a CREBBP specific primary antibody and U2OS EP300 HiBiT line was stained with a EP300 specific primary antibody. Cells were 20 washed three times with PBS-0.1% Tween20. Cells were then incubated in secondary antibody conjugated with Alexa 488 fluorophore appropriately diluted in PBS-0.1% Tween20 for 1 hour at room temperature. A DAPI stain solution (0.1ug / ml) was added to stain the cell nuclei for 5 minutes at room temperature. Cells were washed three times with PBS-0.1% Tween20 and finally 80ul of PBS-only were added to the well. Cells were imaged with a high content imager at 20X magnification and fluorescence 25 was quantified with the imager analyses software. Results: The Inhibition% was calculated using the following formula: %Inhibition = 100 x (1-fluorescence intensity / fluorescence intensity DMSO). The data was fit to a four parameter, non-linear curve fit to calculate DC50 (μM) values using Graphpad PRISM. DC50 and Dmax values are shown in Table 3. 122 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Table 3 123 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Example 50. CBP degrader treatment with CDK4 / 6 inhibition in ER+ breast cancer Procedure: MCF7 and T47D cell lines were treated with either a) abemaciclib, fulvestrant, and DMSO, or 5 b) abemaciclib (e.g, 0nM, 12.5nM, 25nM, or 50nM), fulvestrant (e.g.0 nM, 0.05nM, 0.1nM), and 1 nM Compound A over 14 days. Compound A 10 Results: On day 14, Cells underwent crystal violet staining. Treatment of the MCD7 cell line with the combination of abemaciclib, fulvestrant, and 1 nM Compound A showed better antitumor activity than combination of only abemaciclib, and fulvestrant (Fig.1B, and Fig.1A, respectively). Treatment of the T47D cell line with the combination of abemaciclib, fulvestrant, and 1 nM Compound A showed better antitumor activity than combination of only abemaciclib, and fulvestrant (Fig.2B, and Fig.2A, 15 respectively). 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 124 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 wherein A1is a bond between the linker and A; A2is a bond between B and the linker; m is 0 or 1; C is absent, or carbonyl; 5 E is 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, 10 OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; F is 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 15 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo, 20 each Rais, 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 Raare taken 25 together with the atom to which they are attached to form a carbocyclyl or 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; the CBP binding moiety has the structure of Formula III: 30 wherein 125 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 R1is, independently, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C1-C9 heteroalkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rb; R2is, independently, C1-C12 alkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered 5 heterocycle, wherein each C1-C12 alkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rb; R3is, independently, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)-(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C1210 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1- C20 heteroaryl) and (C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, OC(O)ORf, 15 N(Rf)C(O)R R4is, independently, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)-(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1- 20 C20 heteroaryl) and (C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, and N(Rf)S(O)2N(Rf)2; 25 each Rbis, 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 is optionally substituted with A1and / or one or more groups Re; Rcis, independently, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3- 30 12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Re; Rdis, 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 35 carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Re; or Rcand Rdof Formula (III) taken together with the nitrogen to which they are attached form a 3- 12 membered heterocycle that is optionally substituted with A1and / or one or more groups Re; each Reis, independently, H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered 40 carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 126 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; each Rfis, independently, H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered 5 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 is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; or a pharmaceutically acceptable salt thereof. 10 E2. 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 A1is a bond between the linker and A; A2is a bond between B and the linker; m is 0 or 1; C is absent, or carbonyl; 15 E is 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, 20 OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; F is 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 25 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo, 30 each Rais, 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, 127 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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 Raare taken together with the atom to which they are attached to form a carbocyclyl or heterocyclyl that is optionally 5 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; the CBP binding moiety has the structure of Formula IIIa: 10 wherein Y is CR4, or N; Z is C or N; R1is, independently, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C1-C9 heteroalkyl, 3-12 membered carbocycle, 15 and 3-12 membered heterocycle is optionally substituted with one or more groups Rb; R2is, 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 is optionally substituted with one or more groups Rb; R3is, independently, ORf, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C1220 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1- C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 25 heteroalkyl, OC(O)ORf, N(Rf)C(O)R R4is, independently, H, ORf, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3- C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1- 30 C20 heteroaryl)(C6-C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1- C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, 128 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, and N(Rf)S(O)2N(Rf)2; each Rbis, independently, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, 5 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 is optionally substituted with A1and / or one or more groups Re; Rcis, 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 10 carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Re; Rdis, 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 is optionally substituted with A1and / or one or more groups 15 Re; or Rcand Rdof Formula (III) taken together with the nitrogen to which they are attached form a 3- 12 membered heterocycle that is optionally substituted with A1and / or one or more groups Re; each Reis, independently, H, 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 20 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; each Rfis, independently, H, 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 25 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C(O)OH, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; or a pharmaceutically acceptable salt thereof. E3. The compound of embodiment 1 or 2, wherein the CBP binding moiety has the structure: 30 . E4. The compound of any one of embodiments 1 to 3, wherein R3is NRcRd. 129 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 5 E8. The compound of any one of embodiments 1 to 3, wherein R3is C1-C9 heteroalkyl. 10 E9. The compound of embodiment 8, wherein R3is OMe. E10. The compound of any one of embodiments 1 to 3 , wherein R3is C2-C9 heterocycle. E11. The compound of embodiment 10, wherein 130 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 E12. The compound of any one of embodiments 1 to 3, wherein R4is NRcRd. E13. The compound of embodiment 12, wherein 5 E15. The compound of any one of embodiments 1 to 3, wherein R4is C1-C9 heteroalkyl. 10 E16. The compound of embodiment 15, wherein R4is OMe. E17. The compound of any one of embodiments 1 to 3, wherein R4is C2-C9 heterocycle. E18. The compound of embodiment 17, wherein E19. The compound of embodiment 1 or 2, wherein the CBP binding moiety of Formula III has the structure: 131 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 5 E20. The compound of embodiment 1 or 2, wherein the CBP binding moiety of Formula III has the structure: 132 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 5 133 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 134 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 135 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 E21. The compound of any one of embodiment 1-20, wherein the degradation moiety (B) is a ubiquitin ligase binding moiety. 5 E22. The compound of embodiment 21, wherein 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. E23. The compound of any one of embodiment 1-22, wherein the degradation moiety (B) comprises the structure of Formula V: 10 wherein R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 15 R7is 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; R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; 136 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 R10is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or arylalkyl; wherein one of R5and R7is A2or C(O)A2. E24. The compound of embodiment 23, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-A): 5 Formula V-A, wherein R5is H, A2, C(O)A2, optionally substituted C1-C6alkyl, or optionally substituted C1-C6heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 10 R7is 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; R8is H, optionally substituted C1-C6alkyl, optionally substituted C3-C10carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 15 R10is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or arylalkyl; wherein one of R5and R7is A2or C(O)A2. E25. The compound of embodiment 23, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-B): 20 Formula V-B, wherein R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R7is A2, C(O)A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, 25 optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-6 alkyl, or optionally substituted C1-C6 heteroalkyl; R10is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or optionally 30 substituted arylalkyl; wherein one of R5and R7is A2or C(O)A2. 137 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 5 E28. The compound of any one of embodiments 23 to 25, wherein R10is , R11and R12are, independently, H, or optionally substituted C1-C6 alkyl; each R13is, independently, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1- 10 C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, optionally substituted C2-C9heteroaryl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; n is 0, 1, 2, 3, or 4; and each of R15and R16is, independently, H, halogen, optionally substituted C1-C6 alkyl, or optionally 15 substituted C6-C10aryl. 138 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 E28. The compound of any one of embodiments 23 to 25, wherein , E29. The compound of embodiment 22, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-C): 5 Formula V-C, wherein R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 10 R7is 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; R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-6 alkyl, or optionally substituted C1-6 heteroalkyl; 15 R11and R12are, independently, H, or optionally substituted C1-C6 alkyl; each R13is, 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; 20 R14is optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl; n is 0, 1, 2, 3, or 4; and wherein one of R5and R7is A2or C(O)A2. 139 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 E31. The compound of embodiment 22, wherein the degradation moiety of formula V has the structure: 5 140 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 derivative or analog thereof. E32. The compound of any one of embodiments 1-21, wherein the degradation moiety comprises the structure of Formula VI: Formula VI 5 R6ais, independently, optionally substituted C1-C6 alkyl; R7ais, 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 A2and / or one or more groups Rg; R8ais H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally 10 substituted C6-C10 aryl; R9ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; n1 is 0, 1, 2, 3, or 4; each of R11aand R12ais, independently, H, or optionally substituted C1-C6 alkyl; each R13ais, independently, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1- 15 C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, 141 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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; R14ais optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl; and 5 each Rgis, 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 A2and / or one or more groups independently selected from oxo and halo; or a pharmaceutically acceptable salt thereof. E33. The compound of embodiment 32, wherein the degradation moiety comprises the structure of Formula VIa: Formula VIa 10 R6ais, independently, optionally substituted C1-C6 alkyl; R7ais, 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 A2and / or one or more groups Rg; R8ais H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally 15 substituted C6-C10 aryl; R9ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; n1 is 0, 1, 2, 3, or 4; each of R11aand R12ais, independently, H, or optionally substituted C1-C6 alkyl; each R13ais, independently, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1- 20 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 R15aand R16ais, independently, H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl; and 25 each Rgis, 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 A2and / or one or more groups independently selected from oxo and halo; or a pharmaceutically acceptable salt thereof. E34. The compound of embodiment 32, wherein the degradation moiety has the structure: 142 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 analog thereof. E35. The compound of any one of embodiments 1 to 34, wherein L has the structure of Formula II: A1–(F)–(E)m–C-A2, Formula II wherein A1is a bond between the linker and A; A2is a bond between B and the linker; m is 0 or 1; C is absent, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; 5 E is absent, optionally substituted C1–C10 alkylene; and F is optionally substituted C2–C10 heterocyclylene or optionally substituted C2-C9 heteroarylene. E36. The compound of any one of embodiments 1 to 35, wherein m is 0. E37. The compound of any one of embodiments 1 to 35, wherein m is 1. E38. The compound of any one of embodiments 1 to 35, and 37, wherein E is methylene or ethylene. 10 E39. The compound of any one of embodiments 1 to 38, wherein C is carbonyl. E40. The compound of any one of embodiments 1 to 38, wherein C is absent. E41. The compound of any one of embodiments 1 to 40, wherein F is optionally substituted C2–C10 heterocyclylene. E42. The compound of embodiment 41, wherein F is: 15 E43. The compound of any one of embodiments 1 to 40, wherein F is optionally substituted C2-C9 heteroarylene. E44. The compound of embodiment 43, wherein F is 143 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 5 E45. The compound of any one of embodiments 1 to 44, wherein the compound is any one of compounds 1 to 19, or a pharmaceutically acceptable salt thereof. E46. The compound of any one of embodiments 1 to 44, wherein the compound is any one of compounds 1 to 48, or a pharmaceutically acceptable salt thereof. E47. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 45 and a 10 pharmaceutically acceptable excipient. E48. A method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of embodiments 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46. E49. The method of embodiment 48, wherein the cancer is osteosarcoma, colorectal cancer, bladder 15 cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophogeal, stomach, or lung cancer. E50. The method of embodiment 49, wherein the cancer is gastric cancer. E51. 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 45, or a 20 pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46. E52. The method of any one of embodiments 48 to 51, wherein the cancer is metastatic. E53. The method of any one of embodiments 48 to 52, wherein the subject or cancer has a EP300 loss of function mutation. E54. The method of any one of embodiments 48 to 53, wherein the method further comprises 25 administering to the subject an anticancer therapy. E55. The method of embodiment 54, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof. E56. A method of treating inflammatory and / or autoimmune disorders in a subject in need thereof, the 30 method including administering to the subject an effective amount of a compound of any one of embodiments 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46. 144 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 E57. The method of embodiment 56, 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, 5 non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis. E58. The method of embodiments 56 or 57, wherein the method further comprises administering to the subject a JAK inhibitor. E59. The method of embodiment 58, wherein the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib. 10 E60. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46. E61. The method of embodiment 60, wherein the member of the JAK-STAT pathway is a janus kinase 15 (JAK). E62. The method of embodiment 60, wherein the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT). E63. The method of embodiment 60, wherein the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile 20 idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutières syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis. E64. A method of inducing immune tolerance in a subject in need thereof, including administering to 25 the subject an effective amount of a compound of any one of embodiments 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46. E65. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46. 30 E66. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46. E67. A method of treating an infection in a subject in need thereof, the method including administering 35 to the subject an effective amount of a compound of any one of embodiments 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46. E68. The method of embodiment 67, wherein the infection is Herpesvirus K*. E69. 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 45, or a 40 pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46. 145 PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 Other Embodiments While the invention has been described in connection with specific embodiments thereof, it will be 5 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. 10 Other embodiments are in the claims. 146

Claims

PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 What is claimed is: 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 A1is a bond between the linker and A; A2is a bond between B and the linker; m is 0 or 1; C is absent, or carbonyl; E is 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; F is 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo, each Rais, 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 Raare taken together with the atom to which they are attached to form a carbocyclyl or heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; the CBP binding moiety has the structure of Formula IIIa: 147PATENT ATTORNEY-DOCKET NO.: 51121-101WO3wherein Y is CR4, or N; Z is C or N; R1is, independently, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C1-C9 heteroalkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rb; R2is, 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 is optionally substituted with one or more groups Rb; R3is, independently, ORf, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3- C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1- C20 heteroaryl)(C6-C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1- C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, and N(Rf)S(O)2N(Rf)2; R4is, independently, H, ORf, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1- C20 heteroaryl)(C6-C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1- C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, and N(Rf)S(O)2N(Rf)2; each Rbis, 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 148PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 carbocycle, and 3-12 membered heterocycle is optionally substituted with A1and / or one or more groups Re; Rcis, 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 is optionally substituted with A1and / or one or more groups Re; Rdis, 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 is optionally substituted with A1and / or one or more groups Re; or Rcand Rdof Formula (III) taken together with the nitrogen to which they are attached form a 3- 12 membered heterocycle that is optionally substituted with A1and / or one or more groups Re; each Reis, independently, H, 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 is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; each Rfis, independently, H, 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 is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C(O)OH, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; or a pharmaceutically acceptable salt thereof.

2. 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 A1is a bond between the linker and A; A2is a bond between B and the linker; m is 0 or 1; C is absent, or carbonyl; E is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted 149PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 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(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; F is 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–C10heterocyclylene, C6-C10arylene, or C2-C9heteroarylene is optionally substituted with one or more groups independently selected from oxo, halo, 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, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo, each Rais, 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 Raare taken together with the atom to which they are attached to form a carbocyclyl or 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; the CBP binding moiety has the structure of Formula III:wherein R1is, independently, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C1-C9 heteroalkyl, 3-12 membered carbocycle, and 3-12 membered heterocycle is optionally substituted with one or more groups Rb; R2is, 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 is optionally substituted with one or more groups Rb; R3is, independently, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)-(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 150PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1- C20 heteroaryl) and (C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, OC(O)ORf, N(Rf)C(O)RR4is, independently, NRcRd, C1-C12 alkyl, C1-C9 heteroalkyl, C2-C12 alkenyl, C6-C20 aryl, C3-C12 carbocycle, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)-(C6- C20aryl), and (C1-C20heteroaryl)(C1-C20heteroaryl), wherein each C1-C12alkyl, C1-C9heteroalkyl, C2-C12alkenyl, C6-C20 aryl, C3-C12 carbocycle, C6-C20 aryl, C2-C9 heterocycle, C1-C20 heteroaryl, (C6-C20 aryl)(C1- C20 heteroaryl) and (C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Re, oxo, F, Cl, Br, I, C1-C9 alkyl, C1-C9 heteroalkyl, CHF2, CF3, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, and N(Rf)S(O)2N(Rf)2; each Rbis, 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 is optionally substituted with A1and / or one or more groups Re; Rcis, 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 is optionally substituted with A1and / or one or more groups Re; Rdis, 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 is optionally substituted with A1and / or one or more groups Re; or Rcand Rdof Formula (III) taken together with the nitrogen to which they are attached form a 3- 12 membered heterocycle that is optionally substituted with A1and / or one or more groups Re; each Reis, independently, H, 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 is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; each Rfis, independently, H, 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 is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; or a pharmaceutically acceptable salt thereof. 151PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 3. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:.

4. The compound any one of claims 1 to 3, wherein R3is NRcRd.

6. The compound of claim 5, wherein. 152PATENT ATTORNEY-DOCKET NO.: 51121-101WO38. The compound of any one of claims 1 to 3, wherein R3is C1-C9 heteroalkyl.

9. The compound of claim 8, wherein R3is OMe.

10. The compound of any one of claims 1 to 3, wherein R3is C2-C9 heterocycle.

11. The compound of claim 10, wherein.

12. The compound of any one of claims 1 to 3, wherein R4is NRcRd.153PATENT ATTORNEY-DOCKET NO.: 51121-101WO315. The compound of any one of claims 1 to 3, wherein R4is C1-C9 heteroalkyl.

16. The compound of claim 15, wherein R4is OMe.

17. The compound of any one of claims 1 to 3, wherein R4is C2-C9 heterocycle.

18. The compound of claim 17, wherein.

19. The compound of any one of claims 1 to 3, wherein the CBP binding moiety has the structure: 154PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 ,155PATENT ATTORNEY-DOCKET NO.: 51121-101WO3156PATENT ATTORNEY-DOCKET NO.: 51121-101WO3157PATENT ATTORNEY-DOCKET NO.: 51121-101WO320. The compound of any one of claims 1-19, wherein the degradation moiety (B) is a ubiquitin ligase binding moiety.

21. The compound of claim 20, wherein 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.

22. The compound of any one of claims 1 to 21, wherein the degradation moiety (B) comprises the structure of Formula V:wherein R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R7is 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; 158PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R10is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or optionally substituted arylalkyl; wherein one of R5and R7is A2or C(O)A2.

23. The compound of claim 22, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-A):wherein R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R7is 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; R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R10is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or optionally substituted arylalkyl; wherein one of R5and R7is A2or C(O)A2.

24. The compound of claim 22, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-B):wherein R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 159PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 R7is 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; R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-6alkyl, or optionally substituted C1-C6heteroalkyl; R10is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl or optionally substituted arylalkyl; wherein one of R5and R7is A2or C(O)A2.

27. The compound of any one of claims 22 to 24, wherein, R11and R12are, independently, H, or optionally substituted C1-C6 alkyl; 160PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 each R13is, 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; n is 0, 1, 2, 3, or 4; and each of R15and R16is, independently, H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl.

29. The compound of claim 22, wherein the degradation moiety (B) of Formula (V) comprises the structure of Formula (V-C):Formula V-C, wherein R5is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R6is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R7is 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; R8is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R11and R12are, independently, H, or optionally substituted C1-C6 alkyl; each R13is, 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; 161PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 R14is optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl; n is 0, 1, 2, 3, or 4; and wherein one of R5and R7is A2or C(O)A2.

30. The compound of claim 29, wherein R14is:

31. The compound of claim 22, wherein the degradation moiety of formula V has the structure:162PATENT ATTORNEY-DOCKET NO.: 51121-101WO3derivative or analog thereof.

32. The compound of any one of claims 1 to 21, wherein the degradation moiety (B) comprises the structure of Formula VI:Formula VI R6ais, independently, optionally substituted C1-C6 alkyl; R7ais, 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 A2and / or one or more groups Rg; 163PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 R8ais H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C6-C10 aryl; R9ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; n1 is 0, 1, 2, 3, or 4; each of R11aand R12ais, independently, H, or optionally substituted C1-C6alkyl; each R13ais, 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-C6heteroalkenyl, hydroxy, thiol, or optionally substituted amino; R14ais optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl; and each Rgis, 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 A2and / or one or more groups independently selected from oxo and halo; or a pharmaceutically acceptable salt thereof.

33. The compound of claim 32, wherein the degradation moiety comprises the structure of Formula VI:Formula VI R6ais, independently, optionally substituted C1-C6alkyl; R7ais, 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 A2and / or one or more groups Rg; R8ais H, optionally substituted C1-C6alkyl, optionally substituted C3-C10carbocyclyl, or optionally substituted C6-C10 aryl; R9ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; n1 is 0, 1, 2, 3, or 4; each of R11aand R12ais, independently, H, or optionally substituted C1-C6alkyl; each R13ais, 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; 164PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 each of R15aand R16ais, independently, H, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C6-C10 aryl; and each Rgis, 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-C6alkoxy, carbocyclyl, heterocyclyl, or C1-C6alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; or a pharmaceutically acceptable salt thereof.

34. The compound of claim 32, wherein the degradation moiety has the structure:analog thereof.

35. The compound of any one of claims 1 to 34, wherein L has the structure of Formula II: A1–(F)–(E)m–C-A2, Formula II wherein A1is a bond between the linker and A; A2is 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–C10 alkylene; and F is optionally substituted C2–C10 heterocyclylene or optionally substituted C2-C9 heteroarylene.

36. The compound of any one of claims 1 to 35, wherein m is 0.

37. The compound of any one of claims 1 to 35, wherein m is 1.

38. The compound of any one of claims 1 to 35, and 37, wherein E is methylene or ethylene. 165PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 39. The compound of any one of claims 1 to 38, wherein C is carbonyl.

40. The compound of any one of claims 1 to 38, wherein C is absent.

41. The compound of any one of claims 1 to 40, wherein F is optionally substituted C2–C10 heterocyclylene.

42. The compound of claim 41, wherein F is:

43. The compound of any one of claims 1 to 40, wherein F is optionally substituted C2-C9 heteroarylene.

44. The compound of claim 43, wherein F is:

45. The compound of any one of claims 1 to 44, wherein the compound is any one of compounds 1 to 48, or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition comprising a compound of any one of claims 1 to 45, and a pharmaceutically acceptable excipient.

47. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46. 166PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 48. The method of claim 47, 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.

49. The method of claim 48, wherein the cancer is gastric cancer.

50. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

51. The method of any one of claims 47 to 50, wherein the cancer is metastatic.

52. The method of any one of claims 47 to 51, wherein the subject or cancer has a EP300 loss of function mutation.

53. The method of any one of claims 47 to 52, wherein the method further comprises administering to the subject an anticancer therapy.

54. The method of claim 53, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof.

55. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

56. The method of claim 55, 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-Goutières syndrome, Sjogren’s syndrome, chronic hand eczema, non- anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.

57. The method of claim 55 or 56, wherein the method further comprises administering to the subject a JAK inhibitor.

58. The method of claim 57, wherein the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

59. 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 167PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

60. The method of claim 59, wherein the member of the JAK-STAT pathway is a janus kinase (JAK).

61. The method of claim 59, wherein the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT).

62. The method of claim 59, 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-Goutières syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.

63. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

64. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

65. A method of suppressing a memory CD8+T cell response 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

66. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

67. The method of claim 66, wherein the infection is Herpesvirus K*.

68. 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 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

69. The claim of 53 or 54, wherein the anticancer agent is a CDK4 / 6 inhibitor. 168PATENT ATTORNEY-DOCKET NO.: 51121-101WO3 70. The claim of claim 69, wherein the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib.

71. The method of claims 69 or 70, wherein the method further comprises administering hormone therapy. 169

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