Compounds and uses thereof

Abstract

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

Description

[0001]PATENT ATTORNEY DOCKET NO.: 51121-102WO3 COMPOUNDS AND USES THEREOF BACKGROUND OF THE INVENTION EP300 is a histone acetyltransferase that regulates transcription of genes via chromatin 5 remodeling. EP300 is involved in regulating cell growth and division. The present invention is related to useful compositions and methods for the treatment of EP300-related disorders, such as cancer and infection. SUMMARY EP300 is an intracellular protein that regulates cell growth and division. EP300 is 10 overexpressed in multiple cancer cell lines. Accordingly, agents that reduce the levels and / or activity of EP300 may provide new methods for the treatment of disease and disorders, such as cancer and infection. The inventors have found that depleting EP300 results in the downregulation / depletion of MYC in those cells. Thus, agents that degrade EP300 (e.g., compounds) are useful in the treatment of disorders (e.g., cancers or infections) related to EP300 and / or MYC. 15 The present disclosure features compounds and methods useful for treating EP300-related disorders (e.g., cancer or infection). In an aspect, the disclosure features a compound having the structure of Formula Ia: A-L1-L2-B Formula Ia, wherein A is a EP300 binding moiety; B is a cereblon ligand degradation moiety; L1 is absent or optionally substituted C2–C12 heteroarylene, and L2 has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D)-(B Formula or a pharmaceutically acceptable salt thereof, 20 wherein A1is a bond between the linker and the benzopyridazine core ring system; A2is a bond between the degradation moiety and the linker; each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C12 arylene, optionally substituted C6-C10 aryl C1-4 alkylene, optionally substituted C1-C4 25 heteroalkylene, optionally substituted C3-C10 cycloalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2-C12 heteroarylene (e.g. C2-C8 heteroarylene), O, S, S(O)2, or NRN; each RNis, independently, H, optionally substituted C1–C4 alkylene, optionally substituted C2– C4 alkenylene, optionally substituted C2–C4 alkynylene, optionally substituted C2–C6 heterocyclylene, 30 optionally substituted C2–C6 heteroarylene, or optionally substituted C1–C7 heteroalkylene; each of C1and C2is, independently, carbonylene, thiocarbonylene, sulphonylene, or phosphorylene; each of f, g, h, i, j, and k is, independently, 0 or 1; and 1 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C10 heterocyclylene, optionally substituted C2– C12 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene, 5 wherein the cereblon ligand degradation moiety comprises the structure of Formula Y: Formula Y, where A2is a bond between the degradation moiety and the linker; 10 v1 is 0, 1, 2, 3, 4, or 5; u1 is 1, 2, or 3; R5Ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 15 each RJ1is, independently, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; JAis absent, O, optionally substituted amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; and J is absent, optionally substituted C3-C10 carbocyclylene, optionally substituted C6-C12 arylene, 20 optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C14 heteroarylene (e.g. C2-C9 heteroarylene), or a pharmaceutically acceptable salt thereof. In some embodiments, D is optionally substituted C1–C10 alkylene, optionally substituted C2– C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C10 heterocyclylene, optionally substituted C2–C12 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted 25 C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene, wherein each alkyl, alkenyl, alkynyl, heterocyclyl, heteroayl, and aryl is optionally substituted with A2and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-12 membered carbocyclyl, 3- 12 membered heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. 2 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, each of B1, B2, B3, and B4is, independently, optionally substituted C1- C4 alkylene, optionally substituted C6-C12 arylene, optionally substituted C6-C10 aryl C1-4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C3-C10 cycloalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2-C12 heteroarylene (e.g. C2-C8 5 heteroarylene), O, S, S(O)2, or NRN, wherein each alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl is optionally substituted with A2and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In another aspect, the disclosure features a compound having the structure of Formula I: A-L-B Formula I, wherein A is a EP300 binding moiety; B is a cereblon ligand degradation moiety; and L has the structure of Formula II: 10 A1-(B1)f-(C1)g-(B2)h-(D)-(B Formula or a pharmaceutically acceptable salt thereof, wherein A1is a bond between the linker and the benzopyridazine core ring system; 15 A2is a bond between the degradation moiety and the linker; each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C10 arylene, optionally substituted C6-C10 aryl C1-4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C3-C10 cycloalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2-C12 heteroarylene (e.g. C2-C8 heteroarylene), optionally 20 substituted C6–C12 arylene, O, S, S(O)2, or NRN; each RNis, independently, H, optionally substituted C1–C4 alkylene, optionally substituted C2– C4 alkenylene, optionally substituted C2–C4 alkynylene, optionally substituted C2–C6 heterocyclylene, optionally substituted C2–6 heteroarylene, or optionally substituted C1–C7 heteroalkylene; each of C1and C2is, independently, carbonylene, thiocarbonylene, sulphonylene, or 25 phosphorylene; each of f, g, h, i, j, and k is, independently, 0 or 1; and D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C8 heterocyclylene, optionally substituted C2– C8 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene 30 glycol, or optionally substituted C1–C10 heteroalkylene. In some embodiments, the EP300 binding moiety has the structure: 3 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Formula III, wherein R1is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 5 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1is optionally substituted with A1and / or one or more groups Rb; R2is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6- 10 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 Rc, oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; 15 R3is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups Re; or R2and R3of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 20 membered heterocycle that is optionally substituted with A1and / or one or more groups Re; R4is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with A1and / or one or more substituent groups independently selected from F, Cl, 25 Br, I, 3-5 membered carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, ORh, SRh, OC(O)Rh, OC(O)ORh, C(O)Rh, C(O)ORh, S(O)Rh, S(O)2Rh, OC(O)N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)S(O)Rh, N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Rais, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, 30 and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or C1- C6 alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Raare taken together with the nitrogen to which they are attached to form a 3-5 membered heterocyclyl that is optionally substituted with one or more groups independently selected 35 from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; 4 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 each Rbis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)ORc, OC(O)ORc, C(O)Rc, C(O)ORc, S(O)Rc, S(O)2Rc, OC(O)N(Rc)2, N(Rc)C(O)ORc, N(Rc)C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rc, 5 N(Rc)S(O)N(Rc)2, or N(Rc)S(O)2N(Rc)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)Rc, C(O)Rc, S(O)Rc, S(O)2Rc, C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rcand C1-C6 alkyl that is optionally substituted with one or more groups independently 10 selected from oxo and halo; each Rcis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, 15 S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1-C6 alkyl, wherein the carbocyclyl and the C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rd)2, ORd, 3-5 membered heterocyclyl, and 3-5 membered carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; 20 each Rdis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-12 membered carbocyclyl, 3- 12 membered heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups 25 independently selected from oxo and halo; or two Rdare taken together with the nitrogen to which they are attached to form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Reis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, 30 C3-C12 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from 35 oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, 3-12 membered carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rfis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or 40 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, 3-12 5 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 membered carbocyclyl, 3-12 membered heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, in which carbocyclyl and C1-C6 alkyl are optionally substituted with A1and / or one or more groups independently selected from oxo, halo, C1-C6 alkyl, 5 cyano, N(Rg)2, ORg, 3-12 membered heterocyclyl, and 3-12 membered carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; each Rgis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups10 independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-12 membered carbocyclyl, 3- 12 membered heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rgare taken together with the nitrogen to which they are attached to form a 3-12 membered 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 15 more groups independently selected from oxo and halo; and each Rhis, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with A1and / or one or more groups independently 20 selected from halo; wherein one and only one of R1, R2, R3, or R4comprises A1. In some embodiments, R1is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3- 12 membered carbocycle, and 3-12 membered heterocycle of R1is optionally substituted with A125 and / or one or more groups Rb. In some embodiments, R2is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1- C20 heteroaryl)(C6-C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1- C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently 30 selected from Rc, oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2. In some embodiments, R3is 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- 35 12 membered carbocycle, and 3-12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups Re; or R2and R3of Formula (I) 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. In some embodiments, R4is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered 40 carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, 6 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 and 3-5 membered heterocycle is optionally substituted with A1and / or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, ORh, SRh, OC(O)Rh, OC(O)ORh, C(O)Rh, C(O)ORh, S(O)Rh, S(O)2Rh, OC(O)N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)S(O)Rh, N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and 5 N(Rh)S(O)2N(Rh)2; In some embodiments, each Rais, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocyclyl, heterocyclyl, or C1-C6 alkyl that is 10 optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Raare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; In some embodiments, each Rbis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 15 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)ORc, OC(O)ORc, C(O)Rc, C(O)ORc, S(O)Rc, S(O)2Rc, OC(O)N(Rc)2, N(Rc)C(O)ORc, N(Rc)C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(Rc)S(O)2N(Rc)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more 20 groups independently selected from oxo, halo, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)Rc, C(O)Rc, S(O)Rc, S(O)2Rc, C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rcand C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; In some embodiments, each Rcis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 25 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1-C6 alkyl, in which any 30 carbocyclyl or C1-C6 alkyl is optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rd)2, ORd, 3-5 membered heterocyclyl, and 3-5 membered carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl. In some embodiments, each Rdis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 35 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rdare taken together with the nitrogen 40 to which they are attached to form a 3-12 membered heterocyclyl that is optionally substituted with one 7 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In some embodiments, each Reis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, 5 N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, 10 SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, 3-12 membered carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In some embodiments, each Rfis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 15 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-6alkyl, which carbocyclyl and C1-C6 alkyl are optionally substituted with A1and / or one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, 20 ORg, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl. In some embodiments, each Rgis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or 25 more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rgare taken together with the nitrogen to which they are attached to form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or 30 more groups independently selected from oxo and halo. In some embodiments, each Rhis, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with A1and / or one or more groups 35 independently selected from halo. In some embodiments, R1is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3- 12 membered carbocycle, and 3-12 membered heterocycle of R1is optionally substituted with A1and / or one or more groups Rb. 40 In some embodiments, R2is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1- C20 heteroaryl)(C6-C20 aryl), or (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1- 8 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 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 Rc, oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, 5 N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2. In some embodiments, R3is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3- 12 membered carbocycle, and 3-12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups Re. 10 In some embodiments, R2and R3taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups Re. In some embodiments, R4is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, 15 and 3-5 membered heterocycle is optionally substituted with A1and / or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, ORh, SRh, OC(O)Rh, OC(O)ORh, C(O)Rh, C(O)ORh, S(O)Rh, S(O)2Rh, OC(O)N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)S(O)Rh, N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2. 20 In some embodiments, each Rais, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two 25 Raare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In some embodiments, each Rbis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, 30 S(O)2N(Rc)2, ORc, SRc, OC(O)Rc, OC(O)ORc, C(O)Rc, C(O)ORc, S(O)Rc, S(O)2Rc, OC(O)N(Rc)2, N(Rc)C(O)ORc, N(Rc)C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(R)S(O)2N(Rc)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)Rc, C(O)Rc, 35 C(O)ORc, S(O)Rc, S(O)2Rc, C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rcand C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In some embodiments, each Rcis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected 40 from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, 9 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 N(Rd)S(O)2Rd, and C1-C6 alkyl, which carbocyclyl and C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rd)2, ORd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl. 5 In some embodiments, each Rdis, 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 A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo 10 and halo; or two Rdare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In some embodiments, each Reis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 15 carbocyclyl, heterocyclyl, aryl, heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from 20 oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, 3-12 membered carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. In some embodiments, each Rfis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 25 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, which carbocyclyl and C1-C6 alkyl are optionally substituted with one or 30 more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, ORg, 3-12 membered heterocyclyl, and 3-12 membered carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl. In some embodiments, each Rgis, 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 35 alkynyl, C1-C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rgare taken together with the nitrogen to which they are attached to form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups independently selected 40 from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo. 10 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, In some embodiments, each Rhis, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted 5 with A1and / or one or more groups independently selected from halo. In some embodiments, wherein R1is methyl, cyclohexane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1is optionally substituted with one or more groups Rb. 10 15 In some embodiments, R4is acetyl, carbonate anion, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. In some embodiments, R4has the structure: . In some embodiments, R3is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered 20 carbocycle, or 3-12 membered heterocycle, wherein each alkyl, alkenyl, alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups Re. In some embodiments, NR2R3taken together has the structure: , . 11 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, R2is C6-C20 aryl optionally substituted with A1and / or one or more substituent groups independently selected from Rc. In some embodiments, . In some embodiments, R3is C1-C12 alkyl. 5 In some embodiments, R3is methyl. In some embodiments, R2and R3taken together with the nitrogen to which they are attached 10 form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1and / or one or more groups Re. In some embodiments, R2and R3taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1and / or one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic 15 ring. In some embodiments, NR2R3taken together has the structure: , . 12 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the EP300 binding moiety has the structure: 5 In some embodiments, R2is C6-C20 aryl optionally substituted with A1and / or one or more —F groups. In some embodiments, R3is C1-C12 alkyl. In some embodiments, the EP300 binding moiety has the structure: 13 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 14 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, NR2R3taken together has the structure: , 5 , 15 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 16 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the EP300 binding moiety has the structure: In some embodiments, the EP300 binding moiety has the structure: 5 , 17 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 18 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 , 19 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the EP300 binding moiety has the structure: 5 20 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the EP300 binding moiety has the structure: 5 21 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the EP300 binding moiety has the structure: 5 22 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, R2is C6-C20 aryl optionally substituted with A1and / or one or more F groups. In some embodiments, R3is C1-C12 alkyl. In some embodiments, the EP300 binding moiety has the structure: 5 23 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the structure of Formula Y is 5 , 24 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 25 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 . In some embodiments, the structure of Formula Y has the structure of Formula Y1: 5 Formula Y1, or a pharmaceutically acceptable salt thereof. In some embodiments, T1is a bond. In some embodiments, . In some embodiments, the structure of Formula Y has the structure of Formula Y2: 10 Formula Y2, or a pharmaceutically acceptable salt thereof. 26 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the structure of Formula Y has the structure of Formula Z: Formula Z, or a pharmaceutically acceptable salt thereof. 5 In some embodiments, u1 is 1. In some embodiments, u1 is 2. In some embodiments u1 is 3. In some embodiments, the structure of Formula Z has the structure of Formula AA0: Formula AA0, or a pharmaceutically acceptable salt thereof. 10 In some embodiments, the structure of Formula Z has the structure of Formula AB: Formula AB, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula Z has the structure of Formula AC: 15 Formula AC, or a pharmaceutically acceptable salt thereof. In some embodiments, JAis absent. In some embodiments, JAis optionally substituted C1-C6 alkyl. In some embodiments, JAis optionally substituted C1-C6 heteroalkyl. In some embodiments, JAis 20 O or optionally substituted amino. In some embodiments, . In some embodiments, the structure of Formula AA0 has the structure of Formula AA0: 27 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Formula AA, or a pharmaceutically acceptable salt thereof. In some embodiments, v1 is 0, 1, 2, or 3. In some embodiments, v1 is 0. In some 5 embodiments, v1 is 1. In some embodiments, v1 is 2. In some embodiments, v1 is 3. In some embodiments, the structure of Formula AA has the structure of Formula AA1: Formula AA1, or a pharmaceutically acceptable salt thereof. 10 In some embodiments, the structure of Formula AB has the structure of Formula AB1: Formula AB1, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AC has the structure of Formula AC1: 15 Formula AC1, or a pharmaceutically acceptable salt thereof. In some embodiments, J is absent. In some embodiments, J is optionally substituted C3-C10 carbocyclylene or optionally substituted C6-C10 arylene. In some embodiments, J is optionally 20 substituted C2-C9 heterocyclylene or optionally substituted C2-C14 heteroarylene (e.g. C2-C9 heteroarylene). In some embodiments, J is optionally substituted heterocyclylene. In some embodiments, J is optionally substituted C6-C10 arylene. In some embodiments, . 25 In some embodiments, the structure of Formula AA has the structure of Formula AA2: 28 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Formula AA2, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AA has the structure of Formula AA3: Formula AA3, or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula AA has the structure of Formula AA4: Formula AA4, or a pharmaceutically acceptable salt thereof. In some embodiments, RA5is H or optionally substituted C1-C6 alkyl. In some embodiments, RA5is optionally substituted C1-C6 heteroalkyl. In some embodiments, RA5is H or methyl. In some embodiments, RA5is H. In some 5 embodiments, RA5is methyl. In some embodiments, RA5is . In some embodiments, the structure of Formula AA has the structure of Formula A: , 10 RA5is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RA6is H or optionally substituted C1-C6 alkyl; and RA7is H or optionally substituted C1-C6 alkyl; or RA6and RA7, together with the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl; or RA6and RA7, together with 15 the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl; RA8is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each of RA1, RA2, RA3, and RA4is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally 29 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted O-C3-C6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or RA1and RA2, RA2and RA3, and / or RA3and RA4, together with the carbon atoms to which each is attached, combine to 5 form ; a is optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is optionally substituted with A2, where one is substituted with A2, or a pharmaceutically acceptable salt thereof. In some embodiments, each of RA1, RA2, RA3, and RA4is, independently, H, A2, halogen, 10 optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; or RA1and RA2, RA2and RA3, and / or RA3and RA4, together with the carbon atoms to which each is attached, combine to form ; and 15 is optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is optionally substituted with A2, where one of RA1, RA2, RA3, and RA4is A2, or is substituted with A2, or a pharmaceutically acceptable salt thereof. In some embodiments, each of RA1, RA2, RA3, and RA4is, H, A2, halogen, optionally substituted 20 C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted -O-C3-C6 carbocyclyl, hydroxyl, optionally substituted amino; or RA1and RA2, RA2and RA3, or RA3and RA4, together with the carbon atoms to which each is attached, combine to form ; a is optionally substituted C2-C9 heterocyclyl, which is optionally substituted with A2, where one of RA1, RA2, RA3, and RA4is A2, or substituted with A2. 25 In some embodiments, each of RA1, RA2, RA3, and RA4is, independently, H, A2, F, , together withthe carbon atoms to which each is attached, combine to form is optionally 30 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 substituted C2-C9 heterocyclyl, which is optionally substituted with A2, where one of RA1, RA2, RA3, and RA4is A2, or is substituted with A2. In some embodiments, RA1is A2. In some embodiments, RA2is A2. In some embodiments, RA3is A2. In some embodiments, RA4is A2. In some embodiments, RA5is A2. 5 In some embodiments, RA5is H or optionally substituted C1-C6 alkyl. In some embodiments, RA5is H or . In some embodiments, RA5is H. In some embodiments, RA5is . In some embodiments, Y1is . In some embodiments, Y1is some embodiments, . 10 In some embodiments, each of RA6and RA7is, independently, H, F, , , In some embodiments, 15 some embodiments, . In some embodiments, the structure of Formula A has the structure of Formula A1: , Formula A1 or a pharmaceutically acceptable salt thereof. 20 In some embodiments, the structure of Formula A has the structure of Formula A2: 31 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 , Formula A2 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A3: 5 , Formula A3 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A4: , 10 Formula A4 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A5: , 15 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A6: , Formula A6 or a pharmaceutically acceptable salt thereof. 20 In some embodiments, the structure of Formula A has the structure of Formula A7: 32 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 , Formula A7 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A8: 5 , Formula A8 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A9: , 10 Formula A9 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A10: , Formula A10 15 or a pharmaceutically acceptable salt thereof. In some embodiments, wherein the structure of Formula , , 33 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 34 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 , optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl.5 In some embodiments, RA9is H, A2, or optionally substituted C1-C6 alkyl. In some embodiments, RA9is H, A2, or methyl. In some embodiments, RA9is H. In some embodiments, RA9is methyl. In some embodiments, RA9is A2. 35 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the structure of Formula . In some embodiments, the structure of Formula AA has the structure of Formula B: , 5 where RA5is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each of RA1, RA2, RA3, and RA4is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally 10 substituted C2-C9heterocyclyl, optionally substituted C6-C10aryl, optionally substituted C2-C9heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted -O-C3-C6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or RA1and RA2, RA2and RA3, and / or RA3and RA4, together with the carbon atoms to which each is attached, combine to form ; a is optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, 15 optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is optionally substituted with A2, where one is substituted with A2, or a pharmaceutically acceptable salt thereof. In some embodiments, each of RA1, RA2, RA3, and RA4is, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted -O-C3-C6 carbocyclyl, 20 hydroxyl, optionally substituted amino; or RA1and RA2, RA2and RA3, or RA3and RA4, together with the carbon atoms to which each is attached, combine to form ; a is optionally substituted C2-C9 heterocyclyl, which is optionally substituted with A2, where one of RA1, RA2, RA3, and RA4is A2, or substituted with A2. 36 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, each of RA1, RA2, RA3, and RA4is, independently, H, A2, F, , d 5 substituted with A2. In some embodiments, RA1is A2. In some embodiments, RA2is A2. In some embodiments, RA3is A2. In some embodiments, RA4is A2. In some embodiments, RA5is A2. In some embodiments, RA5is H or optionally substituted C1-C6 alkyl. In some embodiments, RA5is H or . In some embodiments, RA5is H. In some 10 embodiments, RA5is . In some embodiments, the structure of Formula B has the structure of Formula D1: , or a pharmaceutically acceptable salt thereof. 15 In some embodiments, the structure of Formula B has the structure of Formula D2: , Formula D2 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula B has the structure of Formula D3: 20 , Formula D4 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula B has the structure of Formula D4: 37 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 , Formula D4 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula B is or 5 . In some embodiments, each of B1, B2, B3, and B4is, independently, optionally substituted C1- C2alkylene, optionally substituted C1-C3heteroalkylene, optionally substituted C2-C8heterocyclylene, 10 optionally substituted C2–12 heteroarylene (e.g. C2-C8 heteroarylene), or O. In some embodiments, each of C1and C2is, independently, . In some embodiments, f is 0. In some embodiments, f is 1. In some embodiments, g is 0. 15 In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, i is 1. 20 In some embodiments, j is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, L1 is absent. 25 In some embodiments, L1 is optionally substituted C2–C12 heteroarylene that is a 9- or 10- membered bicyclic heterocycle that is optionally substituted with one or more groups Re. 38 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, L1 is the structure , In some embodiments, D is optionally substituted C1–C10alkylene, optionally substituted C2–5 C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C10 heterocyclylene, optionally substituted C2–C12 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene. In some embodiments, D is optionally substituted C2–12heteroarylene. In some embodiments, D is: 10 39 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 40 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, D is optionally substituted C2–C10 heterocyclylene. In some embodiments, D is: 5 In some embodiments, D is optionally substituted C1-C10 alkylene. In some embodiments, D is optionally substituted C2–C4 alkynylene. In some embodiments, the L1-L2has the structure of: 10 41 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 42 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 43 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 44 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 45 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 , 46 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 , 47 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 48 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 , , 5 , , , , 49 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 50 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 , 51 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 , 52 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 53 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 54 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 55 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 , 56 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 57 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 , 58 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 59 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 60 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 61 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 62 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 63 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 64 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 65 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 66 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 67 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 68 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 69 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the shortest chain of atoms connecting two valencies of the linker is 2 to 10 atoms long. In some embodiments, the shortest chain of atoms connecting two valencies of the linker is 6 5 atoms long. In some embodiments, the compound is any one of compounds 1-184 in Table 1A. In some embodiments, the compound is any one of compounds 185-303 in Table 1B. Table 1A. Compounds 1-184 of the invention 70 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 71 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 72 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 73 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 74 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 75 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 76 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 77 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 78 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 79 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 80 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 81 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 82 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 83 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 84 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 85 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 86 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 87 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 88 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 89 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 90 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 91 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 92 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 93 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 94 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 95 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 96 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 97 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 98 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 99 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 100 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 101 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 102 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 103 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 104 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 105 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 106 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 107 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 108 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 109 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 110 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 111 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 112 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 113 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 114 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 115 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 116 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 117 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 118 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 119 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 120 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 121 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 122 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 123 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 124 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 125 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 126 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 127 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 128 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 129 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 130 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 131 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 132 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 133 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 134 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 135 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 136 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Table 1B. Compounds 185-303 of the invention 137 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 138 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 139 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 140 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 141 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 142 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 143 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 144 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 145 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 146 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 1 1 147 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 148 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 149 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 150 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 151 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 152 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 153 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 154 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 155 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 156 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 157 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 158 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 159 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 160 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 161 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 162 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 163 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 164 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 165 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 166 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 167 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 168 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 169 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 170 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 171 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 172 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 173 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 174 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 175 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 176 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 177 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 178 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 179 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 180 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 181 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 182 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 183 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 184 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 185 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 186 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 187 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 188 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 189 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 190 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 191 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 192 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 193 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 194 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 195 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 196 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 197 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In another aspect, the disclosure features a pharmaceutical composition including any of the foregoing compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. 5 In another aspect, the invention features a method of decreasing the levels and / or activity of EP300 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In another aspect, the invention features a method of decreasing the levels and / or activity of CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing 10 compounds or a pharmaceutical composition thereof. In another aspect, the invention features a method of decreasing the levels of or activity of a MYC in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In another aspect, the invention features a method of decreasing the levels of or activity of AR, 15 i.e. androgen receptor, in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell. In another aspect, the invention features a method of treating a EP300-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of 20 the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the EP300-related disorder is cancer. 198 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In a further aspect, the invention features a method of inhibiting EP300, the method involving contacting a cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell. In an aspect, the disclosure features a method of inhibiting the level and / or activity of EP300 in 5 a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. In another aspect, the invention features a method of treating a disorder related to a EP300 loss of function mutation in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. 10 In some embodiments, the disorder related to a EP300 loss of function mutation is cancer. In other embodiments, the subject is determined to have a EP300 loss of function disorder, for example, is determined to have a EP300 loss of function cancer (for example, the cancer has been determined to include cancer cells with loss of EP300 function). In another aspect, the invention features a method of inducing apoptosis in a cell, the method 15 involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell. In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. 20 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, urinary tract cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part 25 sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, myeloma, skin, endometrial, esophageal, cervical, gastric, or breast cancer. In some 30 embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, neuroblastoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some 35 embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma. In some embodiemnts, the cancer is carcinoma. In some embodiments, the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, myeloma, skin, endometrial, cervical, gastric, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, lymphoma, leukemia, esophogeal, stomach, 40 or lung cancer. In some embodiments, the cancer is metastatic. 199 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 In some embodiments, the subject or cancer has a CBP loss of function mutation. In some embodiments, the method further comprises administering to the subject an anticancer therapy. In some embodiment, the anticancer therapy is a chemotherapeutic or cytotoxic agent, 5 immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof. In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, head and neck cancer, prostate cancer, acute leukemia, gastric cancer, or breast cancer. In some embodiments, the breast cancer is found to be ER positive i.e. the cancer cells 10 contain estrogen receptors. In some embodiments, the breast cancer is found to be ER negative i.e. cancer cells do not contain estrogen receptors. In some embodiments, the prostate cancer is found to be AR positive i.e. cancer cells contain androgen receptors. 15 In some embodiments, the prostate cancer is CRPC i.e. castration-resistant prostate cancer. In some embodiments, the prostate cancer is sensitive prostate cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the lymphoma is Diffuse large B cell lymphoma (DLBCL). In an aspect, the disclosure features a method of treating a EP300-related disorder in a 20 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 EP300-related disorder is cancer. In some embodiments, the EP300-related disorder is infection. In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, 25 adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non- Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, 30 peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, 35 liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, 40 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, 200 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, 5 luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal 10 carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal 15 cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary 20 carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors 25 (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, 30 peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column 35 cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, Diffuse large B cell lymphoma (DLBCL), testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T- 40 ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia 201 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 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 5 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, 10 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, 15 unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. In some embodiments of any of the foregoing methods, the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 20 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta, abraxane, Adriamycin®, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, demcizumab, fosbretabulin, or a 25 PDL1 inhibitor). In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non- 30 Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel 35 cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia 40 (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, 202 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 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 5 negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic 10 lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, 15 gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, 20 leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, myeloma, skin, endometrial, esophageal, cervical, gastric, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, 25 monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian 30 epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal 35 cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal 40 cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute 203 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), 5 large granular lymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); Diffuse large B cell lymphoma (DLBCL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cell prolymphocytic 10 leukemia; splenic lymphoma / leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ 15 DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. 20 In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small 25 round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, 30 bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma. 35 In some embodiments of any of the foregoing methods, the cancer has or has been determined to have EP300 mutations. In some embodiments of any of the foregoing methods, the EP300 mutations are homozygous. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has 40 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 204 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the foregoing methods, the cancer has, or has been determined to have, a KRAS mutation. In some embodiments of any of the foregoing methods, the CBP mutation is chromosomal translocation. 5 In another aspect, the disclosure provides a method treating a disorder related to EP300 (e.g., cancer or viral infections) in a subject in need thereof. This method includes contacting a cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the disorder is a viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human 10 immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, 15 varicella-zoster virus), Papillomaviridae family (e.g., Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g., Parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), Togaviridae family (e.g., Rubella virus). In some embodiments, the disorder is Coffin Siris, Neurofibromatosis (e.g., NF-1, NF-2, or Schwannomatosis), or Multiple Meningioma. 20 In another aspect, the disclosure provides a method for treating a viral infection in a subject in need thereof. This method includes administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and25 deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV- II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicella-zoster virus), Papillomaviridae 30 family (e.g., Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g., Parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), or Togaviridae family (e.g., Rubella virus). In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, myeloma, skin, endometrial, esophageal, cervical, gastric, renal cell 35 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, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, bone 40 cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method 205 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 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, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, 5 bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof. In another aspect, the invention features a method of suppressing metastatic colonization of melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate cancer, breast cancer, 10 bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof. In another aspect, the invention features a method of reducing the level and / or activity of EP300 and / or CBP in a melanoma, myeloma, skin, endometrial, esophageal, cervical, gastric, prostate 15 cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophageal, stomach, or hematologic cancer cell, the method including contacting the cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof. In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, myeloma, skin, endometrial, esophageal, cervical, gastric, renal cell carcinoma, 20 osteosarcoma, neuroblastoma, esophagael, stomach, or hematologic cell is in a subject. In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and / or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 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 25 and / or activity of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of EP300 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%). In some embodiments of any of the above aspects, the effective amount of the compound 30 reduces the level of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to the percent of reduction of the level of CBP. In some embodiments, the effective amount of the compound that reduces the level of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to percent of reduction of the level of CBP. In some embodiments, the effective 35 amount of the compound that reduces the level of EP300 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) as compared to the percent of reduction of the level of CBP. In some embodiments, the effective amount of the compound reduces the level and / or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 40 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 206 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 level and / or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more). In some embodiments of any of the above aspects, the effective amount of the compound 5 reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of CBP by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces 10 the level and / or activity of CBP by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%). In some embodiments, the effective amount of the compound reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 15 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the compound that reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more). 20 In some embodiments, the subject has cancer. In some embodiments, the cancer expresses EP300 and / or CBP protein and / or the cell or subject has been identified as expressing EP300 and / or CBP. In some embodiments, the cancer expresses EP300 protein and / or the cell or subject has been identified as expressing EP300. In some embodiments, the cancer expresses CBP protein and / or the cell or subject has been identified as expressing CBP. In some embodiments, the cancer is melanoma 25 (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell 30 acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments, the cancer is breast cancer (e.g., an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer). In some embodiments, the cancer is a bone cancer (e.g., Ewing’s sarcoma). In some embodiments, the cancer is a renal cell carcinoma (e.g., a Microphthalmia Transcription Factor (MITF) family translocation renal cell 35 carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). The metastatic cancer can include cells exhibiting migration and / or invasion of migrating cells and / or include cells exhibiting endothelial recruitment and / or angiogenesis. In other embodiments, the migrating cancer is a cell migration cancer. In still other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. The metastatic cancer can be a cancer spread via seeding the 40 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 207 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 some embodiments, the effective amount of an agent that reduces the level and / or activity of EP300 and / or CBP is an amount effective to inhibit metastatic colonization of the cancer to the liver. In some embodiments, the method further includes administering to the subject or contacting the cell with an anticancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, 5 surgery, radiotherapy, thermotherapy, or photocoagulation. In some embodiments, the anticancer therapy is a chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparagine-specific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA-Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase inhibitor, phosphinositide 3-kinase inhibitor, proteasome 10 inhibitor, or tyrosine kinase inhibitor. Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum). A list of additional compounds having anticancer activity can be found in L. Brunton, B. Chabner and B. Knollman (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition, 2011, McGraw Hill Companies, 15 New York, NY. In some embodiments, the anticancer therapy and the compound of the invention are administered within 28 days of each other and each in an amount that together are effective to treat the subject. In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic 20 agents (e.g., the cancer has been determined to be resistant to chemotherapeutic or cytotoxic agents such as by genetic markers, or is likely to be resistant, to chemotherapeutic or cytotoxic agents such as a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the cancer is resistant or has failed to respond to dacarbazine, temozolomide, 25 cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196). 30 Chemical terms The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting. For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be 35 understood, other atoms, such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula –CH2CH3. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of 40 oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring. 208 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). An alkylene is a divalent alkyl group. The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a 5 straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms). The term “alkynyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms). 10 The term “amino,” as used herein, represents –N(RN1)2, wherein each RN1is, independently, H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN1groups can be optionally substituted; or two RN1combine to form an alkylene or heteroalkylene, and wherein each RN2is, independently, H, alkyl, or aryl. The amino groups of the compounds 15 described herein can be an unsubstituted amino (i.e., –NH2) or a substituted amino (i.e., –N(RN1)2). The term “aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl. The term “carbocyclyl,” as used herein, refers to a non-aromatic C3-C12 monocyclic, bicyclic, 20 or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals. A carbocyclylene is a divalent carbocyclyl group. The term “halo,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical. 25 The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl–O– (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl 30 group. The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroalkenyl groups are an “alkenoxy” which, as used herein, refers alkenyl–O–. A heteroalkenylene is a divalent heteroalkenyl group. The 35 term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyl groups. Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl–O–. A heteroalkynylene is a divalent heteroalkynyl group. 40 The term “heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1, 2, or 3 ring atoms selected from nitrogen, 209 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 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 “heterocyclyl,” as used herein, refers a mono- or polycyclic radical having 3 to 12 5 atoms having at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O or S, wherein no ring is aromatic. Heterocyclyl rings may be spirocyclic or bridged. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. A heterocyclylene is a divalent heteroocyclyl group. 10 The term “hydroxyl,” as used herein, represents an –OH group. The term “thiol,” as used herein, represents an –SH group. The term “carbonyl,” as used herein, represents an –C(O)– group. The term “thiocarbonyl,” as used herein, represents an –C(S)– group. The term “sulfonyl,” as used herein, represents an –S(O)2– group. 15 The term “phosphoryl,” as used herein, represents an P(O) group. The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl 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 20 group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, 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 25 such as arylalkyl (e.g., substituted and unsubstituted benzyl)). Compounds described herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by 30 resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. 35 "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- 40 known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and / or method for separating an enantiomer of a compound 210 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 described herein from a racemic mixture can be readily determined by those of skill in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon- 5 carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on 25 opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting 10 from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds described herein may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of 15 the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide 35 of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic 20 methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 25 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by 30 mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer 35 plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a 40 racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the 211 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), or mixtures 5 of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials 10 known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Definitions 15 In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; and (iii) the terms “including” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps. As used herein, the terms “about” and “approximately” refer to a value that is within 10% 20 above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM. As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, 25 in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal. 30 As used herein, the term “EP300” refers to the EP300 protein in a human cell. As used herein, the term “CBP” refers to the CREB-binding protein in a human cell. As used herein, the term “CBP-related disorder” refers to a disorder that is caused or affected by the level of activity of CBP. As used herein, the term “EP300-related disorder” refers to a disorder that is caused or 35 affected by the level of activity of EP300. As used herein, the term “EP300 loss of function mutation” refers to a mutation in EP300 that leads to the protein having diminished activity (e.g., at least 1% reduction in EP300 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity). Exemplary EP300 loss of function mutations include, but are not limited to, a homozygous EP300 mutation and chromosomal 40 translocations. 212 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 As used herein, the term “EP300 loss of function disorder” refers to a disorder (e.g., cancer) that exhibits a reduction in EP300 activity (e.g., at least 1% reduction in EP300 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in EP300 activity). The term “cancer” refers to a condition caused by the proliferation of malignant neoplastic 5 cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas. As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In 10 some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one 15 agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the 20 same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally. By “determining the level of a protein” or RNA is meant the detection of a protein or an RNA, by methods known in the art, either directly or indirectly. “Directly determining” means performing a 25 process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value. “Indirectly determining” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay 30 (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic 35 activity or interaction with other protein partners. Methods to measure RNA levels are known in the art. As used herein, the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and / or activity of EP300 (e.g., in a cell or a subject) described herein refer to a quantity sufficient to, when administered to the subject, including a human, effect beneficial or desired results, including clinical results, and, as such, an “effective 40 amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and / or activity of EP300 213 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and / or activity of EP300. The amount of a given agent that reduces the level and / or activity of EP300 described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical 5 formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, and / or weight) or host being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. Also, as used herein, a “therapeutically effective amount” of an agent that reduces the level and / or activity of EP300 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 10 therapeutically effective amount of an agent that reduces the level and / or activity of EP300 of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response. As used herein, the term “inhibitor” refers to any agent which reduces the level and / or activity of a protein (e.g., EP300). Non-limiting examples of inhibitors include small molecule inhibitors, 15 degraders, antibodies, enzymes, or polynucleotides (e.g., siRNA). By “level” is meant a level of a protein, or mRNA encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a protein or RNA is meant a decrease or increase, respectively, in a protein or RNA level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 20 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01-fold, 25 about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). A level of a protein may be expressed in mass / vol (e.g., g / dL, mg / mL, μg / mL, ng / mL) or percentage relative to total protein in a 30 sample. By “decreasing the activity of EP300” is meant decreasing the level of an activity related to EP300, or a related downstream effect. The activity level of a EP300 may be measured using any method known in the art, e.g., HiBit assay. The term “pharmaceutical composition,” as used herein, represents a composition containing 35 a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human. Typically, a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, 40 gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous 214 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation. A “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the 5 active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients 10 include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, 15 retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, for example, any compound of Formula Ia. Pharmaceutically 20 acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 25 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 30 as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the 35 appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, 40 hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, 215 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as 5 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. 10 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 15 invention; a sample from a subject that has been treated by a compound of the invention; or a sample of a purified protein or RNA (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), 20 a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound of the invention. In preferred embodiments, the reference sample, standard, 25 or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein or RNA, e.g., any described herein, within the normal reference range can also be used as a reference. As used herein, the term “subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, 30 and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition. As used herein, the terms "treat," "treated," or "treating" mean therapeutic treatment or any 35 measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or 40 disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of 216 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Compounds of the invention may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder. 5 As used herein, the terms “variant” and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material. The details of one or more embodiments of the invention are set forth in the description below. Other 10 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., EP300) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of 15 the level of the protein, e.g., in a cell or subject. As used herein, the term “degradation moiety” refers to a moiety whose binding results in degradation of a protein, e.g., EP300. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., EP300. 20 DETAILED DESCRIPTION OF THE INVENTION The present disclosure features compositions and methods useful for the treatment of EP300- related disorders (e.g., cancer and infection). The disclosure further features compositions and methods useful for inhibition of the level and / or activity of EP300, e.g., for the treatment of disorders such as cancer (e.g., sarcoma) and infection (e.g., viral infection), e.g., in a subject in need thereof. 25 Compounds Compounds described herein reduce the level of an activity related to EP300, or a related downstream effect, or reduce the level of EP300 in a cell or subject. Exemplary compounds described herein have the structure according to Formula Ia. A-L1-L2--B Formula Ia, wherein A is a EP300 binding moiety; B is a cereblon ligand degradation moiety; L1 is absent or optionally substituted C2–12 heteroarylene, and L2 has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D)-(B 30 Formula or a pharmaceutically acceptable salt thereof, wherein A1is a bond between the linker and the benzopyridazine core ring system; A2is a bond between the degradation moiety and the linker; 217 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C12 arylene, optionally substituted C6-C10 aryl C1-4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C3-C10 cycloalkylene, optionally substituted C2-C8 heterocyclylene, C2-C12 heteroarylene (e.g. C2-C8 heteroarylene),, O, S, S(O)2, or NRN; 5 each RNis, independently, H, optionally substituted C1–4 alkylene, optionally substituted C2–4 alkenylene, optionally substituted C2–4 alkynylene, optionally substituted C2–6 heterocyclylene, optionally substituted C2–6 heteroarylene, or optionally substituted C1–7 heteroalkylene; each of C1and C2is, independently, carbonylene, thiocarbonylene, sulphonylene, or phosphorylene; 10 each of f, g, h, i, j, and k is, independently, 0 or 1; and D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C10 heterocyclylene, optionally substituted C2– C12 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene, 15 wherein the cereblon ligand degradation moiety comprises the structure of Formula Y: Formula Y, where A2is a bond between the degradation moiety and the linker; 20 v1 is 0, 1, 2, 3, 4, or 5; u1 is 1, 2, or 3; R5Ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 25 each RJ1is, independently, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; JAis absent, O, optionally substituted amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; and J is absent, optionally substituted C3-C10 carbocyclylene, optionally substituted C6-C12 arylene, 30 optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C14 heteroarylene (e.g. C2-C9 heteroarylene), or a pharmaceutically acceptable salt thereof. 218 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 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, 5 status, and / or activity of EP300, e.g., by inhibiting the activity or level of the EP300 in a cell within a mammal. An aspect of the present invention relates to methods of treating disorders related to EP300 such as cancer in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or 10 more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject. Treating cancer can result in a reduction in size or volume of a tumor. For example, after 15 treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor. Treating cancer may further result in a decrease in number of tumors. For example, after 20 treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x). Treating cancer can result in a decrease in number of metastatic nodules in other tissues or 25 organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 30 2x, 10x, or 50x). Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible 35 means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound 40 described herein. 219 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a 5 population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein. 10 Combination Therapies A method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of therapies to treat cancer. In combination treatments, the dosages of one or more of the 15 therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, dosages of the compounds when combined should provide a therapeutic effect. In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a 20 cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, 25 androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including 30 altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; 35 pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and 40 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 220 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo- L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- 5 doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as 10 fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; 15 bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; 20 spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical 25 Partners, Schaumberg, IL), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase 30 inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol.18:233a 35 (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000). In some embodiments, the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a 40 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 221 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® 5 (tositumomab-I-131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOLIRIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); 10 YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado-trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody-drug conjugates. The second agent may be a therapeutic agent which is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and / or surgical excision 15 of tumor tissue. The second agent may be a checkpoint inhibitor. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor 20 of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion a protein such as ipilimumab / YERVOY® or tremelimumab). In some embodiments, the inhibitor of 25 checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / OPDIVO®; pembrolizumab / KEYTRUDA®; pidilizumab / CT-011). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule 30 inhibitor) of PDL2 (e.g., a PDL2 / Ig fusion protein such as AMP 224). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the anti-cancer therapy is a T cell adoptive transfer (ACT) therapy. In 35 some embodiments, the T cell is an activated T cell. The T cell may be modified to express a chimeric antigen receptor (CAR). CAR modified T (CAR-T) cells can be generated by any method known in the art. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral 40 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 222 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 present invention, any number of T cell lines available in the art, may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 5 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and U.S. Patent Application Publication No.20060121005. In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, 10 up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent. 15 Pharmaceutical Compositions The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. The compounds described herein may be used in the form of the free base, in the form of 20 salts, solvates, and as prodrugs. All forms are within the methods described herein. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or 25 transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. A compound described herein may be orally administered, for example, with an inert diluent or 30 with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound described herein may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. A compound described herein may also be administered parenterally. Solutions of a 35 compound described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are 40 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 223 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and 5 powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which 10 is intended for disposal after use. Where the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and 15 glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. A compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate. A compound 20 described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals. In the case of surgical intervention, the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection. Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature. 25 The compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice. 30 Dosages The dosage of the compounds described herein, and / or compositions including a compound described herein, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; 35 and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.01 mg and 3000 mg 40 (measured as the solid form). Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg). 224 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-50 mg / kg (e.g., 0.25-25 mg / kg). 5 Kits The invention also features kits including (a) a pharmaceutical composition including an agent that reduces the level and / or activity of EP300 in a cell or subject described herein, and (b) a package insert with instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent that reduces the level and / or activity of 10 EP300 in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein. 225 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Examples Definitions used in the following Schemes and elsewhere herein are: ACN or MeCN acetonitrile Ac2O acetic anhydride 5 tBuOK potassium tert-butoxide DCM dichloromethane DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide 10 dppf bis(diphenylphosphino)ferrocene dtbpf di-tert-butylphosphino)ferrocene ESI electrospray ionization Et N or TEA triethylamine 3 EtOAc ethyl acetate 15 EtOH ethyl alcohol FA formic acid FCC flash column chromatography h hours HATU 2-(3H-[ 1,2,3 ]triazolo[ 4,5-b ]pyridin-3-yl)-l, 1,3,3- 20 tetramethylisouronium HPLC high performance liquid chromatography KOAC potassium acetate L liter LCMS liquid chromatography / mass spectrometry 25 LiHMDS lithium hexamethyldisilazide MeOH methyl alcohol mL milliliter mmol millimole mg milligrams 30 MHz megahertz MS mass spectrometry MTBE methyl t-butylether m / z mass / charge ratio NBS N-bromosuccinimide 35 nm nanometer NMR nuclear magnetic resonance ppm parts per million rt room temperature RT retention time 226 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Ruphos Pd 3G (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2- (2′- amino-1,1′-biphenyl)]palladium(II) methanesulfonate SFC supercritical fluid chromatography 5 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 10 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. 15 Preparation of Intermediates (3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4- dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)acetic acid. 20 Step 1: To a stirred solution of 3-bromo-1H-pyrrolo[3,2-c]pyridine in DMF was added 1 equiv of tert- butyl 2-bromoacetate, 3 equiv of cesium carbonate and the resulting mixture was stirred between 10 and 20 C for 16 h to give tert-butyl 2-(3-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)acetate. LC / MS (ESI) m / z [M + H]+311.1. 25 Step 2: To a stirred solution of tert-butyl 2-(3-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)acetate in DMF was added 1 equiv of 1-(3-(7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1-one, 3 equiv of cesium carbonate, and 0.1 equiv of Pd(dppf)Cl2. The resulting mixture was 227 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 heated to 80 C for 4 h to give tert-butyl 2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H- pyrrolo[3,2-c]pyridin-1-yl)acetate. LC / MS (ESI) m / z [M + H]+661.4. 5 Step 3: To a stirred solution of tert-butyl 2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H- pyrrolo[3,2-c]pyridin-1-yl)acetate in DCM was added 1.5 eq of trifluoroacetic acid and the resulting mixture was stirred at 20 C for 2 h to give 2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H- 10 pyrrolo[3,2-c]pyridin-1-yl)acetic acid. LC / MS (ESI) m / z [M + H]+605.3. 1-(3-(7-(difluoromethyl)-6-(1-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroquinolin- 1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1- 15 one Step 1: To a stirred solution of 3-bromo-1H-pyrrolo[3,2-c]pyridine in DMF was added 2 equiv of tert- butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate, 2 equiv of cesium carbonate and the resulting mixture was stirred between 25 and 80 C for 12 h to give tert-butyl 4-(3-bromo-1H-pyrrolo[3,2- c]pyridin-1-yl)piperidine-1-carboxylate. LC / MS (ESI) m / z [M + H]+382.1. 20 Step 2: To a stirred solution of tert-butyl 4-(3-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1- carboxylate in DMF was added 1 equiv of 1-(3-(7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, 3 equiv of cesium carbonate, and 0.1 equiv of Pd(dppf)Cl2. 25 The resulting mixture was heated to 80 C for 4 h to give tert-butyl 4-(3-(1-(5-acetyl-1-(tetrahydro-2H- pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4- tetrahydroquinolin-6-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylate. LC / MS (ESI) m / z [M + H]+730.4. 228 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 3: To a stirred solution of tert-butyl 2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H- pyrrolo[3,2-c]pyridin-1-yl)acetate in EtOAc was added HCl in EtOAc and the resulting mixture was stirred at 20 C for 2 h to give 1-(3-(7-(difluoromethyl)-6-(1-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)- 5 3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridin-5-yl)ethan-1-one. LC / MS (ESI) m / z [M + H]+630.3. Example 1. Preparation of 2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrrolo[3,2- 10 c]pyridin-1-yl)acetic acid (Compound 29). 15 To a stirred solution of (3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)acetic acid (80 mg, 0.132 mmol, 1 equiv) and 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (36.15 mg, 0.132 mmol, 1 equiv) in DMF (2 mL) was added TCFH (40.83 mg, 0.145 mmol, 1.1 equiv) and NMI (32.59 mg, 0.396 mmol, 3 20 equiv) at room temperature. The resulting mixture was stirred for 1h at room temperature. The mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 53% B to 72% B in 11 min; Wave Length: 254nm / 220nm nm; RT1(min): 7.15) to afford compound 29 (2.3 mg, 1.87%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 2H), 8.70 229 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 (s, 1H), 8.27 (d, J = 5.8 Hz, 1H), 8.14 (s,1H),8.01 (s,1H), 7.91 (s,1H), 7.61 (d, J = 5.9 Hz, 1H) 7.52 (s, 1H), 7.21 (s, 1H), 6.91 (s, 1H), 5.23 (s, 2H), 5.20 - 5.01 (m,1H), 4.39 – 4.26 (m, 1H), 4.23 (s, 2H), 4.04 – 3.93 (m, 2H), 3.80 (s, 2H), 3.75 (s, 2H), 3.65 (t, J = 5.6 Hz, 2H), 2.99 - 2.82 (m, 6H), 2.73 – 2.57 (m, 2H), 2.15 (s, 8H), 1.91 - 1.82 (m, 2H) LCMS (ESI) m / z [M+H]+= 860.45. 5 The following compounds in TABLE 1c were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 29 in Example 1. TABLE 1c 230 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 231 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 232 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 233 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 234 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 235 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 236 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 237 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 238 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 2. Preparation of 5-(4-((1-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6- carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 5 (Compound 41). 10 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 To a stirred mixture of 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- (difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid (25.0 mg, 0.053 mmol, 1.00 equiv), 2-(2,6- dioxopiperidin-3-yl)-5-[4-(piperidin-4-ylmethyl)piperazin-1-yl]isoindole-1,3-dione (23.2 mg, 0.053 mmol, 1.00 equiv) and DIEA (20.4 mg, 0.159 mmol, 3.00 equiv) in DMF (1 mL) was added HATU (40.01 mg, 5 0.106 mmol, 2.00 equiv). The resulting mixture was stirred for 1 h at room temperature. Without any additional work-up, the resulting mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 30% B in 8 min, 30% B; Wave Length: 254 / 220 nm; RT1(min): 7.52; Number Of Runs: 0) to afford compound 41 (9.8 mg, 20.76%) as a yellow 10 green solid.1H NMR (400 MHz, Acetonitrile-d3) δ 8.93 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H), 6.91 – 6.55 (m, 2H), 5.06 – 4.88 (m, 1H), 4.57 (s, 1H), 4.30 – 4.13 (m, 3H), 4.05 – 3.95 (m, 2H), 3.80 (s, 1H), 3.71 (t, J = 5.8 Hz, 1H), 3.67 – 3.59 (m, 3H), 3.57 – 3.48 (m, 6H), 3.47 – 3.43 (m, 1H), 2.93 – 2.64 (m, 12H), 2.53 (s, 2H), 2.43 – 1.92 (m, 8H), 1.88 – 1.76 (m, 3H), 1.71 (s, 2H), 1.36 – 0.98 (m, 2H). LCMS (ESI) m / z [M+H]+=896.42. 15 The following compounds in TABLE 2 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 41 in Example 2. TABLE 2 240 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 C 3.55 3. (m, 3 ), 1-(4-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)- 3.28 – 3.19 (m, 3H), 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7- 2.92 – 2.83 (m, 4H), (difluoromethyl)-1,2,3,4-tetrahydroquinoline-6- 2.70 (t, J = 6.7 Hz, carbonyl)piperazin-1-yl)phenyl)dihydropyrimidine- 2H), 2.11 – 1.94 (m, 2,4(1H,3H)-dione 7H), 1.90 – 1.80 (m, 2H). 241 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 242 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 243 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 C 3.91 (m, 2H), 3.83 – 3.67 (m, 2H), 3.66 – 258 897.5 3.55 (m, 2H), 3.66 – 3.56 (m, 2H), 3.31 (s, 3-(5-(4-((1-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)- 3H), 3.11- 3.02 (m, 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7- 6H), 2.99 – 2.75 (m, (difluoromethyl)-1,2,3,4-tetrahydroquinoline-6- 6H), 2.74 – 2.63 (m, carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-3- 2H), 2.64 – 2.55 (m, methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- 5H), 2.36 – 2.16 (m, yl)piperidine-2,6-dione 2H), 2.16 – 2.04 (m, 8H), 2.04 – 1.61 (m, 5H), 1.29 – 0.90 (m, 2H). 244 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 C 4.24 (m, 1H), 4.20 (s, 2H), 4.04 – 3.93 (m, 264 869.5 2H), 3.81 – 3.70 (m, 2H), 3.6A9 – 3.58 (m, 2H), 3.57 – 3.44 (m, 3-(5-(4-((R)-1-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4- 3H), 3.43 – 3.35 (m, yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)- 1H), 3.32 (s, 3H), 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6- 3.18 – 3.07 (m, 4H), carbonyl)pyrrolidin-3-yl)piperazin-1-yl)-3-methyl-2- 3.02 – 2.93 (m, 2H), oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2.93 – 2.78 (m, 5H), 2,6-dione 2.76 – 2.68 (m, 2H), 2.67 – 2.61 (m, 2H), 2.61 – 2.56 (m, 2H), 2.19 – 1.77 (m, 13H). 245 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 246 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 247 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 248 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 C 3.06 (m, 1H), 3.02 – 2.80 (m, 10H), 2.79 – 3-(7-(difluoromethyl)-6-(4-((4-(2-(2,6-dioxopiperidin- 2.71 (m, 2H), 2.68 (s, 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- 3H), 2.67 – 2.61 (m, yl)methyl)piperidine-1-carbonyl)-3,4-dihydroquinolin- 2H), 2.40 – 2.15 (m, 1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)- 2H), 2.14 – 1.99 (m, 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- 4H), 1.97 – 1.82 (m, carboxamide 3H), 1.76 (d, J = 13.0 Hz, 1H), 1.29 (s, 2H). 249 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 250 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 251 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 C . . , , 3.51 – 3.38 (m, 5H), 5-((S)-3-(1-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)- 3.11 – 3.02 (m, 1H), 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7- 2.93 – 2.83 (m, 4H), (difluoromethyl)-1,2,3,4-tetrahydroquinoline-6- 2.80 – 2.72 (m, 1H), carbonyl)azetidin-3-yl)pyrrolidin-1-yl)-2-(2,6- 2.69 – 2.56 (m, 2H), dioxopiperidin-3-yl)isoindoline-1,3-dione 2.56 – 2.53 (m, 1H), 2.21 – 2.09 (m, 1H), 2.10 – 2.05 (m, 2H), 2.02 – 1.89 (m, 6H), 1.86 – 1.76 (m, 2H), 1.73 – 1.62 (m, 1H), . 252 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 3. Preparation of 2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrrolo[3,2- c]pyridin-1-yl)acetic acid (Compound 31). 5 253 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 To a stirred solution of (3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)acetic acid (75.0 mg, 0.124 mmol, 1.00 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (42.4 mg, 0.124 mmol, 1.00 equiv) in DMF (1 mL) were added TCFH (38.3 mg, 0.136 mmol, 1.10 equiv) and NMI (30.5 5 mg, 0.372 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred for 1h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 43% B to 70% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 7.85) to afford Compound 31 (28.6 mg, 23.16%) as a yellow solid.1H 10 NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.82 (s, 1H), 8.31 (d, J = 5.9 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 6.0 Hz, 1H), 7.45 – 7.35 (m, 2H), 7.34 – 7.23 (m, 2H), 6.96 (s, 1H), 6.89 - 6.40 (m,1H), 5.39 (s, 2H), 5.07 (dd, J = 12.4, 5.4 Hz, 1H), 4.34 (d, J = 11.7 Hz, 1H), 4.24 (s, 2H), 3.98 (d, J = 11.5 Hz, 2H), 3.75 (s, 6H), 3.65 (s, 6H), 3.56 – 3.42 (m, 3H), 2.92 (d, J = 7.4 Hz, 5H), 2.60 (t, J = 9.5 Hz, 2H), 2.06 (t, J = 9.5 Hz, 8H), 1.87 (d, J = 9.8 Hz, 2H). LCMS (ESI) m / z [M+H]+=928.38. 15 The following compounds in TABLE 3 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 31 in Example 3. TABLE 3 254 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 255 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 256 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 257 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 258 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 259 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 260 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 261 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 262 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 263 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 264 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 265 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 266 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 267 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 268 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 269 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 270 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 271 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 272 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 273 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 274 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 275 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 276 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 277 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 278 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 279 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 280 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 4. Preparation of 4-(2-(1-(2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H- pyrrolo[3,2-c]pyridin-1-yl)acetyl)azetidin-3-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- 5 dione (Compound 35). 281 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 1: 4-(2-(1-(2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrrolo[3,2-c]pyridin-1- yl)acetyl)azetidin-3-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 35). 5 To a solution of (3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)- 3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)acetic acid (91.37 mg, 0.151 mmol, 1.2 equiv), 4- [2-(azetidin-3-yl)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (45 mg, 0.126 mmol, 1.00 equiv) and DIEA (65.80 uL, 0.378 mmol, 3 equiv) in DMF (1 mL) was added HATU (143.64 mg, 0.378 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2h. The 10 resulting mixture was purified by reversed-phase flash chromatography with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3+0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 26%B to 36%B in10min; Wave Length: 254nm / 220nm nm; RT1(min): 12 to afford compound 35 (37.7 mg, 31.72%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.75 (d, J = 4.1 Hz, 1H), 8.26 15 (d, J = 5.8 Hz, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.52 (t, J = 7.9 Hz, 2H), 7.46 (d, J = 7.3 Hz, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.25 (d, J = 3.5 Hz, 1H), 6.94 (d, J = 5.5 Hz, 1H), 6.83 – 6.51 (m, 1H), 5.13 – 4.94 (m, 3H), 4.43 – 4.17 (m, 6H), 4.06 (t, J = 8.6 Hz, 2H), 3.96 (d, J = 11.6 Hz, 2H), 3.82 – 3.69 (m, 3H), 3.63 (t, J = 6.1 Hz, 2H), 3.46 (t, J = 11.9 Hz, 2H), 2.97 – 2.75 (m, 6H), 2.57 (d, J = 16.1 Hz, 2H), 2.11 (d, J = 18.2 Hz, 4H), 2.01 (d, J = 9.2 Hz, 6H), 1.84 (d, J = 12.7 Hz, 2H).. LCMS (ESI) m / z [M+H]+=944.40. 20 The following compounds on TABLE 4 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 35 in Example 4. TABLE 4 282 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 283 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 284 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 285 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 5. Preparation of 2-{4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,286yridineidin-3-yl]- 6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-7-yl}-N-[2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindol-5-yl]-[1,3]thiazolo[5,4-b]pyridine-6-carboxamide (Compound 4). 5 10 286 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 To a stirred solution of 1-{3-[7-bromo-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-1-(oxan-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (500 mg, 0.978 mmol, 1 equiv) and bis(pinacolato)diboron (496.59 mg, 1.956 mmol, 2 equiv) in 1,4-dioxane (10 mL) was added KOAc (383.84 mg, 3.912 mmol, 4 equiv) and Pd(dppf)Cl2 (71.54 mg, 0.098 mmol, 0.1 equiv). The resulting 5 mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (30:1) to afford Intermediate 2 (448 mg, 82.05%) as a light yellow solid. LCMS (ESI) m / z [M+H]+= 559. 10 To a stirred solution of methyl 5-amino-6-chloropyridine-3-carboxylate (1 g, 5.359 mmol, 1 equiv) in acetic acid (10 mL) was added potassium thiocyanate (1562.38 mg, 16.077 mmol, 3 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 80°C for 6h. The 15 resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford Intermediate 2 (800 mg, 71.35%) as a 20 yellow solid. LCMS (ESI) m / z: [M+H]+= 210. To a stirred solution of Intermediate 2 (630 mg, 3.011 mmol, 1.00 equiv), CuBr2 (874.33 mg, 3.915 25 mmol, 1.30 equiv) in ACN (40 mL) was added tert-butylnitrite (558.93 mg, 5.420 mmol, 1.8 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 5h under argon atmosphere. The reaction was quenched by the addition of 1eq. sat. NH2SO3 (aq.) (40 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous MgSO4. After filtration, the 30 filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (10:1~ 1:1) to afford Intermediate 3 (557 mg, 67.73%) as a yellow solid. LCMS (ESI) m / z: [M+H]+=273 / 275. 287 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 3: methyl 2-{4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-6-(difluoromethyl)-2,3- dihydro-1,4-benzoxazin-7-yl}-[1,3]thiazolo[5,4-b]pyridine-6-carboxylate (Intermediate 4) 5 To a stirred mixture of methyl 2-bromo-[1,3]thiazolo[5,4-b]pyridine-6-carboxylate (80 mg, 0.293 mmol, 1 equiv) and 1-{3-[6-(difluoromethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4- benzoxazin-4-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (163.58 mg, 0.293 mmol, 1 equiv) in H2O (0.2 mL) and 1,4-dioxane (1 mL) was added K3PO4 (202.37 mg, 0.879 mmol, 3 equiv), 10 XPhos Pd G3 (24.80 mg, 0.029 mmol, 0.1 equiv) and XPhos (17.46 mg, 0.037 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm. The resulting mixture was 15 concentrated under reduced pressure. This resulted in methyl Intermediate 4 (120 mg, 64.60%) as a white solid. LCMS (ESI) m / z: [M+H]+=625 Step 4: 2-{4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-6-(difluoromethyl)-2,3- dihydro-1,4-benzoxazin-7-yl}-[1,3]thiazolo[5,4-b]pyridine-6-carboxylic acid (Intermediate 5). 20 A mixture of Intermediate 4 (118 mg, 0.189 mmol, 1 equiv) and LiOH.H2O (23.78 mg, 0.567 mmol, 3 equiv) in THF (0.5 mL) and H2O (0.5 mL) was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water 25 (0.1% TFA), 0% to 100% gradient in 30 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in Intermediate 5 (98 mg, 97.30%) as a green solid. LCMS (ESI) m / z: [M+H]+=611 288 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 5: 2-{4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-6-(difluoromethyl)-2,3- dihydro-1,4-benzoxazin-7-yl}-[1,3]thiazolo[5,4-b]pyridine-6-carboxamide (Intermediate 6). 5 To a stirred mixture of of Intermediate 5 (96 mg, 0.157 mmol, 1 equiv), ammonium chloride (8.41 mg, 0.157 mmol, 1 equiv) in DMF (1 mL) was added DIEA (60.96 mg, 0.471 mmol, 3 equiv) and HATU (71.73 mg, 0.188 mmol, 1.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1h. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water 10 (10mmol / L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. This resulted in Intermediate 6 (66 mg, 65.83%) as a white solid. LCMS (ESI) m / z: [M+H]+=610 Step 6: 2-{4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-6-(difluoromethyl)-2,3-15 dihydro-1,4-benzoxazin-7-yl}-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-[1,3]thiazolo[5,4- b]pyridine-6-carboxamid). (Compound 4). To a stirred mixture of Intermediate 6 (36 mg, 0.059 mmol, 1 equiv), 5-bromo-2-(2,6-dioxopiperidin-3- 20 yl)isoindole-1,3-dione (19.91 mg, 0.059 mmol, 1 equiv) in 1,4-dioxane (2 mL) was added K3PO4 (37.60 mg, 0.177 mmol, 3 equiv) and XPhos Pd G3 (5.00 mg, 0.006 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water(0.1% FA), 25 Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 35% B to 55% B in 8 min; Wave Length: 289 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 254nm / 220nm nm; RT1(min): 6.88) to afford Compound 4 (8.3 mg, 16.12%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 2H), 9.23 – 9.12 (m, 1H), 9.04 – 8.94 (m, 1H), 8.44 (s, 1H), 8.32 – 8.23 (m, 1H), 8.04 – 7.58 (m, 2H), 7.43 (s, 1H), 7.34 (s, 1H), 5.18 – 5.07 (m, 1H), 4.52 – 4.41 (m, 2H), 4.39 – 4.28 (m, 3H), 4.06 – 3.95 (m, 2H), 3.89 – 3.82 (m, 2H), 3.81 – 3.73 (m, 2H), 3.59 – 3.46 (m, 2H), 5 2.97 – 2.79 (m, 3H), 2.73 – 2.57 (m, 2H), 2.20 – 1.99 (m, 6H), 1.96 – 1.80 (m, 2H). LCMS (ESI) m / z: [M+H]+=866.25 Example 6. Preparation of 5-(4-(8-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrrolo[1,2- 10 a]pyrazin-4-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 3). Step 1: Preparation of 4-iodopyrrolo[1,2-a]pyrazine (Intermediate 2). 15 In a 100 mL round bottom flask, to a solution of pyrrolo[1,2-a]pyrazine (1.50 g, 12.697 mmol, 1.00 equiv) in THF (20 mL) was added dropwise 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (1.0M in THF) (25.3 mL, 25.394 mmol, 2.00 equiv) at -78 degrees C under N2 atmosphere. The reaction mixture was stirred at -45 degrees C for 40 mins. Then a solution of Iodine (3.54 g, 13.967 mmol, 1.1 equiv) in 10 mL THF was added dropwise at -78 degrees C and the mixture was stirred for 20 another 10 h at room temperature. The reaction was quenched with sat. NH4Cl (100 mL), and then the mixture was extracted with EtOAc (3*100 mL). The combined organic extracts were washed with brine (3*50 mL), dried over by anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 20 25 min; detector, UV 220 and 254 nm. This resulted in intermediate 2 (754 mg, 24.33%) as a brown solid. LCMS (ESI) m / z: [M+H]+= 245. 290 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 2: Preparation of 8-bromo-4-iodopyrrolo[1,2-a]pyrazine (Intermediate 3). A mixture of intermediate 2 (512.0 mg, 2.098 mmol, 1.00 equiv) and AlCl3 (419.6 mg, 3.147 mmol, 1.50 equiv) in DCM (15 mL) was stirred at room temperature for 45min. To the above mixture was added the 5 solution of Br2 (335.2 mg, 2.098 mmol, 1.00 equiv) in DCM (3 mL) dropwise over 5 min at room temperature. The resulting mixture was stirred at room temperature for 2 h. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4Cl (aq.). The resulting mixture was extracted with EtOAc (3*50 mL). The combined organic layers were washed with water (3*30 mL), dried over by anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The 10 residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 20 min; detector, UV 220 and 254 nm. This resulted in intermediate 3 (643 mg, 94.90%) as a brown solid. LCMS (ESI) m / z: [M+H]+= 323 15 Step 3: Preparation of tert-butyl 4-(8-bromopyrrolo[1,2-a]pyrazin-4-yl)piperazine-1-carboxylate (Intermediate 4). To a solution of intermediate 3 (200.0 mg, 0.619 mmol, 1.00 equiv) and tert-butyl piperazine-1- carboxylate (173.0 mg, 0.928 mmol, 1.50 equiv) in dioxane (5 mL) were added Cs2CO3 (403.5 mg, 1.238 20 mmol, 2.00 equiv) and BINAP Pd G3 (122.9 mg, 0.124 mmol, 0.20 equiv). The mixture was stirred for overnight at 80°C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3x20 mL), dried over by anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified 25 by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 20 min; detector, UV 220 and 254 nm. This resulted in intermediate 4 (141 mg, 59.71%yield) as a light yellow solid. LCMS (ESI) m / z: [M+H]+=381. 291 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 To a solution of intermediate 4 (131.0 mg, 0.344 mmol, 1.00 equiv) and 1-{3-[7-(difluoromethyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl}ethanone (229.4 mg, 0.413 mmol, 1.20 equiv) in dioxane (3 mL) and H2O (0.6 mL) were added Cs2CO3 (335.8 mg, 1.032 mmol, 3.00 equiv) and Pd(dppf)Cl2 (50.3 mg, 0.069 mmol, 0.20 equiv). The mixture was stirred for 2 h at 80°C under a nitrogen atmosphere. Desired product could 10 be detected by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3x20 mL), dried over by anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 20 min; detector, UV 15 220 and 254 nm. This resulted in intermediate 5 (204 mg, 81.24%) as a Brown yellow solid. LCMS (ESI) m / z: [M+H]+=731. 20 A solution of intermediate 5 (110.0 mg, 0.151 mmol, 1.00 equiv) and TFA (0.8 mL) in DCM (2.4 mL) was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The mixture was neutralized to pH 7 with saturated NaHCO3 (aq.). The residue was purified by reversed-phase flash 292 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in Water (0.1% FA), 10% to 100% gradient in 20 min; detector, UV 220 and 254 nm. This resulted in intermediate 6 (81 mg, 85.32%) as an off-white solid. LCMS (ESI) m / z: [M+H]+= 631. 5 Step 6: Preparation of 5-(4-(8-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)pyrrolo[1,2-a]pyrazin-4- yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 3). A solution of intermediate 6 (72.0 mg, 0.114 mmol, 1.00 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5- 10 fluoroisoindole-1,3-dione (37.8 mg, 0.137 mmol, 1.20 equiv) in DMSO (3 mL) was stirred at 100°C for 24 h. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 20% B to 35% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 6.1) to afford Compound 3 (18.9 mg, 18.67%) as a 15 yellow solid. LCMS (ESI) m / z: [M+H]+= 887.35.1H NMR (300 MHz, DMSO-d6) δ 10.92 (br s, 1H), 8.48 (s, 1H), 7.81 – 7.65 (m, 2H), 7.46 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.6, 2.2 Hz, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 6.97 – 6.93 (m, 2H), 6.65 (t, J = 55.3 Hz, 1H), 5.12 – 5.03 (m, 1H), 4.40 – 4.27 (m, 1H), 4.24 (s, 2H), 4.04 – 3.93 (m, 2H), 3.88 – 3.71 (m, 6H), 3.65 (t, J = 5.7 Hz, 2H), 3.56 – 3.42 (m, 2H), 3.36 – 3.26 (m, 4H), 3.00 – 2.73 (m, 5H), 2.69 – 2.53 (m, 2H), 2.18 – 1.96 (m, 8H), 1.92 – 1.79 (m, 2H). 20 The following compounds in TABLE 5 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 3 in Example 6. TABLE 5 293 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 294 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 295 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 296 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 297 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 298 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 299 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 300 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 301 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 302 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 303 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 304 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 7. Preparation of 4-({2-[4-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin- 3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl]-2- oxoethyl}amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 17). 5 Step 1: tert-butyl 2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}acetate. (Intermediate 2). To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (2 g, 7.241 mmol, 1 equiv) and tert-butyl 2-aminoacetate (0.95 g, 7.242 mmol, 1.00 equiv) in DMSO (10 mL) was 10 added DIEA (2.81 g, 21.723 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred at 90 °C for overnight. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. To afford intermediate 2 (2 g, 71.30%) as a green solid. LCMS (ESI) m / z [M+H]+=388. 15 305 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 2: {[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}acetic acid (Intermediate 3). To a stirred solution of tert-butyl 2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}acetate (950 mg, 2.452 mmol, 1 equiv) in HCl(gas) in 1,4-dioxane (20 mL, 4N) at room temperature. The 5 resulting mixture was stirred at room temperature for 4 h. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford intermediate 3 (700 mg, 86.16%) as a green solid. LCMS (ESI) m / z [M+H]+ =332. 10 Step 3: 4-({2-[4-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)- 3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl]-2-oxoethyl}amino)-2-(2,6- dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 17). 15 To a stirred solution of {[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}acetic acid (15 mg, 0.045 mmol, 1 equiv) and 1-{3-[7-(difluoromethyl)-6-[1-(piperidin-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-3,4- dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (28.51 mg, 0.045 mmol, 1 equiv) in DMF (1 mL) was added HATU (37.88 mg, 0.099 mmol, 2.2 equiv) and DIPEA (23.41 mg, 0.180 mmol, 4 equiv) dropwise at room temperature. The resulting mixture was stirred 20 at room temperature for 4 h. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. To afford compound 17 (4.9 mg, 11.48%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 5.3 Hz, 1H), 8.28 (d, J = 5.8 Hz, 1H), 7.71 (d, J = 5.9 Hz, 1H), 7.67 – 7.56 (m, 1H), 7.52 (d, J = 5.7 Hz, 1H), 7.08 (d, J = 7.1 Hz, 4H), 6.95 – 6.84 (m, 1H), 6.73 306 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 (d, J = 4.6 Hz, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.82 (s, 1H), 4.63 (d, J = 12.7 Hz, 1H), 4.37 – 4.25 (m, 3H), 4.23 (s, 1H), 4.18 (s, 1H), 4.15 – 4.07 (m, 1H), 3.99 – 3.91 (m, 2H), 3.73 (dt, J = 21.2, 5.9 Hz, 2H), 3.63 (q, J = 6.0 Hz, 2H), 3.48 (d, J = 9.9 Hz, 2H), 3.45 – 3.39 (m, 1H), 2.89 (d, J = 6.7 Hz, 5H), 2.77 (s, 1H), 2.64 – 2.54 (m, 2H), 2.14 (d, J = 10.8 Hz, 1H), 2.08 (s, 4H), 1.98 (d, J = 4.5 Hz, 7H), 1.83 5 (d, J = 12.0 Hz, 2H). LCMS (ESI) m / z [M+H]+= 943.35. Example 8. Preparation of 5-{2-[4-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin- 3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl]-2- oxoethoxy}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 27). 10 Step 1: tert-butyl 2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy}acetate (Intermediate 2). To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindole-1,3-dione (2 g, 7.293 mmol, 1.00 15 equiv) and tert-butyl 2-bromoacetate (2.13 g, 10.940 mmol, 1.50 equiv) in DMF (20 mL) was added KI (1.21 g, 7.293 mmol, 1.00 equiv) and K2CO3 (2.02 g, 14.586 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% 20 gradient in 10 min; detector, UV 254 nm) to afford intermediate 2 (2.6 g, 91.79%) as a purple solid. LCMS (ESI) m / z [M+H]+=389. 25 To a stirred solution of intermediate 2 (2.6 g, 6.695 mmol, 1.00 equiv) in HCl(gas) in 1,4-dioxane (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash 307 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford intermediate 3 (1.2 g, 53.95%) as a white solid. LCMS (ESI) m / z [M+H]+=333. 5 To a stirred solution of intermediate 3 (20.0 mg, 0.060 mmol, 1.00 equiv) and 1-{3-[7-(difluoromethyl)-10 6-[1-(piperidin-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl}ethanone (37.9 mg, 0.060 mmol, 1.00 equiv) in DMF (2 mL) was added HATU (50.3 mg, 0.132 mmol, 2.20 equiv) and DIEA (31.1 mg, 0.240 mmol, 4.00 equiv) dropwise at room temperature. The resulting mixture was stirred at room temperature for 4 h. The residue was purified by reversed-phase flash chromatography with the following conditions 15 (column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford compound 27 (10.4 mg, 18.30%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.95 (s, 1H), 8.46 (s, 1H), 8.14 (d, J = 9.3 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.3, 2.3 Hz, 1H), 7.25 (s, 1H), 6.93 (d, J = 11.2 Hz, 2H), 5.12 (dd, J = 12.9, 5.3 Hz, 3H), 4.98 (s, 1H), 4.56 (d, J = 12.8 Hz, 1H), 4.24 (s, 1H), 4.18 (s, 2H), 4.04 20 (d, J = 13.3 Hz, 3H), 4.00 – 3.92 (m, 2H), 3.76 (d, J = 5.8 Hz, 2H), 3.52 – 3.45 (m, 2H), 2.89 (dt, J = 11.3, 7.7 Hz, 7H), 2.64 – 2.52 (m, 2H), 2.19 (d, J = 11.6 Hz, 1H), 2.11 – 1.96 (m, 11H), 1.84 (d, J = 12.4 Hz, 2H). LCMS (ESI) m / z [M+H]+=944.01. The following compounds in TABLE 6 were prepared using standard chemical manipulations and 25 procedures similar to those used for the preparation of Compound 27 in Example 8. 308 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 TABLE 6 309 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 310 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 311 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 312 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 9. Preparation of 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 28). 5 To a stirred solution of 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (30.0 mg, 0.085 mmol, 1.00 equiv) and 1-{3-[7-(difluoromethyl)-6-[1-(piperidin-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-3,4- 10 dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (53.8 mg, 0.085 mmol, 1.00 equiv) in DMF (2 mL) was added K2CO3 (23.6 mg, 0.170 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred at 60°C for 2h. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 35% 15 B to 60% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 6.25) to afford compound 28 (23.1 mg, 29.29%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.70 (s, 1H), 8.25 (d, J = 5.8 Hz, 1H), 7.94 – 7.83 (m, 3H), 7.61 (d, J = 5.9 Hz, 1H), 7.52 (s, 1H), 7.21 (s, 1H), 6.91 (s, 1H), 6.70 (s, 1H), 5.13 (dd, J = 12.3, 5.4 Hz, 1H), 4.47 (d, J = 5.5 Hz, 1H), 4.39 – 4.26 (m, 1H), 4.23 (s, 2H), 4.04 – 3.93 (m, 2H), 3.80 (s, 4H), 3.75 (s, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.49 (td, J = 11.9, 2.3 Hz, 2H), 3.01 20 (d, J = 11.1 Hz, 5H), 2.71 – 2.52 (m, 2H), 2.44 – 2.31 (m, 2H), 2.03 (q, J = 6.4 Hz, 12H), 1.91 - 1.82 (m, 2H) LCMS (ESI) m / z [M+H]+=899.39. The following compounds in TABLE 7 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 28 in Example 9. 25 313 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 TABLE 7 314 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 315 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 316 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 10. Preparation of 5-(4-(2-(7-(4-((5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(methyl)amino)-2-(difluoromethyl)phenyl)imidazo[1,2- a]pyridin-6-yl)acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 5 Preparation of 1-[3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]ethenone (Intermediate A). 317 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 1: 3-bromo-1-(oxan-4-yl)pyrazolo[4,3-c]pyridine (Intermediate 2). To a stirred mixture of 3-bromo-1H-pyrazolo[4,3-c]pyridine (20 g, 100.998 mmol, 1 equiv) and oxan-4- yl methanesulfonate (20.02 g, 111.098 mmol, 1.1 equiv) in DMF (200 mL) was added Cs2CO3 (65.81 5 g, 201.996 mmol, 2 equiv). The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was diluted with water (800 mL) and extracted with EtOAc (800 mL x 3). 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 flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (containing 0.1% FA). Pure fractions were evaporated to 10 dryness to afford intermediate 2 (21.5 g, 75.1%) as a white solid. LCMS (ESI) m / z [M+H]+ =282.6. Step 2: 3-bromo-1-(oxan-4-yl)-4H,5H,6H,7H-pyrazolo[4,3-c]pyridine (Intermediate 3) To a solution of intermediate 2 (10 g, 35.443 mmol, 1 equiv) in MeOH (100 mL) was added PtO2 (2.82 15 g, 12.405 mmol, 0.35 equiv). The resulting mixture was stirred for 4 h at room temperature under 10 atm with hydrogen atmosphere. The resulting mixture was filtered to remove insoluble solids. After filtration, the filtrate was concentrated under reduced pressure to give intermediate 3 (10.4 g, crude) as a white solid that was used directly without further purification. LCMS (ESI) m / z [M+H]+ =286.2. 20 To a stirred solution of intermediate 3 (10.4 g, 36.342 mmol, 1 equiv) and TEA (11.03 g, 109.026 mmol, 3 equiv) in DCM (110 mL) was added Ac2O (5.57 g, 54.513 mmol, 1.5 equiv) dropwise at 0℃. The resulting mixture was stirred for 2h at room temperature. The resulting mixture was diluted with water 25 (400 mL) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (900 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under 318 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions was evaporated under reduced pressure to afford intermediate A (8.5 g, 68.41%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 4.38 – 4.30 (m, 1H), 4.28 (s, 2H), 4.03 – 3.86 (m, 2H), 3.71 (dt, J = 11.4, 5.8 Hz, 2H), 3.43 (td, J = 11.8, 2.1 Hz, 2H), 2.83 (t, J = 5.8 Hz, 5 1H), 2.71 (t, J = 5.8 Hz, 1H), 2.09 (d, J = 4.4 Hz, 3H), 2.03 – 1.86 (m, 2H), 1.84 – 1.71 (m, 2H). LCMS (ESI) m / z [M+H]+=328.2. 10 A solution of 5-bromo-4-chloropyridin-2-amine (2.0 g, 9.640 mmol, 1.00 equiv) and chloroacetaldehyde (3.78 g, 48.200 mmol, 5.00 equiv) in IPA (15 mL) was stirred for 2 h at 80°C. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following 15 conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 40% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in intermediate 2 (1.26 g, 29.9%) as a brown solid. LCMS (ESI) m / z: [M+H]+=230. 20 To a stirred mixture of intermediate 2 (1.25 g, 5.400 mmol, 1.00 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2-oxazole (2.11 g, 10.800 mmol, 2.00 equiv) in dioxane (15 mL) and H2O (3 mL) were added K3PO4 (3.44 g, 16.200 mmol, 3.00 equiv) and Pd(dtbpf)Cl2 (351.95 mg, 0.540 mmol, 0.100 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was 25 stirred for 2 h at 80°C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3x50 mL), dried over anhydrous 319 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 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), 40% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in intermediate 3 (512 mg, 43.2%) as an off-white solid. LCMS (ESI) m / z: [M+H]+= 219. 5 To a stirred solution of intermediate 3 (500.0 mg, 2.277 mmol, 1.00 equiv) and KF (661.3 mg, 11.385 mmol, 5.00 equiv) in MeOH (3 mL) and H2O (3 mL) was stirred for 1h at 120°C. Desired product could 10 be detected by LCMS. The mixture was allowed to cool down to room temperature. 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), 50% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in intermediate 4 (224 mg, 51.3%) as a white solid. LCMS (ESI) m / z: [M+H]+= 191. 15 To a stirred mixture of intermediate 4 (219.0 mg, 1.143 mmol, 1.00 equiv) in H2SO4 (0.8 mL) and H2O (0.8 mL) followed by the addition of EtOH (1.6 mL) in portions at 0°C. The resulting mixture was stirred for 2 h at 100°C. Desired product could be detected by LCMS. The reaction was quenched by the 20 addition of water (10 mL) at 0°C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in intermediate 5 (92.0 mg, 6.75%) as a white solid. LCMS (ESI) m / z: [M+H]+= 238. 25 To a stirred solution of 2-chloro-5-nitrobenzaldehyde (5 g, 26.945 mmol, 1 equiv) in DCM (60 mL) was added DAST (21.72 g, 134.725 mmol, 5 equiv) dropwise at 0°C. The resulting mixture was stirred at 320 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 room temperature for 4h under nitrogen atmosphere. The reaction was quenched with Sat. sodium bicarbonat(aq.) at 0°C.The aqueous layer was extracted with CH2Cl2 (3 x 200 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (8:1) to afford 1-chloro-2-(difluoromethyl)-4-nitrobenzene 5 (5.2 g, 92.98%) as a yellow liquid. LCMS (ESI) m / z [M+H]+= 208. A mixture of intermediate 2 (4.2 g, 20.235 mmol, 1 equiv), Fe (6.78 g, 121.410 mmol, 6 equiv) and 10 NH4Cl (8.66 g, 161.880 mmol, 8 equiv) in EtOH / H2O 4:1 (60 mL) was refluxed for 2 h at 90°C. The resulting mixture was filtered while hot and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-chloro-3- (difluoromethyl)aniline (3.3 g, 84.49%) as an orange solid.1H NMR (300 MHz, DMSO-d6) δ 7.22 – 6.82 15 (m, 3H), 6.71 (dd, J = 8.7, 3.0, 1.4 Hz, 1H), 5.57 (s, 2H). LCMS (ESI) m / z [M+H]+= 178. 20 To a stirred solution of 1-[3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1 g, 3.047 mmol, 1 equiv) and 4-chloro-3-(difluoromethyl)aniline (541.06 mg, 3.047 mmol, 1 equiv) in THF (15 mL) was added sodium trimethylsilanolate (683.58 mg, 6.094 mmol, 2 equiv) and GPhos Pd G6 (576.13 mg, 0.609 mmol, 0.2 equiv). The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was 25 extracted with EtOAc (3 x 200mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 25 min; detector, UV 254 nm. to afford 1-(3-{[4-chloro-3-(difluoromethyl)phenyl]amino}-1-(oxan-4-yl)- 321 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (944 mg, 72.92%) as a brown solid. LCMS (ESI) m / z [M+H]+= 425. 5 A solution of 1-(3-{[4-chloro-3-(difluoromethyl)phenyl]amino}-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-5-yl)ethanone (1.1 g, 2.589 mmol, 1 equiv) in DMF (15 mL) was treated with NaH (207.10 mg, 5.178 mmol, 2 equiv, 60%) at 0°C for 10min under nitrogen atmosphere followed by the addition 10 of CH3I (734.95 mg, 5.178 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (150 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed- 15 phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 30 min; detector, UV 254 nm. to afford 1-(3-{[4- chloro-3-(difluoromethyl)phenyl](methyl)amino}-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5- yl)ethanone (1 g, 88.01%) as a white solid. LCMS (ESI) m / z [M+H]+= 439. 20 To a stirred solution of 1-(3-{[4-chloro-3-(difluoromethyl)phenyl](methyl)amino}-1-(oxan-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (350 mg, 0.797 mmol, 1 equiv), 2-(5,5-dimethyl-1,3,2- 25 dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (360.27 mg, 1.594 mmol, 2 equiv) and KOAc (234.79 mg, 2.391 mmol, 3 equiv) in 1,4-dioxane (1 mL) was added XPhos Pd G3 (135.00 mg, 0.159 mmol, 0.2 equiv). The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The 322 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 resulting mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 30% gradient in 30 min; detector, UV 254 nm. to afford 4-{[5-acetyl- 1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl](methyl)amino}-2-(difluoromethyl)phenylboronic 5 acid (274 mg, 98%purity) as a white solid. LCMS (ESI) m / z [M+H]+= 449. Step 6: Preparation of ethyl 2-(7-(4-((5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)(methyl)amino)-2-(difluoromethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)acetate (Intermediate 7). 10 To a solution of 4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl](methyl)amino}-2- (difluoromethyl)phenylboronic acid (75.0 mg, 0.167 mmol, 1.00 equiv) and ethyl 2-{7-chloroimidazo[1,2- a]pyridin-6-yl}acetate (39.9 mg, 0.167 mmol, 1.00 equiv) in dioxane (3 mL) and H2O (0.6 mL) were added Cs2CO3 (163.5 mg, 0.501 mmol, 3.00 equiv) and XPhos Pd G3 (28.3 mg, 0.033 mmol, 0.20 equiv). The 15 mixture was stirred for 2 h at 80°C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 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 20 gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 20 min; detector, UV 220 and 254 nm). This resulted in intermediate 7 (84 mg,77.3%) as a brown solid. LCMS (ESI) m / z: [M+H]+= 607. 323 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 7: Preparation of ethyl 2-(7-(4-((5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)(methyl)amino)-2-(difluoromethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)acetic acid (Intermediate 8). 5 A solution of intermediate 7 (79.0 mg, 0.130 mmol, 1.00 equiv) and LiOH (62.3 mg, 2.60 mmol, 20 equiv) in THF (3 mL) and H2O (1 mL) was stirred at 60°C for 1.5 h. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 20 min; detector, UV 220 and 254 nm. This resulted in 10 intermediate 8 (59 mg, 75.4%) as an off-white solid. LCMS (ESI) m / z: [M+H]+= 579 15 A solution of intermediate 8 (20.0 mg, 0.035 mmol, 1.00 equiv), TCFH (19.4 mg, 0.070 mmol, 2.00 equiv), 1-methyl-1H-imidazole (8.5 mg, 0.105 mmol, 3.00 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1- yl) isoindole-1,3-dione (11.8 mg, 0.035 mmol, 1.00equiv) in DMF (2 mL) was stirred at room temperature for 2 h. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with 20 the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 9% B to 25% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 10) to afford Compound 7 (12.9 mg, 40.2%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 903.35.1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.55 (s, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.24 – 25 7.11 (m, 2H), 7.08 (s, 1H), 7.01 – 6.90 (m, 1H), 6.63 (t, J = 55.1 Hz, 1H), 5.05 (dd, J = 12.3, 5.4 Hz, 1H), 4.36 – 4.21 (m, 1H), 4.12 (s, 2H), 4.00 – 3.87 (m, 2H), 3.84 – 3.63 (m, 3H), 3.59 – 3.46 (m, 8H), 3.38 – 3.27 (m, 3H), 3.22 (s, 3H), 2.97 – 2.70 (m, 3H), 2.68 – 2.55 (m, 2H), 2.17 – 1.89 (m, 6H), 1.87 – 1.70 (m, 2H). 324 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 11. Preparation of 5-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 40). 5 Step 1: dimethyl 4-(4-bromo-1H-pyrazol-1-yl)phthalate (Intermediate 2). To a stirred solution of 1,2-dimethyl 4-fluorophthalate (500 mg, 2.357 mmol, 1 equiv) and 4- 10 bromopyrazole (415.62 mg, 2.828 mmol, 1.2 equiv) in DMF (5 mL) was added K2CO3 (651.37 mg, 4.714 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for overnight at 120 °C under nitrogen atmosphere. The reaction mixture was diluted with EA (100 mL), the resulting mixture was washed with water (50 mL x 2) and saturated brine (100 mL x 1). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The residue was purified 15 by silica gel column chromatography, eluted with PE / EA (5:1) to afford Intermediate 2 (166 mg, 20.77%) as a yellow solid. LCMS (ESI) m / z [M+H]+ =339.0. 325 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 2: dimethyl4-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)phthalate (Intermediate 3). 5 To a stirred solution of Intermediate 2 (100 mg, 0.295 mmol, 1 equiv), 1-{3-[7-(difluoromethyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl}ethanone (246.12 mg, 0.443 mmol, 1.5 equiv) and K3PO4 (125.18 mg, 0.590 mmol, 2 equiv) in dioxane (2 mL) and H2O (0.5 mL) was added XPhos Pd G3 (49.92 mg, 0.059 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred 10 for 2 h at 100 °C under nitrogen atmosphere. The reaction mixture was diluted with EA (50 mL), the resulting mixture was washed with water (25 mL x 2) and saturated brine (50 mL x 1). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1), to afford Intermediate 3 (73 mg, 35.95%) as a yellow solid. LCMS (ESI) m / z [M+H]+=689.3. 15 Step 3: 4-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3- yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)phthalicacid (Intermediate 4) To a stirred solution of Intermediate 3 (60 mg, 0.087 mmol, 1 equiv) in MeOH (1 mL) and H2O (1 mL) was added LiOH (8.35 mg, 0.348 mmol, 4 equiv) at room temperature. The resulting mixture was 20 stirred for 2 h at 60 °C. The mixture was acidified to pH 5 with 1N HCl. The resulting mixture was diluted with water (5 mL), extracted with EtOAc (20 mL x 2). The combined organic layers were washed with saturated brine (10 mL x 1), dried over anhydrous Na2SO4, filtered and evaporated to afford crude product. 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% 326 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 gradient in 30 min; detector, UV 254 nm, to afford Intermediate 4 (51 mg, 88.61%) as a yellow solid. LCMS (ESI) m / z [M+H]+=661.3. Step 4: 5-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3- 5 yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 40) To a stirred solution of Intermediate 4 in Pyridine (2 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (34.38 mg, 0.210 mmol, 3 equiv) at room temperature. The resulting mixture was stirred 10 for 24 h at 120 °C under nitrogen atmosphere. The reaction mixture was diluted with EA (20 mL), the resulting mixture was washed with water (10 mL x 2) and saturated brine (20 mL x 1). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; 15 Gradient: 32% B to 52% B in 8 min; Wave Length: 254 / 220 nm; RT1(min): 9.43) to afford Compound 40 (28.1 mg, 53.61%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.82 (s, 1H), 8.42 (s, 2H), 8.14 – 8.00 (m, 1H), 7.98 (s, 1H), 7.28 (s, 1H), 7.21 – 6.78 (m, 2H), 5.23 – 5.08 (m, 1H), 4.38 – 4.22 (m, 1H), 4.20 (s, 2H), 3.98 (d, J = 11.7 Hz, 2H), 3.75 (s, 2H), 3.64 (t, J = 5.7 Hz, 2H), 3.49 (t, J = 11.7 Hz, 2H), 3.00 – 2.81 (m, 5H), 2.71 – 2.56 (m, 2H), 2.19 – 1.94 (m, 8H), 1.86 (d, J = 12.8 20 Hz, 2H). LCMS (ESI) m / z [M+H]+=753.35. Example 12: Preparation of 5-{2-[(3R)-3-[3-(4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl](methyl)amino}-2-(difluoromethyl)phenyl)pyrrolo[3,2-c]pyridin-1-yl]pyrrolidin-1- yl]-2-oxoethoxy}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 8). 25 327 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 To a stirred solution of 3-bromo-1H-pyrrolo[3,2-c]pyridine (400 mg, 2.030 mmol, 1 equiv), Cs2CO3 (1984.33 mg, 6.090 mmol, 3 equiv) in DMF (4 mL) was added tert-butyl (3S)-3- (methanesulfonyloxy)pyrrolidine-1-carboxylate (1184.98 mg, 4.466 mmol, 2.2 equiv) at room temperature. The resulting mixture was stirred for 6h at 80°C. The resulting mixture was diluted with H2O (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic 10 layers were washed with brine (2 x 50 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford intermediate 2 (550 mg, 73.97%) as a yellow solid. LCMS (ESI) m / z [M+H]+= 366 / 368. 15 Step 2: tert-butyl (3R)-3-[3-(4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3- yl](methyl)amino}-2-(difluoromethyl)phenyl)pyrrolo[3,2-c]pyridin-1-yl]pyrrolidine-1-carboxylate (Intermediate 3). To a stirred solution of tert-butyl (3R)-3-{3-bromopyrrolo[3,2-c]pyridin-1-yl}pyrrolidine-1-carboxylate (4020 mg, 0.109 mmol, 1 equiv) and 4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3- yl](methyl)amino}-2-(difluoromethyl)phenylboronic acid (48.96 mg, 0.109 mmol, 1 equiv) in H2O (0.2 328 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 mL) and 1,4-dioxane (1.0 mL) was added Pd(dppf)Cl2.CH2Cl2 (8.90 mg, 0.011 mmol, 0.1 equiv) and Cs2CO3 (106.75 mg, 0.327 mmol, 3 equiv) in portions at room temperature under argon atmosphere. The final reaction mixture was stirred at 80°C for 3h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column 5 chromatography, eluted with CH2Cl2 / MeOH (20:1) to afford Intermediate 3 (45 mg, 59.73 %) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 690. Step 3: 1-(3-{[3-(difluoromethyl)-4-{1-[(3R)-pyrrolidin-3-yl]pyrrolo[3,2-c]pyridin-3- yl}phenyl](methyl)amino}-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate 10 4). A solution of TFA (1.72 mL, 23.032 mmol, 371.48 equiv) and Intermediate 3 (43 mg, 0.062 mmol, 1 equiv) in DCM (1.72 mL, 26.910 mmol, 434.04 equiv) was stirred at room temperature for 1h . The resulting mixture was concentrated under reduced pressure. This resulted in Intermediate 4 (33 mg, 15 crude) as a yellow oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m / z: [M+H]+=590. Step 4: 5-{2-[(3R)-3-[3-(4-{[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl](methyl)amino}- 2-(difluoromethyl)phenyl)pyrrolo[3,2-c]pyridin-1-yl]pyrrolidin-1-yl]-2-oxoethoxy}-2-(2,6-dioxopiperidin-3- 20 yl)isoindole-1,3-dione ( Compound 8). To a stirred solution of Intermediate 4 (28 mg, 0.047 mmol, 1 equiv) and {[2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindol-5-yl]oxy}acetic acid (15.78 mg, 0.047 mmol, 1 equiv) in DMF (0.5 mL) was added HATU (27.08 mg, 0.071 mmol, 1.5 equiv) and DIEA (18.41 mg, 0.141 mmol, 3 equiv) at room 25 temperature. The final reaction mixture was stirred at room temperature for 2h. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 11% B to 29% B in 8 min; Wave Length: 254nm / 220nm nm; 329 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 RT1(min): 8.38) to afford compound 8 (13.1 mg, 30.15%) as a off-white solid.1H NMR (300 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.86 (s, 1H), 8.54 – 8.31 (m, 1H), 8.06 – 7.94 (m, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 7.53 – 7.38 (m,2H), 7.37 (s, 1H), 7.25 – 7.15 (m, 1H), 7.12 – 7.01 (m, 1H), 6.74 (t, J = 54.9 Hz, 1H), 5.62 – 5.27 (m, 1H), 5.17 – 4.79 (m, 3H), 4.45 – 4.25 (m, 1H), 4.17 (s, 3H), 4.06 – 3.88 (m, 2H), 3.87 (s, 5 5H), 3.60 – 3.42 (m, 2H), 3.36 (s, 3H), 2.94 – 2.73 (m, 3H), 2.67 – 2.58 (m, 3H), 2.28 (s, 1H), 2.12 – 1.94 (m, 6H), 1.93 – 1.75 (m, 2H). LCMS (ESI) m / z: [M+H]+= 904.35. Example 13. Preparation of 2-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]- 7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)-N-[3-(2,4-dioxo-1,3- 10 diazinan-1-yl)-1-methylindazol-6-yl]acetamide; trifluoroacetic acid (Compound 69). 15 To a stirred solution of 1-(6-amino-1-methylindazol-3-yl)-1,3-diazinane-2,4-dione (8.57 mg, 0.033 mmol, 1 equiv) and (3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4- dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)acetic acid (19.99 mg, 0.033 mmol, 1 equiv) in DCM 20 (2 mL) was added Pyridine (13.07 mg, 0.165 mmol, 5 equiv) and TCFH (9.27 mg, 0.033 mmol, 1 equiv) at 0°C. The resulting mixture was stirred at room temperature for 1h. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: X-select CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water (0.05%TFA, Mobile 330 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 20%B to 30%B in10 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.82) to afford compound Compound 69 (14.6 mg, 46.01%) as a light brown solid.1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 10.37 (s, 1H), 9.11 – 9.06 (m, 1H), 8.49 (d, J = 6.7 Hz, 1H), 8.20 (d, J = 6.7 Hz, 1H), 8.01 – 7.90 (m, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 7.20 5 – 7.11 (m, 1H), 6.97 – 6.89 (m, 1H), 6.72 (t, J = 55.1 Hz, 1H), 5.45 (s, 2H), 4.37 – 4.25 (m, 1H), 4.22 (s, 2H), 3.99 – 3.90 (m, 4H), 3.87 (s, 3H), 3.75 – 3.71 (m, 2H), 3.68 – 3.61 (m, 2H), 3.53 – 3.42 (m, 2H), 2.97 – 2.86 (m, 3H), 2.79 – 2.71 (m, 3H), 2.11 – 1.94 (m, 7H), 1.89 – 1.81 (m, 2H). LCMS (ESI) m / z: [M+H]+= 846.35. 10 The following compounds in TABLE 8 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 69 in Example 13. TABLE 8 Example 14. Preparation of 5-(4-(1-(5-acetyl-1-cyclohexyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-15 c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 117). 331 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (300 mg, 1.086 mmol, 1 5 equiv) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (210.74 mg, 1.086 mmol, 1 equiv) in DMF (3 mL) was added t-BuOK (365.62 mg, 3.258 mmol, 3 equiv) at 0oC. The resulting mixture was stirred at room temperature for 2h. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in Intermediate 2 (72 10 mg, 14.72%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 451. Step 2: 5-(4-(1-(5-acetyl-1-cyclohexyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7- (difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 117). 15 To a stirred solution of Intermediate 2 (21.30 mg, 0.047 mmol, 1.2 equiv), 1-{3-[6-bromo-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-cyclohexyl-4H,6H,7H-pyrazolo[4,3-c]pyridin-5- yl}ethanone (20 mg, 0.039 mmol, 1 equiv) and K3PO4 (25.10 mg, 0.117 mmol, 3 equiv) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was added XPhos Pd G3 (6.67 mg, 0.008 mmol, 0.2 equiv) and XPhos (1.88 20 mg, 0.004 mmol, 0.1 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred at 60oC for 2h under argon atmosphere. The mixture solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 60% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in Compound 117 (3 mg, 10.14%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.98 – 8.85 (m, 1H), 25 8.51 – 8.35 (m, 2H), 8.15 – 8.06 (m, 1H), 8.00 (s, 1H), 7.29 (s, 1H), 7.24 – 6.56 (m, 2H), 5.26 – 5.12 (m, 1H), 4.26 – 4.12 (m, 2H), 4.10 – 3.93 (m, 1H), 3.86 – 3.63 (m, 2H), 3.65 – 3.54 (m, 2H), 2.98 – 2.81 (m, 332 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5H), 2.79 – 2.70 (m, 1H), 2.17 – 2.07 (m, 3H), 1.99 (s, 3H), 1.97 – 1.57 (m, 8H), 1.50 – 1.29 (m, 2H), 1.28 – 1.07 (m, 1H). LCMS (ESI) m / z: [M+H]+= 751.35. The following compounds in TABLE 9 were prepared using standard chemical manipulations and 5 procedures similar to those used for the preparation of Compound 117 in Example 14. TABLE 9 333 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 334 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 15. Preparation of 1-(3-(6-(2-aminobenzo[d]thiazol-6-yl)-7-(difluoromethyl)-3,4- dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridin-5-yl)ethan-1-one (Compound 95). 5 335 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 1: 1-(3-(6-(2-aminobenzo[d]thiazol-6-yl)-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1- (tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (Intermediate 2). 5 To a stirred mixture of 6-bromo-1,3-benzothiazol-2-amine (30.88 mg, 0.135 mmol, 1.5 equiv) and 1-{3- [7-(difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-1- (oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (50 mg, 0.090 mmol, 1.00 equiv) in 1,4- dioxane (1 mL) and H2O (0.3 mL) was added XPhos Pd G3 (7.61 mg, 0.009 mmol, 0.1 equiv) and 10 XPhos (4.28 mg, 0.009 mmol, 0.1 equiv) and Cs2CO3 (58.55 mg, 0.180 mmol, 2 equiv) at 25 °C under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16h under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 1-{3-[6-(2-amino-1,3-benzothiazol-6-yl)-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]- 15 1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (50 mg, 96.16%) as a yellow oil. LCMS (ESI) m / z: [M+H]+= 579. 336 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 2: 1-(3-(6-(2-aminobenzo[d]thiazol-6-yl)-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1- (tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (Compound 95). 5 To a stirred solution of 1-{3-[6-(2-amino-1,3-benzothiazol-6-yl)-7-(difluoromethyl)-3,4-dihydro-2H- quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (50 mg, 0.086 mmol, 1 equiv) and 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (29.13 mg, 0.086 mmol, 1 equiv) in 1,4-dioxane (1 mL) was added XPhos Pd G3 (14.63 mg, 0.017 mmol, 0.2 equiv), XPhos (8.24 mg, 0.017 mmol, 0.2 equiv) and Cs2CO3(84.46 mg, 0.258 mmol, 3 equiv) at room temperature under 10 nitrogen atmosphere. The resulting mixture was stirred at 100°C for 1h under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: X-select CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 57% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 15 7.55 min) to afford Compound 95 (8.5 mg, 11.78%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 11.32 (s, 1H), 11.14 (s, 1H), 8.46 (s, 1H), 8.11 (m, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.85 (m, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.32 (m, 1H), 7.11 (s, 1H), 7.00 – 6.24 (m, 2H), 5.15 (m, 1H), 4.31 (m, 1H), 4.21 (m, 2H), 3.97 (m, 2H), 3.75 (m, 2H), 3.63 (m, 2H), 3.47 (t, J = 11.7 Hz, 2H), 2.90 (m, 4H), 2.78 (m, 1H), 2.61 (m, 2H), 2.09 (m, 3H), 2.01 (m, 5H), 1.84 (m, 2H). LCMS (ESI) m / z [M+H]+= 883.40. 20 The following compounds in TABLE 10 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 95 in Example 15. 337 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 TABLE 10 338 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 339 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 340 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 341 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 342 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 343 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 344 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 16.5-(4-{[4-(7-{4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-6- (difluoromethyl)-2,3-dihydro-1,4-benzoxazin-7-yl}imidazo[1,2-a]pyridin-6-yl) piperazin-1- yl]methyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 116). 5 Preparation of 4-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-6-(difluoromethyl)- 2,3-dihydro-1,4-benzoxazin-7-ylboronic acid. (Intermediate A) 345 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 1: (3S)-oxan-3-yl methanesulfonate (Intermediate A). To a stirred solution of 1-{3-[7-bromo-6-(difluoromethyl)-2,3-dihydro-1,4-benzoxazin-4-yl]-1-(oxan-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (2 g, 3.911 mmol, 1 equiv) and 2-(5,5-dimethyl-1,3,2- 5 dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (1.77 g, 7.822 mmol, 2 equiv) in dioxane (20 mL) were added Pd(dppf)Cl2 (0.57 g, 0.782 mmol, 0.2 equiv) and AcOK (1.15 g, 11.733 mmol, 3 equiv). The resulting mixture was stirred at 80°C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford intermediate A (800 mg, 42.95%) as a yellow solid. LCMS 10 (ESI) m / z [M+H]+=477. Step 1: 7-chloro-6-iodoimidazo[1,2-a]pyridine (Intermediate 2). To a stirred solution of 4-chloro-5-iodopyridin-2-amine (1 g, 3.930 mmol, 1 equiv) in ethyl alcohol (15 15 mL) was added chloroacetaldehyde (3.86 g, 19.650 mmol, 5 equiv, 40%). The resulting mixture was stirred at 80 °C for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by slurry with acetone (20 mL) to afford intermediate 2 (1.02 g, 93.20%) as a yellow solid. LCMS (ESI) m / z [M+H]+= 279. 20 Step 2: tert-butyl 4-[(4-{7-chloroimidazo[1,2-a]pyridin-6-yl}piperazin-1-yl)methyl]piperidine-1- carboxylate (Intermediate 3). To a stirred solution of intermediate 2 (400 mg, 1.436 mmol, 1 equiv), tert-butyl 4-(piperazin-1- ylmethyl)piperidine-1-carboxylate (488.51 mg, 1.723 mmol, 1.2 equiv) and t-BuONa (345.11 mg, 3.590 25 mmol, 2.5 equiv) in DMF (10 mL) were added t-BuXPhos Pd G3 (161.15 mg, 0.144 mmol, 0.1 equiv) and t-BuXPhos (483.45 mg, 0.431 mmol, 0.3 equiv). The resulting mixture was stirred at 60 °C for 3h under nitrogen atmosphere. Without any additional work-up, the resulting mixture was purified by flash 346 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 C18-flash chromatography, elution gradient 0 to 100% MeCN in water (containing 10mmol / L NH4HCO3). Pure fractions were evaporated to dryness to afford intermediate 3 (196 mg, 31.44%) as a brown solid. LCMS (ESI) m / z [M+H]+= 434. 5 To a stirred solution of intermediate 3 (95 mg, 0.219 mmol, 1 equiv) and 4-[5-acetyl-1-(oxan-4-yl)- 10 4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-6-(difluoromethyl)-2,3-dihydro-1,4 benzoxazin-7-ylboronic acid (125.11 mg, 0.263 mmol, 1.2 equiv) in 1,4-dioxane (1 mL) and H2O (0.3 mL) were added K2CO3 (90.76 mg, 0.657 mmol, 3.0 equiv), XPhos Pd G3 (18.53 mg, 0.022 mmol, 0.1 equiv) and XPhos (31.31 mg, 0.066 mmol, 0.3 equiv). The resulting mixture was stirred at 80 °C for 2h under nitrogen atmosphere. Without any additional work-up, the resulting mixture was purified by flash C18-flash chromatography, 15 elution gradient 0 to 100% MeCN in water (containing 10mmol / L NH4HCO3). Pure fractions were evaporated to dryness to afford intermediate 4 (92 mg, 50.64%) as a light yellow solid. LCMS (ESI) m / z [M+H]+= 830. Step 4: 1-{3-[6-(difluoromethyl)-7-{6-[4-(piperidin-4-ylmethyl)piperazin-1-yl]imidazo[1,2-a] pyridin-7-yl}- 20 2,3-dihydro-1,4-benzoxazin-4-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5 -yl}ethanone (Intermediate 5). 347 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 To a stirred solution of intermediate 4 (82 mg, 0.099 mmol, 1 equiv) in DCM (1.5 mL) was added trifluoroacetic acid (0.5 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography, elution gradient 0 to 80% MeCN in water (containing 0.1% TFA). Pure 5 fractions were evaporated to dryness to afford intermediate 5 (63 mg, 87.37%) as a light yellow solid. LCMS (ESI) m / z [M+H]+= 730. 10 To a stirred solution of intermediate 5 (58 mg, 0.079 mmol, 1 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5- fluoroisoindole-1,3-dione (21.95 mg, 0.079 mmol, 1 equiv) in DMSO (2 mL) was added DIEA (30.81 mg, 0.237 mmol, 3.0 equiv) dropwise. The resulting mixture was stirred at 100 °C for 2 h. The resulting 15 mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water(0.1%FA, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 13%B to 21% B in 10min; Wave Length: 254nm / 220 nm; RT1(min): 8.13) to afford compound 116 (21.8 mg, 27.82%) as a light yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.24 – 8.19 (m, 1H), 7.87 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.33 – 7.26 20 (m, 2H), 7.24 – 7.18 (m, 1H), 7.04 (s, 1H), 6.88 (s, 1H), 6.60 (t, J = 55.6 Hz, 1H), 5.03 (dd, J = 12.3, 5.4 Hz, 1H), 4.38 (s, 2H), 4.36 – 4.25 (m, 2H), 4.03 – 3.94 (m, 4H), 3.82 – 3.71 (m, 3H), 3.70 – 3.61 (m, 1H), 3.56 – 3.44 (m, 3H), 3.03 – 2.88 (m, 5H), 2.82 – 2.73 (m, 4H), 2.67 – 2.58 (m, 2H), 2.32 – 2.22 (m, 4H), 2.14 – 2.01 (m, 8H), 1.93 – 1.84 (m, 2H), 1.82 – 1.74 (m, 3H), 1.22 – 1.09 (m, 2H). LCMS (ESI) m / z [M+H]+= 986.40. 25 The following compounds in TABLE 11 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 116 in Example 16. 348 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 TABLE 11 349 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 350 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 17.3-((4-(1-(2-(3-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrrolo[3,2- c]pyridin-1-yl)acetyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (Compound 74). 5 10 To a stirred solution of 3-{[3-fluoro-4-(piperidin-4-yl)phenyl]amino}piperidine-2,6-dione (10.10 mg, 0.033 mmol, 1 equiv), 1-methyl-1H-imidazole (13.58 mg, 0.165 mmol, 5 equiv) in MeCN (0.5 mL) was added (3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4- dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)acetic acid (20 mg, 0.033 mmol, 1.00 equiv) and 15 Benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (34.43 mg, 0.066 mmol, 2 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 25°C for 16h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: SunfireC18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1%FA, Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; 20 Gradient: 18%B to 30%B in 10min; Wave Length: 254nm / 220nm nm; RT1(min): 10.86) to afford Compound 74 (2.2 mg, 14.9%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.75 (s, 1H), 8.32 – 8.24 (m, 1H), 7.55 – 7.47 (m, 1H), 7.36 (s, 1H), 7.24 (s, 1H), 7.04 – 6.93 (m, 2H), 6.69 – 6.63 (m, 1H), 6.55 – 6.43 (m, 2H), 5.84 – 5.76 (m, 1H), 5.29 (s, 2H), 4.32 – 4.27 (m, 2H), 4.27 – 4.22 (m, 3H), 4.04 – 3.94 (m, 2H), 3.79 – 3.73 (m, 2H), 3.71 – 3.61 (m, 2H), 3.57 – 3.44 (m, 2H), 2.99 – 25 2.92 (m, 3H), 2.90 – 2.84 (m, 3H), 2.83 – 2.75 (m, 1H), 2.74 – 2.61 (m, 1H), 2.22 – 1.96 (m, 9H), 1.91 – 1.75 (m, 6H), 1.66 – 1.60 (m, 2H). LCMS (ESI) m / z [M+H]+=892.50. The following compounds in TABLE 12 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 74 in Example 17. 30 351 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 TABLE 12 352 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 353 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 354 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 355 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 18. Preparation of 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- 5 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4-dihydro- 2H-quinoline-6-carboxylic acid (Intermediate A) 356 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 1: methyl 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4- dihydro-2H-quinoline-6-carboxylate (Intermediate 2). To a solution of 1-{3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H- 5 pyrazolo[4,3-c]pyridin-5-yl}ethanone (12 g, 23.557 mmol, 1 equiv) in 300 mL MeOH was added TEA (32.74 mL, 235.570 mmol, 10 equiv) and Pd(dppf)Cl2 (8.62 g, 11.778 mmol, 0.5 equiv) in a pressure tank. The mixture was purged with nitrogen for 2 min and then was pressurized to 20 atm with carbon monoxide at 100°C for 2days. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The residue was purified by reversed-phase flash chromatography with the 10 following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 100% gradient in 40 min; detector, UV 254 nm. This resulted in Intermediate 2 (4 g, 34.76%yield) as a light yellow solid. LCMS (ESI) m / z: [M+H]+= 489. Step 2: 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4-dihydro- 15 2H-quinoline-6-carboxylic acid (Intermediate A). To a stirred solution of Intermediate 2 (2.8 g, 5.731 mmol, 1 equiv) in MeOH (10 mL) and THF (10 mL) wad added LiOH (1372.67 mg, 57.310 mmol, 10 equiv) and H2O (10 mL) in portion. The mixture was stirred for 2 h at room temperature. The mixture was acidified to pH 3 with HCl (aq.). The resulting 20 mixture was filtered, the filter cake was washed with EtOAc (3x50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 60% gradient in 30 min; detector, UV 254 nm.to afford Intermediate A (1.85 g, 68.02%yield) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 475. 25 357 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 A solution of benzyl 3-oxopiperidine-1-carboxylate (2.5 g, 10.717 mmol, 1 equiv) in THF (20 mL) was added LiHMDS (1.0 M in THF) (24.97 mL, 24.971mmol, 2.33 equiv) at -78°C for 15min under 5 nitrogen atmosphere. To the above mixture was added N-(4-chlorophenyl)-1,1,1-trifluoro-N- trifluoromethanesulfonylmethanesulfonamide (5.04 g, 12.860 mmol, 1.20 equiv) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for overnight under nitrogen atmosphere. The reaction was quenched with sat. NH4Cl (aq.) (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were 10 washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5:1) to afford Intermediate 2 (963 mg, 24.60%) as an off-white oil. LCMS (ESI) m / z [M+H]+= 366. 15 To a stirred solution of Intermediate 2 (963 mg, 2.636 mmol, 1 equiv)，1,2-dimethyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phthalate (843.93 mg, 2.636 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) and H2O( 2 mL) was added Pd(dppf)Cl2.CH2Cl2 (215.27 mg, 0.264 mmol, 0.1 equiv) and Cs2CO3 20 (2576.62 mg, 7.908 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (1 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the 25 following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 20% to 90% gradient in 30 min; detector, UV 254 nm. This resulted in Intermediate 3 (479 mg, 44.38%yield) as a yellow oil. LCMS (ESI) m / z [M+H]+= 410. Step 3: 1,2-dimethyl 4-(piperidin-3-yl)phthalate (Intermediate 4). 30 358 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 To a stirred mixture of Intermediate 3 (479 mg, 1.170 mmol, 1 equiv) and Pd / C (249.00 mg, 2.340 mmol, 2 equiv) in 2,2,2-trifluoroethan-1-ol (5 mL) was added Pd(OH)2 / C (328.58 mg, 2.340 mmol, 2 equiv) in portions at room temperature. The mixture was hydrogenated at room temperature under 150psi of hydrogen pressure for 2h, filtered through a Celite pad and concentrated under reduced 5 pressure. This resulted in Intermediate 4 (231 mg, 71.20%) as a yellow solid. The crude product mixture was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+= 278. Step 4: 1,2-dimethyl 4-(1-{[(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl]methyl}piperidin-3- yl)phthalate (Intermediate 5). 10 To a stirred mixture of Intermediate 4 (231 mg, 0.833 mmol, 1 equiv), tert-butyl N-[(1r,4r)-4- formylcyclohexyl]carbamate (189.34 mg, 0.833 mmol, 1 equiv) in methanol (3 mL) was added AcOH (0.1 mL) in portion. After stirred for 1 h, the Sodium cyanoborohydride (157.03 mg, 2.499 mmol, 3.00 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for 2h. 15 The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 70% gradient in 30 min; detector, UV 254 nm. This resulted in Intermediate 5 (310 mg, 76%) as a colorless oil. LCMS (ESI) m / z [M+H]+=489. 20 Step 5: 1,2-dimethyl 4-[(3S)-1-{[(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl]methyl}piperidin-3- yl]phthalate (Intermediate 6). The Intermediate 5 (311mg) was separated by Prep-Chiral-HPLC with the following conditions(Column: CHIRALPAK ID, 3*25 cm, 5 μm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile 25 Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30; Wave Length: 209 / 240 nm; RT1(min): 6.793; RT2(min): 9.129; Sample Solvent: EtOH; Injection Volume: 1 mL; Number Of Runs: 8) to afford Intermediate 6 (133 mg, 42.77%) as a white solid. LCMS (ESI) m / z [M+H]+=489. 359 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 6: 4-[(3S)-1-{[(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl]methyl}piperidin-3-yl]benzene-1,2- dicarboxylic acid (Intermediate 7). To a stirred mixture of Intermediate 6 (133 mg, 0.272 mmol, 1 equiv) in methanol (0.9 mL) and H2O 5 (0.3 mL) was added LiOH.H2O (114.21 mg, 2.722 mmol, 10.00 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 1h. The mixture was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in Intermediate 7 (46 mg, 36.69%) as a white solid. LCMS (ESI) m / z [M+H]+= 461. 10 A solution of Intermediate 7 (46 mg, 0.100 mmol, 1 equiv) and 3-aminopiperidine-2,6-dione (38.39 mg, 15 0.300 mmol, 3 equiv) in pyridine (1 mL) was stirred at 120°C for 3h under nitrogen atmosphere. The mixture solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in Intermediate 8 (44 mg, 79.71%) as a colorless oil. LCMS (ESI) m / z [M+H]+= 553. 20 Step 8: 2-(2,6-dioxopiperidin-3-yl)-5-[(3S)-1-{[(1r,4r)-4-aminocyclohexyl]methyl}piperidin-3-yl]isoindole- 1,3-dione (Intermediate 9). To a stirred solution of Intermediate 8 (44 mg, 0.080 mmol, 1 equiv) in DCM (0.9 mL) was 25 added trifluoroacetic acid (0.3 mL) in portion. The solution was stirred at room temperature for 1h. The reaction solution was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, 360 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 MeCN in Water (0.1% TFA), 10% to 100% gradient in 30 min; detector, UV 254 nm. This resulted in Intermediate 9 (33 mg, 91.59%) as a colorless oil. LCMS (ESI) m / z [M+H]+=453. Step 9: 1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-N-[(1r,4r)-4- 5 {[(3S)-3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-1-yl]methyl}cyclohexyl]-3,4-dihydro- 2H-quinoline-6-carboxamide (Compound 143). To a stirred solution of Intermediate 9 (20 mg, 0.044 mmol, 1 equiv) and 1-[5-acetyl-1-(oxan-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinoline-6-carboxylic acid 10 (20.97 mg, 0.044 mmol, 1 equiv) in DMF (1 mL) was added TCFH (18.60 mg, 0.066 mmol, 1.5 equiv) and 1-methyl-1H-imidazole (10.89 mg, 0.132 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 30min. The crude product was purified by Prep- HPLC with the following conditions (Column: X-select CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 15 16% B to 31% B in 8min; Wave Length: 254nm / 220 nm; RT1(min): 10.77min) to afford compound 143 (10.4 mg, 25.89%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.93 – 7.85 (m, 2H), 7.84 – 7.69 (m, 2H), 7.43 – 7.05 (m, 2H), 6.80 (s, 1H), 5.26 – 4.92 (m, 1H), 4.35 – 4.20 (m, 1H), 4.13 (s, 2H), 4.00 – 3.89 (m, 2H), 3.73 – 3.68 (m, 2H), 3.65 – 3.61 (m, 2H), 3.52 – 3.40 (m, 3H), 3.40 – 3.28 (m, 2H), 3.28 – 3.19 (m, 1H), 3.07 – 2.93 (m, 3H), 2.94 – 2.87 (m, 1H), 2.86 – 2.77 (m, 4H), 2.69 20 – 2.54 (m, 2H), 2.13 – 2.06 (m, 2H), 2.05 – 1.93 (m, 13H), 1.93 – 1.74 (m, 5H), 1.43 – 1.28 (m, 2H), 1.21 – 1.05 (m, 2H). LCMS (ESI) m / z [M+H]+= 909.60. The following compounds in TABLE 13 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 143 in Example 18. 25 361 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 TABLE 13 Example 19. Preparation of 5-{[5-(4-{[5-acetyl-1-(1-methylpiperidin-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl](methyl)amino}-2-(difluoromethyl)phenyl)pyrimidin-2-yl]amino}-2-(2,6- 5 dioxopiperidin-3-yl)isoindole-1,3-dione; trifluoroacetic acid (Compound 173). Step 1: 1-methylpiperidin-4-yl 4-methylbenzenesulfonate (Intermediate 2). To a stirred solution of 1-methylpiperidin-4-ol (5.00 g, 43.412 mmol, 1 equiv) and 1- 10 chloromethanesulfonyl-4-methylbenzene (17.77 g, 86.824 mmol, 2 equiv) in DCM (50 mL). Et3N (30.2 mL, 217.060 mmol, 5 equiv) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. Desired product could be detected by LCMS. The resulting mixture 362 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford intermediate 2 (7.3 g, 62.43%) as a yellow solid. LCMS (ESI) 5 m / z [M+H]+= 270. Step 2: 4-{3-bromopyrazolo[4,3-c]pyridin-1-yl}-1-methylpiperidine (Intermediate 3). To a stirred solution of intermediate 2 (500.0 mg, 1.856 mmol, 1 equiv) and 3-bromo-1H-pyrazolo[4,3- 10 c]pyridine (441.1 mg, 2.227 mmol, 1.2 equiv) in DMF (3 mL). Cs2CO3 (1.21 g, 3.712 mmol, 2 equiv) was added at room temperature. The resulting mixture was stirred at 80°C for 4h. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3·H2O), 10% to 50% gradient in 20 min; detector, UV 254 nm to afford intermediate 3 (156 mg, 28.47%) as a yellow 15 solid. LCMS (ESI) m / z [M+H]+= 295. Step 3: N-[4-chloro-3-(difluoromethyl)phenyl]-N-methyl-1-(1-methylpiperidin-4-yl)pyrazolo[4,3-c]pyridin- 3-amine (Intermediate 4). 20 To a stirred solution of intermediate 3 (146.0 mg, 0.532 mmol, 1 equiv) and 4-chloro-3-(difluoromethyl)- N-methylaniline (101.9 mg, 0.532 mmol, 1 equiv) in Dioxane (3 mL) were added XantPhos Pd G4 (51.2 mg, 0.053 mmol, 0.1 equiv), XantPhos (30.8 mg, 0.053 mmol, 0.1 equiv) and Cs2CO3 (346.6 mg, 1.064 mmol, 2 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred at 80°C for 2h under argon atmosphere. Desired product could be detected by LCMS. The resulting 25 mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash 363 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 80% gradient in 25 min; detector, UV 254 nm to afford intermediate 4 (166 mg, 76.80%) as a light yellow solid. LCMS (ESI) m / z [M+H]+= 406. 5 Step 4: 1-(3-{[4-chloro-3-(difluoromethyl)phenyl](methyl)amino}-1-(1-methylpiperidin-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate 5). To a stirred solution of intermediate 4 (150.0 mg, 0.370 mmol, 1 equiv) and Platinum(IV)oxide (41.9 mg, 0.185 mmol, 0.5 equiv) in MeOH (3 mL) was added Acetic anhydride (377.3 mg, 3.700 mmol, 10 10 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2h under hydrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 80% gradient in 15 25 min; detector, UV 254 nm to afford intermediate 5 (106 mg, 63.46%) as a light yellow solid. LCMS (ESI) m / z [M+H]+= 452. Step 5: 1-(3-{[4-(2-aminopyrimidin-5-yl)-3-(difluoromethyl)phenyl](methyl)amino}-1-(1-methylpiperidin- 4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (Intermediate 6). 20 To a stirred solution of intermediate 5 (96.0 mg, 0.212 mmol, 1 equiv) and 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrimidin-2-amine (56.4 mg, 0.254 mmol, 1.2 equiv) in Dioxane (3 mL) and H2O (0.6 mL) were added XPhos Pd G3 (17.9 mg, 0.021 mmol, 0.1 equiv) and Cs2CO3 (138.4 mg, 0.424 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at 100°C for 2h under nitrogen 25 atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine 364 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 (3 x 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% NH3·H2O), 10% to 80% gradient in 25 min; detector, UV 254 nm to afford intermediate 6 (71 mg, 65.46%) as a white 5 solid. LCMS (ESI) m / z [M+H]+= 511. Step 6: 5-{[5-(4-{[5-acetyl-1-(1-methylpiperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3- yl](methyl)amino}-2-(difluoromethyl)phenyl)pyrimidin-2-yl]amino}-2-(2,6-dioxopiperidin-3-yl)isoindole- 1,3-dione; trifluoroacetic acid (Compound 173). 10 To a stirred solution of intermediate 6 (30.0 mg, 0.059 mmol, 1 equiv) and 5-bromo-2-(2,6- dioxopiperidin-3-yl)isoindole-1,3-dione (25.8 mg, 0.076 mmol, 1.3 equiv) in Dioxane (2 mL) were added Cs2CO3 (38.3 mg, 0.118 mmol, 2 equiv) and EPhos Pd G4 (5.4 mg, 0.006 mmol, 0.1 equiv), Ephos (3.1 mg, 0.006 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting 15 mixture was stirred at 100°C for overnight under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 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 20 phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 25 min; detector, UV 254 nm to afford 21 mg crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 20% B to 30% B in 10 min; Wave Length: 254nm / 220 nm; RT1(min): 10.48) to afford compound 173 (16.4 mg, 31.69%) as a yellow 25 solid.1H NMR (300 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.47 (s, 1H), 9.41 (s, TFA, 1H), 8.57 (s, 2H), 8.49 (d, J = 1.9 Hz, 1H), 8.19 (dd, J = 8.4, 2.0 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.14 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 54.6 Hz, 1H), 5.10 (dd, J = 12.3, 5.4 Hz, 1H), 4.38 (s, 1H), 4.16 (s, 2H), 3.76 (s, 2H), 3.62 – 3.52 (m, 2H), 3.35 (s, 3H), 2.93 – 2.73 (m, 6H), 2.67 – 2.53 (m, 3H), 2.34 – 2.22 (m, 3H), 2.20 – 1.98 (m, 6H). LCMS (ESI) m / z [M+H]+= 767.40. 30 The following compounds in TABLE 14 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 173 in Example 19. 365 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 TABLE 14 366 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 367 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 368 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 20. Preparation of 5-{4-[4-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin- 3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl]- 5 3,3-dimethyl-4-oxobut-1-yn-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 43). Step1:1-[4-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4- dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl]-2,2-dimethylbut-3-yn-1-one 10 (Intermediate 2). To a stirred solution of 1-{3-[7-(difluoromethyl)-6-[1-(piperidin-4-yl)pyrrolo[3,2-c]pyridin-3-yl]-3,4- dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (50.0 mg, 0.079 369 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 mmol, 1 equiv) and 2,2-dimethylbut-3-ynoic acid (13.4 mg, 0.118 mmol, 1.5 equiv) in DMF (1 mL) was added TCFH (33.4 mg, 0.118 mmol, 1.5 equiv) and NMI (22.8 mg, 0.277 mmol, 3.5 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature for 2h. Desired product could be detected by LCMS. The mixture solution was purified by reversed-phase flash 5 chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford intermediate 2 (35 mg, 60.90%) as a yellow solid. LCMS (ESI) m / z [M+H]+= 724. Step2: 5-{4-[4-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-10 (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl]-3,3- dimethyl-4-oxobut-1-yn-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 43). To a stirred solution of intermediate 2 (35.0 mg, 0.048 mmol, 1 equiv) and 5-bromo-2-(2,6- dioxopiperidin-3-yl)isoindole-1,3-dione (32.6 mg, 0.096 mmol, 2 equiv) in DMF (1 mL) were 15 added Pd(PPh3)2Cl2 (6.8 mg, 0.010 mmol, 0.2 equiv), CuI (1.8 mg, 0.010 mmol, 0.2 equiv) and Et3N (24.5 mg, 0.240 mmol, 5 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h. Desired product could be detected by LCMS. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was 20 concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 25 min; detector, UV 254 nm to afford 24 mg crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: X-select CSH C18 OBD Column 30*150mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 25 mL / min mL / min; Gradient: 18% B to 33% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.85) to afford Compound 43 (16.5 mg, 34.82%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.70 (s, 1H), 8.27 (d, J = 5.8 Hz, 1H), 8.00 – 7.81 (m, 3H), 7.63 (d, J = 5.8 Hz, 1H), 7.50 (s, 1H), 7.19 (s, 1H), 6.91 (s, 1H), 6.65 (t, J = 55.4 Hz, 1H), 5.16 – 5.07 (m, 1H), 4.90 – 4.68 (m, 3H), 4.40 – 4.25 (m, 1H), 4.22 (s, 2H), 4.05 – 3.93 (m, 2H), 3.83 – 3.70 (m, 2H), 3.69 – 3.57 (m, 2H), 3.57 – 3.42 30 (m, 3H), 2.99 – 2.71 (m, 6H), 2.68 – 2.53 (m, 2H), 2.20 – 1.92 (m, 12H), 1.92 – 1.82 (m, 2H), 1.60 (s, 6H). LCMS (ESI) m / z [M+H]+= 980.45. 370 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 21.Preparation of 5-[4-(1'-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3- yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}-2'H-spiro[piperidine-4,3'-pyrrolo[2,3- c]pyridin]-1-ylmethyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 5 10 Step 1: 5-[4-(dimethoxymethyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Intermediate 2). To a stirred solution of 4-(dimethoxymethyl)piperidine (200 mg, 1.256 mmol, 1 equiv) and 2-(2,6- dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (346.95 mg, 1.256 mmol, 1 equiv) in DMSO (3 mL) was 15 added DIEA (486.79 mg, 3.768 mmol, 3 equiv). The resulting mixture was stirred at 100°C for 1 h. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.05% TFA), 10% to 100% gradient in 10 min; 371 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 detector, UV 254 nm) to afford intermediate 2 (382 mg, 73.21%) as a yellow solid. LCMS (ESI) m / z [M+H]+=416. Step 2: 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carbaldehyde (Intermediate 3). 5 To a stirred solution of intermediate 2 (30 mg, 0.072 mmol, 1 equiv) in DCM (1 mL) was added TFA (0.5 mL). The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to afford intermediate A (25 mg, 93.73%) as a light yellow solid. LCMS (ESI) m / z [M+H]+=370. 10 Step 1: Preparation of tert-butyl 4-cyano-4-(3-fluoropyridin-4-yl)piperidine-1-carboxylate (intermediate 2) To a stirred solution of 4-chloro-3-fluoropyridine (2.48 g, 18.832 mmol, 1.1 equiv) and tert-butyl 4- cyanopiperidine-1-carboxylate (3.6 g, 17.120 mmol, 1.00 equiv) in Toluene (50 mL) was added KHMDS 15 (34.24 mL, 34.240 mmol, 2 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2h under nitrogen atmosphere. The reaction was quenched with Water (100 mL, 0.1% TFA) at room temperature. The resulting mixture was extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel 20 column chromatography, eluted with Petroleum ether / THF (3:1) to afford intermediate 2 (1.51 g, 28.88%) as a yellow oil. LCMS (ESI) m / z: [M+H]+= 306. Step 2: Preparation of tert-butyl 4-(aminomethyl)-4-(3-fluoropyridin-4-yl)piperidine-1-carboxylate (intermediate 3) 25 To a solution of intermediate 2 (1.51 g, 4.945 mmol, 1 equiv) in 2,2,2-trifluoroethan-1-ol (30 mL) was added PtO2 (224.59 mg, 0.989 mmol, 0.2 equiv) in a pressure tank. The mixture was hydrogenated at room temperature under 150psi of hydrogen pressure for overnight, filtered through a Celite pad and concentrated under reduced pressure. The crude was purified by silica gel column chromatography, 372 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 eluted with Petroleum ether / THF (4:1) to afford intermediate 3 (680 mg, 44.45%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 310. Step 3: Preparation of tert-butyl 1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine]-1-carboxylate 5 (intermediate 4) A solution of intermediate 3 (780 mg, 2.521 mmol, 1 equiv) and Cs2CO3 (2464.30 mg, 7.563 mmol, 3 equiv) in NMP (10 mL) was stirred at 130°C for overnight. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in 10 Water (0.1% TFA), 0% to 60% gradient in 20 min; detector, UV 220 nm. This resulted in intermediate 4 (100 mg, 13.71%) as a yellow oil. LCMS (ESI) m / z: [M+H]+= 290. Step 4: Preparation of tert-butyl 1'-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}-2'H-spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine]-1- 15 carboxylate (intermediate 5) To a stirred solution of intermediate 4 (95 mg, 0.328 mmol, 1 equiv) and 1-{3-[6-bromo-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5- yl}ethanone (183.95 mg, 0.361 mmol, 1.1 equiv) in toluene (2 mL) was added RuPhos (30.64 mg, 0.066 20 mmol, 0.2 equiv), RuPhos Pd G3 (27.46 mg, 0.033 mmol, 0.1 equiv) and t-BuONa (94.65 mg, 0.984 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 50% gradient in 15 min; detector, UV 254 nm. This 25 resulted in intermediate 5 (190 mg, 80.62%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 718. 373 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 5: Preparation of 1-{3-[7-(difluoromethyl)-6-{2'H-spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-1'-yl}- 3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (intermediate 6) 5 A solution of intermediate 5 (190 mg, 0.265 mmol, 1 equiv) and TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in intermediate 6 (100 mg, 61.16%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 10 618. 15 A solution of intermediate 6 (40 mg, 0.065 mmol, 1 equiv) and 1-[2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindol-5-yl]piperidine-4-carbaldehyde (35.88 mg, 0.098 mmol, 1.5 equiv) in DCM (2 mL) was stirred at room temperature for 1h. To the above mixture was added STAB (27.45 mg, 0.130 mmol, 2 equiv) at room temperature. The resulting mixture was stirred at room temperature for additional 2h. The20 resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC with the following conditions (Column: X-Select CSH Fluoro Phenyl, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 7% B to 21% B in 10 min; Wave Length: 254nm / 220 nm; RT1(min): 11.07) to afford Compound 116 (26.7 mg, 42.46%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 971.55.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 374 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 7.94 (d, J = 4.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.41 – 7.30 (m, 2H), 7.28 – 7.20 (m, 2H), 7.14 (s, 1H), 7.08 – 6.76 (m, 2H), 5.11 – 5.02 (m, 1H), 4.36 – 4.25 (m, 1H), 4.24 – 4.16 (m, 2H), 4.10 – 4.02 (m, 2H), 4.00 – 3.92 (m, 2H), 3.80 – 3.69 (m, 2H), 3.64 – 3.55 (m, 3H), 3.53 – 3.41 (m, 3H), 3.04 – 2.73 (m, 9H), 2.63 – 2.53 (m, 3H), 2.24 – 2.18 (m, 2H), 2.12 – 2.07 (m, 3H), 2.06 – 1.92 (m, 7H), 1.88 – 1.76 (m, 8H), 5 1.26 – 1.10 (m, 2H). The following compounds in TABLE 15 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 116 in Example 21. 10 TABLE 15 375 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 376 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 22. Preparation of 5-(4-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3-triazol-1- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 85). 5 377 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Preparation of methyl 2-{3-[(3R)-3-{3-bromopyrrolo[3,2-c]pyridin-1-yl}pyrrolidin-1-yl]-1,2-oxazol- 5-yl}-3-methylbutanoate (Intermediate A) 5 To a stirred solution of 1-{3-[6-bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)- 4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (500 mg, 0.982 mmol, 1 equiv) and 10 tributyl(ethynyl)stannane (618.55 mg, 1.964 mmol, 2 equiv) in dioxane (10 mL) was added CsF (298.20 mg, 1.964 mmol, 2 equiv) and Pd(PPh3)4 (170.14 mg, 0.147 mmol, 0.15 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 2.5h at 120°C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (3x300 mL), 15 dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford Intermediate A (427 mg, 95.71%) as a light brown solid. LCMS (ESI) m / z [M+H]+= 455. 20 To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1 g, 3.620 mmol, 1 equiv) in DMSO (15 mL) was added NaN3 (706.07 mg, 10.860 mmol, 3 equiv) in portion at room temperature. The resulting mixture was stirred at 60oC for 1h. The reaction was poured into Water (200 mL) at room temperature. The precipitated solid was collected by filtration and dried under vacuum to afford 378 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Intermediate 2 (610 mg, crude) as a white solid. The crude product mixture was used in the next step directly without further purification. LCMS (ESI) m / z: [M+H]+= 300. 5 To a stirred solution of Intermediate 2 (16.46 mg, 0.055 mmol, 1.00 equiv) and 1-{3-[7-(difluoromethyl)- 6-ethynyl-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone10 (25 mg, 0.055 mmol, 1.00 equiv) in methanol (1 mL) and H2O (0.5 mL) was added sodium (2S)-2-[(1S)- 1,2-dihydroxyethyl]-4-hydroxy-5-oxooxolan-3-olate (5.45 mg, 0.028 mmol, 0.5 equiv) and CuSO4.5H2O (1.37 mg, 0.006 mmol, 0.1 equiv) in portions at room temperature. The resulting mixture was stirred at 80°C for 2h. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 40% gradient in 10 15 min; detector, UV 254 nm. This resulted in Compound 85 (10 mg, 24.12%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.24 (s, 1H), 8.56 – 8.44 (m, 2H), 8.20 – 8.09 (m, 1H), 7.66 – 7.29 (m, 2H), 6.95 (s, 1H), 5.25 – 5.11 (m, 1H), 4.38 – 4.27 (m, 1H), 4.20 (s, 2H), 4.01 – 3.91 (m, 2H), 3.72 (s, 2H), 3.68 – 3.59 (m, 2H), 3.48 (t, J = 11.9, 2.1 Hz, 2H), 2.99 – 2.86 (m, 4H), 2.78 (s, 1H), 2.69 – 2.53 (m, 2H), 2.21 – 1.93 (m, 8H), 1.89 – 1.79 (m, 2H). LCMS (ESI) m / z: [M+H]+= 754.35. 20 379 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 23. Preparation of 5-{4-[2-(3-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin- 3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}pyrrolo[3,2-c]pyridin-1-yl)ethyl]-2- oxopiperazin-1-yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 81). 5 . 380 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 1: tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3-oxopiperazine-1-carboxylate (Intermediate 2). To a stirred mixture of tert-butyl 3-oxopiperazine-1-carboxylate (100 mg, 0.499 mmol, 1 equiv) and 5- 5 bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (185.20 mg, 0.549 mmol, 1.1 equiv) in dioxane (5 mL) were added Cs2CO3 (325.43 mg, 0.998 mmol, 2 equiv) and 3-chloropyridine; {1,3-bis[2,6- bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl} dichloropalladium (48.63 mg, 0.050 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in 10 water (containing 0.1% TFA). Pure fractions were evaporated to dryness to afford intermediate 2 (125 mg, 54.84%) as a light yellow solid. LCMS (ESI) m / z [M+H]+=457. Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(2-oxopiperazin-1-yl)isoindole-1,3-dione (Intermediate A). 15 To a stirred solution of intermediate 2 (120 mg, 0.263 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford intermediate 3 (120 mg, crude) as a brown solid that was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+=357. 20 3-bromo-1H-pyrrolo[3,2-c]pyridine (200 mg, 1.015 mmol, 1 equiv) and 1-(3-(7-(difluoromethyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4- 381 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (677.80 mg, 1.218 mmol, 1.2 equiv) in dioxane (12 mL) and H2O (3 mL) were added XPhos Pd G3 (171.84 mg, 0.203 mmol, 0.2 equiv), XPhos (193.56 mg, 0.406 mmol, 0.4 equiv) and Cs2CO3 (661.44 mg, 2.030 mmol, 2 equiv). The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was 5 purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford intermediate 2 (301 mg, 54.25%) as a yellow solid. LCMS (ESI) m / z [M+H]+=547. 10 To a stirred solution of intermediate 2 (180 mg, 0.329 mmol, 1 equiv) and 2-bromo-1,1-diethoxyethane (71.38 mg, 0.362 mmol, 1.1 equiv) in DMF (6 mL) was added Cs2CO3(214.58 mg, 0.658 mmol, 2 equiv). The resulting mixture was stirred for 2h at 80 °C. The resulting mixture was diluted with water 15 (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (10mmol / L NH4HCO3). Pure fractions were evaporated to dryness to afford intermediate 3 (110 mg, 50.40%) as a purple solid. LCMS (ESI) m / z [M+H]+=663. 20 To a stirred solution of intermediate 3 (100 mg, 0.151 mmol, 1 equiv) in H2O (2 mL) was added HCl in 25 1,4-dioxane (4.0 M) (1 mL, 0.005 mmol, 0.73 equiv). The resulting mixture was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure to afford intermediate 4 (110 mg, crude) as a brown oil. That was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+=589. 382 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 5 The intermediate 4 (80 mg, 0.136 mmol, 1 equiv) and intermediate A (53.27 mg, 0.150 mmol, 1.1 equiv) in DMF (4 mL) was added STAB (86.41 mg, 0.408 mmol, 3 equiv). The resulting mixture was stirred for 2h at room temperature. without any additional work up, the resulting mixture was purified by Prep-HPLC with the following conditions (Column: X-Select CSH Fluoro Phenyl 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 11% 10 B to 23% B in 10 min; Wave Length: 254nm / 220 nm; RT1(min): 12.21) to afford compound 81 (46.7 mg, 36.99%) as a light yellow solid.1H NMR (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.24 – 8.90 (m, 1H), 8.53 (dd, J = 6.8, 2.5 Hz, 1H), 8.30 (d, J = 6.8 Hz, 1H), 8.04 – 7.89 (m, 3H), 7.83 (dd, J = 7.9, 1.9 Hz, 1H), 7.30 (s, 1H), 7.02 – 6.51 (m, 2H), 5.25 – 5.07 (m, 1H), 4.73 – 4.55 (m, 2H), 4.40 – 4.25 (m, 1H), 4.27 – 4.09 (m, 2H), 4.04 – 3.85 (m, 2H), 3.84 – 3.67 (m, 4H), 3.68 – 3.56 (m, 2H), 3.54 – 3.44 15 (m, 2H), 3.44 – 3.39 (m, 2H), 3.06 – 2.80 (m, 9H), 2.81 – 2.70 (m, 1H), 2.68 – 2.52 (m, 1H), 2.09 (s, 3H), 2.04 – 1.92 (m, 5H), 1.93 – 1.74 (m, 2H). LCMS (ESI) m / z [M+H]+=929.45. 383 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 24. Preparation of 5-{4-[(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3- yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}imidazo[1,2-a]pyridin-6-yl)oxy]piperidin-1- yl}-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 145). 5 To a stirred solution of 4-chloro-5-methoxypyridin-2-amine (2 g, 12.611 mmol, 1 equiv) in EtOH (10 mL) was added chloroacetaldehyde (12.37 g, 63.055 mmol, 5 equiv, 40%). The resulting mixture was stirred 10 for 2h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm. to afford 7-chloro-6-methoxyimidazo[1,2-a]pyridine (2.37 g, 97.76%) as a yellow solid. LCMS (ESI) m / z: [M+H]+= 183. 15 384 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 To a solution of 7-chloro-6-methoxyimidazo[1,2-a]pyridine (2.37 g, 12.978 mmol, 1 equiv) in DCM (8 mL) was added added BBr3 (38.94 mL, 38.934 mmol, 3 equiv) dropwise over 5 min at 0°C. The resulting 5 mixture was stirred for additional 30 min at room temperature. The mixture solution was quenched with methanol (5 mL) dropwise slowly at 0°C. The mixture was concentrated under reduced pressure The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 0% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in 7-chloroimidazo[1,2-a]pyridin-6-ol (1.98 g, 90.50%) as a yellow 10 solid. LCMS (ESI) m / z: [M+H]+= 169. To a stirred solution of intermediate 3 (200 mg, 1.186 mmol, 1 equiv) and tert-butyl 4- 15 (methanesulfonyloxy) piperidine-1-carboxylate (397.70 mg, 1.423 mmol, 1.2 equiv) in DMF (4 mL) was added Cs2CO3 (773.09 mg, 2.372 mmol, 2 equiv). The resulting mixture was stirred at 80°C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel 20 column chromatography, eluted with PE / EA (1:4) to afford intermediate 4 (143 mg, 34.26%) as a light yellow oil. LCMS (ESI) m / z [M+H]+= 352. Step 4: tert-butyl 4-[(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}imidazo[1,2-a]pyridin-6-yl)oxy]piperidine-1-carboxylate 25 (Intermediate 5). To a stirred solution of intermediate 4 (50 mg, 0.142 mmol, 1 equiv) and intermediate 5 (79.08 mg, 0.142 mmol, 1 equiv) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was added XPhos Pd G3 (18.04 mg, 0.021 mmol, 0.15 equiv) and Cs2CO3 (138.91 mg, 0.426 mmol, 3 equiv). The resulting mixture was 385 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 stirred at 80°C for 2 h under nitrogen atmosphere. 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 (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH 5 (10:1) to afford intermediate 5 (82 mg, 77.36%) as a light yellow solid. LCMS (ESI) m / z [M+H]+= 746. 10 To a stirred solution of intermediate 5 (140 mg, 0.188 mmol, 1 equiv) in DCM (1.5 mL) was added TFA (0.5 mL). The resulting mixture was stirred at 25 °C for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford intermediate 6 (112 mg, 92.40%) as a 15 light yellow solid. LCMS (ESI) m / z [M+H]+= 646. 20 To a stirred solution of intermediate 6 (30 mg, 0.046 mmol, 1 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5- fluoroisoindole-1,3-dione (15.40 mg, 0.056 mmol, 1.20 equiv) in DMSO (1 mL) was added DIEA (30.02 mg, 0.230 mmol, 5 equiv). The resulting mixture was stirred at 100 °C for 2h. The resulting mixture was purified by Prep-HPLC with the following conditions (Column: X-Select CSH Fluoro Phenyl, 25 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 15% B to 27% B in 10 min; Wave Length: 254nm / 220 nm; RT1(min): 10.8) to afford compound 145 (13.4 mg, 31.98%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.61 – 8.14 (m, 1H), 7.87 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.40 – 7.29 (m, 2H), 7.22 (dd, J = 8.7, 2.3 Hz, 1H), 7.03 (s, 1H), 6.85 – 6.77 (m, 1H), 6.78 – 6.47 (m, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 30 1H), 4.51 – 4.33 (m, 1H), 4.34 – 4.23 (m, 1H), 4.24 – 4.07 (m, 2H), 4.03 – 3.92 (m, 2H), 3.81 – 3.63 (m, 2H), 3.59 (s, 3H), 3.54 – 3.39 (m, 5H), 2.99 – 2.71 (m, 5H), 2.65 – 2.51 (m, 2H), 2.09 (s, 2H), 2.07 – 1.87 (m, 7H), 1.89 – 1.78 (m, 3H), 1.70 – 1.55 (m, 2H). LCMS (ESI) m / z [M+H]+= 902.40. 386 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 The following compounds in TABLE 16 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 145 in Example 24. 5 TABLE 16 387 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 388 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 389 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 390 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 25. Preparation of 5-(4-{[4-(5-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}-1,3-benzothiazol-7-yl)piperidin-1- yl] methyl}piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound 184). 5 Step 1: tert-butyl 4-(3-amino-5-chloro-2-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (Intermediate 2). To a stirred solution of 3-bromo-5-chloro-2-fluoroaniline (500 mg, 2.228 mmol, 1 equiv) and tert-butyl 10 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (688.79 mg, 2.228 mmol, 1 equiv) in dioxane (8 mL) and H2O (2 mL) were added Pd(dppf)Cl2(244.49 mg, 0.334 mmol, 0.15 equiv) and Cs2CO3 (2.18 g, 6.684 mmol, 3 equiv). The resulting mixture was stirred at 391 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 80 °C for 1 h under nitrogen atmosphere. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 80 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 silica gel column chromatography, eluted with PE / EA (10:1) to 5 afford intermediate 2 (651 mg, 89.43%) as a colorless oil. LCMS (ESI) m / z [M+H]+= 327. Step 2: tert-butyl 4-(5-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}-3-amino-2-fluorophenyl)-3,6-dihydro-2H-pyridine-1- carboxylate (Intermediate 3). 10 To a stirred solution of intermediate 2 (100 mg, 0.306 mmol, 1 equiv) and intermediate 8 (170.28 mg, 0.306 mmol, 1 equiv) in toluene (2 mL) and H2O (0.5 mL) were added XPhos Pd G3 (25.90 mg, 0.031 mmol, 0.1 equiv), XPhos (29.18 mg, 0.061 mmol, 0.2 equiv) and t-BuONa (58.82 mg, 0.612 mmol, 2 equiv). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting 15 mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). 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 reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford intermediate 3 (107 mg, 20 48.51%) as a white solid. LCMS (ESI) m / z [M+H]+= 721. 392 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 3: tert-butyl 4-(5-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}-3-amino-2-fluorophenyl)piperidine-1-carboxylate (Intermediate 4). 5 To a stirred solution of intermediate 3 (102 mg, 0.142 mmol, 1 equiv) in EtOAc (2 mL) was added Pd / C (15.06 mg, 0.142 mmol, 1 equiv). The mixture was hydrogenated at room temperature under 150psi of hydrogen pressure for 2h. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 3 mL). The filtrate was concentrated under reduced pressure to afford intermediate 4 (85 mg, 83.10%) as a white solid. The crude product was used directly without further purification. LCMS (ESI) m / z 10 [M+H]+= 723. Step 4: tert-butyl 4-(5-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}-2-sulfanylidene-3H-1,3-benzothiazol-7-yl)piperidine-1- carboxylate (Intermediate 5). 15 To a stirred solution of intermediate 4 (80 mg, 0.111 mmol, 1 equiv) in DMF (1 mL) was added ethoxy(potassiosulfanyl)methanethione (53.22 mg, 0.333 mmol, 3 equiv). The resulting mixture was stirred at 130 °C for 2h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous 20 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 393 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford intermediate 4 (65 mg, 75.40%) as a white solid. LCMS (ESI) m / z [M+H]+= 779. Step 5: tert-butyl 4-(5-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- 5 (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}-1,3-benzothiazol-7-yl)piperidine-1-carboxylate (Intermediate 6). To a stirred solution of intermediate 5 (60 mg, 0.077 mmol, 1 equiv) in AcOH (2 mL) was added H2O2 (26.20 mg, 0.770 mmol, 10 equiv). The resulting mixture was stirred at 25 °C for 1h. The reaction was 10 quenched with sat. Na2S2O3 (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). 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% TFA), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford 15 intermediate 6 (48 mg, 83.43%) as a white solid. LCMS (ESI) m / z [M+H]+=747. Step 6: 1-{3-[7-(difluoromethyl)-6-[7-(piperidin-4-yl)-1,3-benzothiazol-5-yl]-3,4-dihydro-2H-quinolin-1- yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (Intermediate 7). 20 To a stirred solution of intermediate 6 (43 mg, 0.058 mmol, 1 equiv) in DCM (0.75 mL) was added TFA (0.25 mL). The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% 394 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 gradient in 10 min; detector, UV 254 nm) to afford intermediate 7 (33 mg, 88.62%) as a white solid. LCMS (ESI) m / z [M+H]+=647. 5 To a stirred solution of intermediate 7 (30 mg, 0.046 mmol, 1 equiv) and intermediate 9 (17.13 mg, 0.046 mmol, 1 equiv) in DMF (1 mL) were added STAB (29.49 mg, 0.138 mmol, 3 equiv) and AcOH 10 (2.79 mg, 0.046 mmol, 1 equiv). The resulting mixture was stirred at 25 °C for 1h. The resulting mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20%Bto32%Bin10min; Wave Length: 254nm / 220 nm; RT1(min): 11.37) to afford compound PHT-0093506-001 (8.7 mg, 18.75%) as a light yellow solid.1H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 15 1H), 9.47 (s, 1H), 7.95 – 7.86 (m, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.34 (s, 1H), 7.32 – 7.23 (m, 2H), 7.17 (s, 1H), 6.96 – 6.47 (m, 2H), 5.07 (dd, J = 12.7, 5.3 Hz, 1H), 4.41 – 4.23 (m, 1H), 4.19 (s, 2H), 4.09 (d, J = 12.6 Hz, 2H), 4.02 – 3.91 (m, 2H), 3.83 – 3.68 (m, 2H), 3.69 – 3.59 (m, 2H), 3.47 (t, J = 11.7 Hz, 3H), 3.08 – 2.72 (m, 10H), 2.66 – 2.53 (m, 3H), 2.10 (s, 3H), 2.08 – 1.93 (m, 11H), 1.91 – 1.76 (m, 5H), 1.26 – 1.18 (m, 2H). LCMS (ESI) m / z [M+H]+=1000.45. 20 The following compounds in TABLE 17 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 184 in Example 25. 395 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 TABLE 17 396 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 397 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 398 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 399 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 26. Preparation of 4-(((1-(7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)imidazo[1,2- a]pyridin-6-yl)azetidin-3-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (224). 5 400 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 To a stirred mixture of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (1.00 g, 5.341 mmol, 1.00 equiv), phthalimide (0.79 g, 5.3 mmol, 1.00 equiv) and PPh3 (2.80 g, 10.7 mmol, 2.07 equiv) in THF 5 (10 mL) was added DIAD (2.16 g, 10.7 mmol, 2.00 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography under the following conditions (column, C18 silica gel; mobilegel; mobile phase, MeCN in Water (0.1% TFA), 0% to 80% gradient in 25 min; detector, UV 254 nm) to afford intermediate 2 (1.02 g, 60%) as a yellow 10 solid. LCMS (ESI) m / z [M+H]+ = 317. To a stirred mixture of intermediate 2 (1.02 g, 3.224 mmol, 1.00 equiv) in DCM (6 mL) was added 15 TFA (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 40% gradient in 15 min; detector, UV 254 nm to afford intermediate 3 (586 mg, 84%) as a yellow solid. LCMS (ESI) m / z [M+H]+ =217. 401 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 3: 3: 2-((1-(7-chloroimidazo[1,2-a]pyridin-6-yl)azetidin-3-yl)methyl)isoindoline-1,3-dione (Intermediate 4). To a stirred mixture of intermediate 3 (576.0 mg, 2.664 mmol, 1.00 equiv) and 6-bromo-7- 5 chloroimidazo[1,2-a]pyridine (616.6 mg, 2.664 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added Cs2CO3 (1.73 g, 5.328 mmol, 2.00 equiv), BINAP Pd G3 (264.4 mg, 0.266 mmol, 0.10 equiv) and BINAP (165.9 mg, 0.266 mmol, 0.10 equiv). The resulting mixture was stirred at 100 °C for 3h under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was purified directly by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile 10 phase, MeCN in Water (0.1% FA), 0% to 70% gradient in 25 min; detector, UV 254 nm to afford intermediate 4 (139 mg, 14.23%) as a yellow solid. LCMS (ESI) m / z [M+H]+ =367. 15 To a stirred mixture of intermediate 4 (129.0 mg, 0.352 mmol, 1.00 equiv) and 1-[5-acetyl-1-(oxan- 4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-ylboronic acid (166.8 mg, 0.352 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Cs2CO3 (229.2 20 mg, 0.704 mmol, 2.00 equiv) and XPhos Pd G3 (29.8 mg, 0.035 mmol, 0.10 equiv). The resulting mixture was stirred at 100 oC for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 45% gradient in 15 min; detector, UV 254 nm to afford intermediate 5 (86 mg, 32.14%) as a yellow solid. LCMS (ESI) m / z 25 [M+H]+ = 761. 402 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 5: 1-(3-(6-(6-(3-(aminomethyl)azetidin-1-yl)imidazo[1,2-a]pyridin-7-yl)-7-(difluoromethyl)-3,4- dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1-one (Intermediate 6). 5 To a stirred mixture of intermediate 5 (76.0 mg, 0.100 mmol, 1.00 equiv) in MeOH (2 mL) was added N2H4·H2O (15.0 mg, 0.300 mmol, 3.00 equiv). The resulting mixture was stirred at 60 °C for 2h. Desired product could be detected by LCMS. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 60% gradient in 20 min; detector, UV 254 nm to afford intermediate 5 (38 mg, 10 60.31%) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 631 Step 6: 4-(((1-(7-(1-(5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin- 3-yl)-7-(difluoromethyl)-1,2,3,4-tetrahydroquinolin-6-yl)imidazo[1,2-a]pyridin-6-yl)azetidin-3- yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 224). 15 To a stirred mixture of intermediate 6 (33 mg, 0.052 mmol, 1.00 equiv) and 2-(2,6-dioxopiperidin- 3-yl)-4-fluoroisoindole-1,3-dione (18.8 mg, 0.068 mmol, 1.30 equiv) in DMSO (2 mL) was added DIEA (20.3 mg, 0.156 mmol, 3.00 equiv). The resulting mixture was stirred at 100 °C for 2h. Desired product 20 could be detected by LCMS. The mixture was purified by reverse phase flash with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 20% B to 30% B in 10 min; Wave Length: 254nm / 220 nm; RT1(min): 9.91) to afford compound 224 (6.5 mg, 23.11%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.64 – 7.51 403 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 (m, 2H), 7.33 (s, 1H), 7.15 – 6.98 (m, 3H), 6.83 (s, 1H), 6.65 (s, 1H), 6.38 (s, 1H), 5.02 (dd, J = 12.7, 5.4 Hz, 1H), 4.38 – 4.25 (m, 1H), 4.24 – 4.05 (m, 2H), 4.01 – 3.94 (m, 2H), 3.74 – 3.68 (m, 2H), 3.67 – 3.58 (m, 4H), 3.54 – 3.51 (m, 1H), 3.50 – 3.43 (m, 4H), 3.23 – 3.19 (m, 2H), 2.94 – 2.78 (m, 5H), 2.77 – 2.72 (m, 1H), 2.62 (s, 2H), 2.14 – 2.05 (m, 4H), 2.04 – 1.91 (m, 3H), 1.90 – 1.80 (m, 2H). LCMS 5 (ESI) m / z [M+H]+= 887.50. The following compounds in TABLE 18 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Compound 224 in Example 26. TABLE 18 404 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 405 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 406 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 407 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 408 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 409 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 410 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 411 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 412 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 413 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 27. Preparation of 1-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]- 7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}imidazo[1,2-a]pyridin-3-yl)-1,3-diazinane-2,4- dione (Compound 288) 5 Step 1: Preparation of 1-(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]-7- (difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}imidazo[1,2-a]pyridin-3-yl)-1,3-diazinane-2,4-dione (Compound 288). 10 To a stirred mixture of Intermediate 1, 1-(7-Bromoimidazo[1,2-a]pyridin-3-yl)dihydro-2,4(1H,3H)- pyrimidinedione (50 mg, 0.162 mmol, 1 equiv) and intermediate 2 (90.01 mg, 0.162 mmol, 1 equiv) in 1,4-doxane (2 mL) and H2O (0.4 mL) was added K3PO4 (68.67 mg, 0.324 mmol, 2 equiv) and XPhos Pd G3 (27.38 mg, 0.032 mmol, 0.2 equiv) in portions at room temperature. The resulting mixture was stirred 15 at 80°C for 1h under nitrogen atmosphere. The mixture was purified by reversed-phase flash chromatography with the following conditions (Column: Xbridge BEH Prep OBD Amide, 30*150mm 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 97% B to 92% B in 10 min; Wave Length: 254nm / 220 nm; RT1(min): 8.45) to afford compound 288 (40.4 mg, 37.92%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.91 – 8.75 (m, 1H), 8.19 20 (d, J = 2.4 Hz, 1H), 7.84 – 7.71 (m, 1H), 7.57 – 7.40 (m, 1H), 7.38 – 7.15 (m, 1H), 7.12 – 6.65 (m, 2H), 4.43 – 4.27 (m, 1H), 4.25 – 4.12 (m, 2H), 4.05 – 3.93 (m, 2H), 3.93 – 3.83 (m, 2H), 3.82 – 3.69 (m, 2H), 414 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 3.69 – 3.57 (m, 2H), 3.57 – 3.37 (m, 2H), 3.04 – 2.72 (m, 6H), 2.10 (s, 2H), 2.06 – 1.92 (m, 5H), 1.92 – 1.76 (m, 2H). LCMS (ESI) m / z: [M+H]+ = 659.35. The following compounds in TABLE 19 were prepared using standard chemical manipulations and 5 procedures similar to those used for the preparation of Compound 288 in Example 27. TABLE 19 415 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Example 28. Preparation of 1-(3-{4-[(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridin-3-yl]-7-(difluorome thyl)-3,4-dihydro-2H-quinolin-6-yl}imidazo[1,2-a]pyridin-6- yl)amino]but-1-yn-1-yl}-2-methylphenyl)-1,3-diazinane-2,4-dione (Compound 223) 5 To a stirred mixture of intermediate 1 (600 mg, 2.155 mmol, 1 equiv) and but-3-yn-1-amine (223.34 mg, 3.232 mmol, 1.5 equiv) in DMF (30 mL) was added t-BuXPhos (365.98 mg, 0.862 mmol, 10 0.4 equiv), t-BuXPhos Pd G3 (342.31 mg, 0.431 mmol, 0.2 equiv) and t-BuONa (414.13 mg, 4.310 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred at room temperature 416 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 for 3 h under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL), extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in PE. Pure fractions 5 were evaporated to dryness to afford intermediate 2 (150 mg, 31.69%) as a yellow oil. LCMS (ESI) m / z [M+H]+=220. Step 2: Preparation of 1-{3-[4-({7-chloroimidazo[1,2-a]pyridin-6-yl}amino)but-1-yn-1-yl]-2- methylphenyl}-1,3-diazinane-2,4-dione (Intermediate 3). 10 To a stirred mixture of intermediate 2 (60 mg, 0.273 mmol, 1 equiv) and 1-(3-iodo-2- methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (90.17 mg, 0.273 mmol, 1 equiv) in DMF (5 mL) was added Et3N (276.40 mg, 2.730 mmol, 10 equiv), CuI (5.20 mg, 0.027 mmol, 0.10 equiv) and Pd(PPh3)4 (63.13 mg, 0.055 mmol, 0.20 equiv) in portions at room temperature. The resulting mixture was stirred at 60 °C for overnight under nitrogen atmosphere. The mixture was purified by reversed- 15 phase flash chromatography， elution gradient 0 to 100% MeCN in Water (0.1% FA). Pure fractions were evaporated to dryness to afford intermediate 3 (80 mg, 69.42%) as a yellow oil. LCMS (ESI) m / z [M+H]+=422. 417 PATENT ATTORNEY DOCKET NO.: 51121-102WO3 Step 3: Preparation of 1-(3-{4-[(7-{1-[5-acetyl-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-3-yl]- 7(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}imidazo[1,2-a]pyridin-6-yl)amino] but-1-yn-1-yl}-2- methylphenyl)-1,3-diazinane-2,4-dione (Compound 223). 5 To a solution of intermediate 3 (70 mg, 0.166 mmol, 1 equiv) and (1-(5-acetyl-1-(tetrahydro-2H- pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-7-(difluoromethyl)-1,2,3,4- tetrahydroquinolin-6-yl)boronic acid (78.70 mg, 0.166 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) and H2O (1 mL) was added K3PO4 (105.66 mg, 0.498 mmol, 3 equiv), XPhos (15.82 mg, 0.033 mmol, 0.2 equiv) and XPhos Pd G3 (14.04 mg, 0.017 mmol, 0.1 equiv). After stirring for 1 h at 60 °C under a 10 nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to100% gradient in 20 min; detector, UV 254 nm. to afford products. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile 15 Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 20% B to 29% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.18) to afford compound 223 (26.1 mg, 19.28%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.43 (s, 1H), 7.30 – 7.15 (m, 3H), 7.14 (s, 1H), 7.00 (s, 1H), 6.93 (s, 1H), 6.54 (t, J = 55.4 Hz, 1H), 4.38 – 4.27 (m, 1H), 4.27 – 4.17 (m, 2H), 4.03 – 3....

Claims

PATENT ATTORNEY DOCKET NO.: 51121-102WO3 What is claimed is: CLAIMS 1. A compound having the structure of Formula Ia: A-L1-L2-B Formula Ia, wherein A is a EP300 binding moiety; B is a cereblon ligand degradation moiety; L1 is absent or optionally substituted C2–12 heteroarylene, and L2 has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D)-(B Formulaor a pharmaceutically acceptable salt thereof, wherein A1is a bond between the linker and the benzopyridazine core ring system; A2is a bond between the degradation moiety and the linker; each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C12 arylene, optionally substituted C6-C10 aryl C1-C4 alkylene, optionally substituted C1- C4 heteroalkylene, optionally substituted C3-C10 cycloalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2-C12 heteroarylene (e.g. C2-C8 heteroarylene), O, S, S(O)2, or NRN; each RNis, independently, H, optionally substituted C1–C4 alkylene, optionally substituted C2– C4 alkenylene, optionally substituted C2–C4 alkynylene, optionally substituted C2–C6 heterocyclylene, optionally substituted C2–C6 heteroarylene, or optionally substituted C1–C7 heteroalkylene; each of C1and C2is, independently, carbonylene, thiocarbonylene, sulphonylene, or phosphorylene; each of f, g, h, i, j, and k is, independently, 0 or 1; and D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C10 heterocyclylene, optionally substituted C2– C12 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene, wherein the cereblon ligand degradation moiety comprises the structure of Formula Y:Formula Y, where A2is a bond between the degradation moiety and the linker; 482PATENT ATTORNEY DOCKET NO.: 51121-102WO3 v1 is 0, 1, 2, 3, 4, or 5; u1 is 1, 2, or 3;R5Ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; each RJ1is, independently, halogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; JAis absent, O, optionally substituted amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; and J is absent, optionally substituted C3-C10 carbocyclylene, optionally substituted C6-C12 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C14 heteroarylene (e.g. C2-C9 heteroarylene), or a pharmaceutically acceptable salt thereof.

2. A compound having the structure of Formula I: A-L-B Formula I, wherein A is a EP300 binding moiety; B is a cereblon ligand degradation moiety; and L has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D)-(B Formulaor a pharmaceutically acceptable salt thereof, wherein A1is a bond between the linker and the benzopyridazine core ring system; A2is a bond between the degradation moiety and the linker; each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkylene, optionally substituted C6-C10 arylene, optionally substituted C6-C10 aryl C1-C4 alkylene, optionally substituted C1- C4 heteroalkylene, optionally substituted C3-C10 cycloalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2-C8 heteroarylene, optionally substituted C6–C12 arylene, O, S, S(O)2, or NRN; each RNis, independently, H, optionally substituted C1–C4 alkylene, optionally substituted C2– C4 alkenylene, optionally substituted C2–C4 alkynylene, optionally substituted C2–C6 heterocyclylene, optionally substituted C2–C6 heteroarylene, or optionally substituted C1–C7 heteroalkylene; each of C1and C2is, independently, carbonylene, thiocarbonylene, sulphonylene, or phosphorylene; 483PATENT ATTORNEY DOCKET NO.: 51121-102WO3 each of f, g, h, i, j, and k is, independently, 0 or 1; and D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C8 heterocyclylene, optionally substituted C2– C8 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene;, wherein the cereblon ligand degradation moiety comprises the structure of Formula A:, Formula A wherein each of RA1, RA2, RA3, and RA4is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; or RA1and RA2, RA2and RA3, and / or RA3and RA4, together with the carbon atoms to which each is attached, combine to form optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl; RA5is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;each of RA6and RA7is, independently, H or optionally substituted C1-C6 alkyl; or RA6and RA7, together with the carbon atom to which each is bound, form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl; RA8is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; and where one of RA1, RA2, RA3, and RA4is A2.

3. The compound of claim 1 or 2, wherein the EP300 binding moiety has the structure:Formula III wherein R1is 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 484PATENT ATTORNEY DOCKET NO.: 51121-102WO3 carbocycle, and 3-12 membered heterocycle of R1is optionally substituted with A1and / or one or more groups Rb; R2is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6- C20 aryl)(C1-C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Rc, oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups Re; or R2and R3of Formula (I) 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; R4is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with A1and / or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, ORh, SRh, OC(O)Rh, OC(O)ORh, C(O)Rh, C(O)ORh, S(O)Rh, S(O)2Rh, OC(O)N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)S(O)Rh, N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Rais, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, or C1- C6 alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Raare taken together with the nitrogen to which they are attached to form a 3-5 membered heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rbis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered carbocyclyl, C3-C12 heterocyclyl, C6-C20 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)ORc, OC(O)ORc, C(O)Rc, C(O)ORc, S(O)Rc, S(O)2Rc, OC(O)N(Rc)2, N(Rc)C(O)ORc, N(Rc)C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(Rc)S(O)2N(Rc)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)Rc, C(O)Rc, S(O)Rc, S(O)2Rc, C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rcand C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; 485PATENT ATTORNEY DOCKET NO.: 51121-102WO3 each Rcis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1-C6 alkyl, wherein the carbocyclyl and the C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rd)2, ORd, 3-5 membered heterocyclyl, and 3-5 membered carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; each Rdis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-12 membered carbocyclyl, 3- 12 membered heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rdare taken together with the nitrogen to which they are attached to form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Reis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C20 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, 3-12 membered carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rfis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, in which any carbocyclyl or C1-C6 alkyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, ORg, 3-12 membered heterocyclyl, and 3-12 membered carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; each Rgis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-12 membered carbocyclyl, 3- 486PATENT ATTORNEY DOCKET NO.: 51121-102WO3 12 membered heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rgare taken together with the nitrogen to which they are attached to form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and each Rhis, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with A1and / or one or more groups independently selected from halo; wherein one and only one of R1, R2, R3, or R4comprises A1.

4. The compound of claim 3, wherein: R1is C1-C12 alkyl, C2-C12 alkenyl, C2-C12alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1is optionally substituted with A1and / or one or more groups Rb; R2is C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1-C20 heteroaryl), (C1-C20 heteroaryl)(C6- C20 aryl), or (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6- C20 aryl)(C1-C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Rc, oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups Re; or R2and R3taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1 and / or one or more groups Re; R4is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with A1and / or one or more substituent groups independently selected from F, Cl, Br, I, 3-5 membered carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, ORh, SRh, OC(O)Rh, OC(O)ORh, C(O)Rh, C(O)ORh, S(O)Rh, S(O)2Rh, OC(O)N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)S(O)Rh, N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Rais, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered carbocyclyl, or 3-12 membered heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Raare taken together with the nitrogen to which they are attached to form a heterocyclyl 487PATENT ATTORNEY DOCKET NO.: 51121-102WO3 that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rbis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered carbocyclyl, C3-C12 heterocyclyl, C6-C20 aryl, C2-C10 heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)Rc, OC(O)ORc, C(O)Rc, C(O)ORc, S(O)Rc, S(O)2Rc, OC(O)N(Rc)2, N(Rc)C(O)ORc, N(Rc)C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(R)S(O)2N(Rc)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)Rc, C(O)Rc, C(O)ORc, S(O)Rc, S(O)2Rc, C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rcand C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rcis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, 3-5 membered carbocyclyl, 3-5 membered heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1-C6 alkyl, which 3-5 membered carbocyclyl and C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rd)2, ORd, 3-5 membered heterocyclyl, and 3-5 membered carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; each Rdis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-5 membered carbocyclyl, 3-5 membered heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rdare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Reis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C20 aryl, C1-C20 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2,N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, 3-12 membered carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; 488PATENT ATTORNEY DOCKET NO.: 51121-102WO3 each Rfis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, 3-15 membered carbocyclyl, 3-15 membered heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, in which carbocyclyl and C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, ORg, 3-15 membered heterocyclyl, and 3-15 membered carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; each Rgis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, 3-15 membered carbocyclyl, 3- 15 membered heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rgare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and each Rhis, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C5 cycloalkyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with A1and / or one or more groups independently selected from halo.

5. The compound of claim 3 or 4, wherein R1is methyl, cyclohexane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1is optionally substituted with one or more groups Rb.

6. The compound of any one of claims 3 to 5, wherein R1is:, ,7. The compound of any one of claims 3 to 6, wherein R4is acetyl, carbonate anion, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole. 489PATENT ATTORNEY DOCKET NO.: 51121-102WO3 8. The compound of any one of claims 3 to 7, wherein R4has the structure:

9. The compound of any one of claims 3 to 8, wherein R2and R3taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1and / or one or more groups Re.

10. The compound of any one of claims 3 to 9, wherein R2and R3taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1and / or one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring.

11. The compound of any one of claims 3 to 10, wherein NR2R3taken together has the structure: ,12. The compound of any one of claims 3 to 11, wherein the EP300 binding moiety has the structure:, , 490PATENT ATTORNEY DOCKET NO.: 51121-102WO3491PATENT ATTORNEY DOCKET NO.: 51121-102WO3 13. The compound of any one of claims 3 to 8, wherein R2is C6-C20 aryl optionally substituted with A1and / or one or more F groups.

14. The compound of any one of claims 3 to 8, wherein R3is C1-C12 alkyl.

15. The compound of any one of claims 3 to 8, or 13 to 14, wherein the EP300 binding moiety has the structure:.

16. The compound of any one of claims 1 to 15, wherein the structure of Formula Y is:. 492PATENT ATTORNEY DOCKET NO.: 51121-102WO3 17. The compound of any one of claims 1 to 15, wherein the structure of Formula Y is:, 493PATENT ATTORNEY DOCKET NO.: 51121-102WO3, , 494PATENT ATTORNEY DOCKET NO.: 51121-102WO3.

18. The compound of any one of claims 1 to 15, wherein the structure of Formula Y has the structure Formula A:, Formula A wherein each of RA1, RA2, RA3, and RA4is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; or RA1and RA2, RA2and RA3, and / or RA3and RA4, together with the carbon atoms to which each is attached, combine to form optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl; RA5is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; 495PATENT ATTORNEY DOCKET NO.: 51121-102WO3each of RA6and RA7is, independently, H or optionally substituted C1-C6 alkyl; or RA6and RA7, together with the carbon atom to which each is bound, form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl; RA8is H, optionally substituted C1-C6alkyl, or optionally substituted C1-C6heteroalkyl; and where one of RA1, RA2, RA3, and RA4is A2.

19. The compound of claim 18, wherein each RA1, RA2, RA3, and RA4is, independently, A2, H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, hydroxyl, optionally substituted amino; or RA1and RA2, RA2and RA3, or RA3and RA4, together with the carbon atoms to which each is attached, combine to form optionally substituted C2-C9 heterocyclyl.

20. The compound of claim 18 or 19, wherein the structure of Formula A is:, wherein RA9is H, A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl.

21. The compound of claim 18, wherein RA5is H.

22. The compound of any one of claims 18 to 21, wherein Y1is.

23. The compound of claim 22, wherein Y1is. The compound of claim 22, wherein Y1is.

25. The compound of claim 24, wherein RA6and RA7are each individually H.

26. The compound of any one of claims 18 to 25, wherein the structure of Formula A is:. 496PATENT ATTORNEY DOCKET NO.: 51121-102WO3 27. The compound of any one of claims 18 to 26, wherein the structure of Formula A has the structure of Formula A1:, Formula A1 or a pharmaceutically acceptable salt thereof.

28. The compound of any one of claims 18 to 26, wherein the structure of Formula A has the structure of Formula A3:, Formula A3 or a pharmaceutically acceptable salt thereof.

29. The compound of any one of claims 18 to 26, wherein the structure of Formula A has the structure of Formula A7:, Formula A7 or a pharmaceutically acceptable salt thereof.

30. The compound of any one of claims 18 to 26, wherein the structure of Formula A has the structure Formula A9:, Formula A9 or a pharmaceutically acceptable salt thereof.

31. The compound of any one of claims 27 to 30, wherein RA5is H. 497PATENT ATTORNEY DOCKET NO.: 51121-102WO3 32. The compound of any one of claims 27 to 31, wherein Y1is.

33. The compound of any one of claims 27 to 32, wherein Y1is.

34. The compound of any one of claims 27 to 32, wherein Y1is.

35. The compound of claim 34, wherein RA6and RA7are each individually H.

36. The compound of any one of claims 27 to 35, wherein the structure of Formula A is:The compound of any one of claims 27 to 36, wherein the structure of Formula A is:derivative or an analog thereof.

38. The compound of any one of claims 27 to 37, wherein the structure of Formula A has the structure of Formula A4:, Formula A4 or a pharmaceutically acceptable salt thereof. 498PATENT ATTORNEY DOCKET NO.: 51121-102WO3 39. The compound of any one of claims 27 to 38, wherein the structure of Formula A is:alog thereof.

40. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each of B1, B2, B3, and B4is, independently, optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, optionally substituted C2-C8 heterocyclylene, optionally substituted C2–C12 heteroarylene, or O.

41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein each of C1and C2is, independently,.

42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein f is 0.

43. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein f is 1.

44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein g is 0.

45. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein g is 1.

46. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein h is 0.

47. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein h is 1.

48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein i is 0. 499PATENT ATTORNEY DOCKET NO.: 51121-102WO3 49. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein i is 1.

50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein j is 0.

51. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein j is 1.

52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein k is 0.

53. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein k is 1.

54. The compound of any one of claims 1, 3 to 53, or a pharmaceutically acceptable salt thereof, wherein L1 is absent.

55. The compound of any one of claims 1, 3 to 53, or a pharmaceutically acceptable salt thereof, wherein L1 is optionally substituted C2–C12 heteroarylene that is a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups Re.500PATENT ATTORNEY DOCKET NO.: 51121-102WO3 57. The compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C10 heterocyclylene, optionally substituted C2– C12 heteroarylene, optionally substituted C6–C12 arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1–C10 heteroalkylene.

58. The compound of any one of claims 1 to 57, wherein D is optionally substituted C2–C12 heteroarylene.

59. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein D is:501PATENT ATTORNEY DOCKET NO.: 51121-102WO360. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein D is:

61. The compound of any one of claims 1 to 57, wherein D is optionally substituted C2–C10 heterocyclylene.

62. The compound of claim 61, wherein D is:502PATENT ATTORNEY DOCKET NO.: 51121-102WO3 63. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C1-C10 alkylene.

64. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein D is optionally substituted C2–C4 alkynylene.

65. The compound of any one of claims 1, 3 to 63, or a pharmaceutically acceptable salt thereof, wherein the L1-L2has the structure:503PATENT ATTORNEY DOCKET NO.: 51121-102WO3504PATENT ATTORNEY DOCKET NO.: 51121-102WO3505PATENT ATTORNEY DOCKET NO.: 51121-102WO3506PATENT ATTORNEY DOCKET NO.: 51121-102WO3507PATENT ATTORNEY DOCKET NO.: 51121-102WO3508PATENT ATTORNEY DOCKET NO.: 51121-102WO3 ,509PATENT ATTORNEY DOCKET NO.: 51121-102WO3510PATENT ATTORNEY DOCKET NO.: 51121-102WO3, , , , , , 511PATENT ATTORNEY DOCKET NO.: 51121-102WO3512PATENT ATTORNEY DOCKET NO.: 51121-102WO3513PATENT ATTORNEY DOCKET NO.: 51121-102WO3514PATENT ATTORNEY DOCKET NO.: 51121-102WO3515PATENT ATTORNEY DOCKET NO.: 51121-102WO3516PATENT ATTORNEY DOCKET NO.: 51121-102WO3517PATENT ATTORNEY DOCKET NO.: 51121-102WO3, 518PATENT ATTORNEY DOCKET NO.: 51121-102WO3519PATENT ATTORNEY DOCKET NO.: 51121-102WO3, 520PATENT ATTORNEY DOCKET NO.: 51121-102WO3, 521PATENT ATTORNEY DOCKET NO.: 51121-102WO3522PATENT ATTORNEY DOCKET NO.: 51121-102WO3523PATENT ATTORNEY DOCKET NO.: 51121-102WO3524PATENT ATTORNEY DOCKET NO.: 51121-102WO3525PATENT ATTORNEY DOCKET NO.: 51121-102WO3, 526PATENT ATTORNEY DOCKET NO.: 51121-102WO3527PATENT ATTORNEY DOCKET NO.: 51121-102WO3528PATENT ATTORNEY DOCKET NO.: 51121-102WO3529PATENT ATTORNEY DOCKET NO.: 51121-102WO3530PATENT ATTORNEY DOCKET NO.: 51121-102WO366. The compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, wherein the shortest chain of atoms connecting two valencies of the linker is 2 to 10 atoms long.

67. The compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, wherein the shortest chain of atoms connecting two valencies of the linker is 6 atoms long. 531PATENT ATTORNEY DOCKET NO.: 51121-102WO3 68. The compound of any one of claims 1 to 67, wherein the compound is any one of compounds 1 to 303, or a pharmaceutically acceptable salt thereof.

69. A pharmaceutical composition comprising a compound of any one of claims 1 to 68 and a pharmaceutically acceptable excipient.

70. 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 68, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 69.

71. The method of claim 70, wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myeloma, skin, endometrial, esophageal, cervical, gastric, lymphoma, leukemia, esophageal, stomach, lung cancer, or non-small cell lung cancer.

72. The method of claim 70 or 71, wherein the cancer is metastatic.

73. The method of any one of claims 70 to 72, wherein the subject or cancer has a CBP loss of function mutation.

74. The method of any one of claims 70 to 73, wherein the cancer is prostate cancer.

75. The method of claim 74, wherein the cancer is castration-resistant prostate cancer (CRPC).

76. The method of claim 74, wherein the cancer is castration-sensitive prostate cancer.

77. The method of claim 74, wherein the cancer is AR+ prostate cancer.

78. The method of any one of claims 70 to 73, wherein the cancer is lymphoma.

79. The method of claim 78, wherein the lymphoma is Diffuse large B cell lymphoma (DLBCL), 80. The method of any one of claims 70 to 79, wherein the method further comprises administering to the subject an anticancer therapy.

81. The method of claim 80, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof. 532

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