Small molecules targeting bromo / acetyl proteins and uses thereof

Abstract

Bispecific compounds (degrading agents) that target EP300 / CBP for degradation are disclosed. Pharmaceutical compositions containing the degrading agents and methods of using the compounds to treat disease are also disclosed.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. Section 119(e) to U.S. Provisional Application No. 62 / 862,879, filed June 18, 2019, which is incorporated by reference in its entirety. [Background technology]

[0002] High-risk neuroblastoma (NB) is a pediatric tumor of the peripheral sympathetic nervous system that originates from primitive neural crest cells. Survival rates in high-risk NB are poor. These neuroendocrine tumors are characterized by high expression of oncogenic MYC family members. (Matthay et al., Nat. Rev. Dis. Primers 2:16078(2016); Zimmerman et al., Cancer Discov.8(3):320-35(2018)). MYCN is an essential member of a positive feed-forward autoregulatory loop of transcription factors (TFs) that establishes cell fate in MYCN-amplified NBs. This group of TFs is called the core-regulatory circuitry (CRC). Each member is controlled by a super-enhancer (SE) gene that is critically required for NB survival. One mechanism by which MYC family oncogenes drive tumor growth is by invading gene enhancers and recruiting transcriptional and epigenetic machinery (Zeid et al., Nat. Genet. 50(4):515-23(2018)). Combined pharmacological inhibition of SE-mediated transcription initiation and elongation has been shown to rapidly disrupt NB CRC in vitro and in vivo, leading to transcriptional collapse and apoptosis (Durbin et al., Nat. Genet. 50(9):1240-60(2018)). As inhibition of transcription was insufficient to drive tumor regression in vivo (Morton et al., Mol. Oncol. 7(2):248-58(2013)), alternative approaches are needed.

[0003] EP300 or histone acetyltransferase (HAT) p300 was recently identified as a component required for NB cell survival (Durbin et al., Nat. Genet. 50(9):1240-60(2018)). Like its paralog cAMP response element (CREB) binding protein (CBP, CREBBP), EP300 catalyzes the H3K27ac mark typical of SE elements (Dancy et al., Chem. Rev. 115(6):2419-52(2015)). Numerous tumor types show dependency on EP300 but not on CBP, suggesting that this finding may be a generalizable characteristic of distinct human cancer subsets. Other EP300-dependent and MYC family-dependent cancers include acute myeloid leukemia (AML), multiple myeloma (MM), melanoma, rhabdomyosarcoma, and diffuse large B-cell lymphoma. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Matthay et al., Nat.Rev.Dis.Primers 2:16078(2016) [Non-Patent Document 2] Zimmerman et al., Cancer Discov.8(3):320-35(2018) [Non-Patent Document 3] Zeid et al., Nat. Genet. 50(4):515-23(2018) [Non-Patent Document 4] Durbin et al., Nat. Genet. 50(9):1240-60(2018) [Non-Patent Document 5] Morton et al.,Mol.Oncol.7(2):248-58(2013) [Non-Patent Document 6] Dancy et al.,Chem.Rev.115(6):2419-52(2015) Summary of the Invention [Means for solving the problem]

[0005] A first aspect of the present invention is a bispecific compound comprising a moiety (targeting ligand) that binds histone acetyltransferase p300 (also referred to herein as EP300) and cAMP response element binding protein-binding protein (CBP), a degron that binds an E3 ubiquitin ligase, and a linker (L) that covalently links said targeting ligand and said degron, said compound having formula (I): [ka] A bispecific compound having a structure represented by [In the formula, X represents C or N, X1 is CR1 or NR3, X2 is CR2 or CR4, X3 is N; With the proviso that when X is N, X1 is CR1, X2 is CR2, and X3 is N; and when X is C, X1 is NR3, X2 is CR4, and X3 is N; R1 is NHR 1 R 1 is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle; R2 is [ka] wherein X' is O, HNC2H4NH or NH; represents; R3 is an optionally substituted C1-C3 alkyl group, [ka] represents; R4 is an optionally substituted C5-C6 carbocyclic group or an optionally substituted C5-C6 heterocyclic group; [ka] where one of R3 and R4 is [ka] is], or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0006] In some embodiments, X represents N, X is CR, X is CR, X is N, and R is NHR. 1 R 1 is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle, and R2 is [ka] and X' is O or NH.

[0007] In some embodiments, X represents C, X is NR, X is CR, X is N, and R is an optionally substituted C-C alkyl; [ka] R4 represents an optionally substituted C5-C6 carbocyclic group, [ka] where one of R3 and R4 is [ka] It is.

[0008] In some embodiments, X represents N, X1 is CR1, and R1 is NHR 1 R 1is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle, X2 is CR2 and X3 is N, and when X is C, X1 is NR3, X2 is CR4, and X3 is N, and R2 is [ka] and X' represents NHC2H4NH.

[0009] In some embodiments, when X is C, X1 is NR3, X2 is CR4, and X3 is N, and R3 is an optionally substituted C1-C3 alkyl or [ka] R4 represents an optionally substituted C5-C6 carbocyclic ring or an optionally substituted C5-C6 heterocyclic ring, [ka] where one of R3 and R4 is [ka] It is.

[0010] In some embodiments, R 1 is an optionally substituted C1-C3 alkyl.

[0011] In some embodiments, R 1 is an optionally substituted C5-C6 carbocycle. In some embodiments, the optionally substituted C5-C6 carbocycle is an optionally substituted aralkyl.

[0012] In some embodiments, R2 is [ka] and X' is O, HNC2H4NH or NH.

[0013] In some embodiments, R3 is an optionally substituted C1-C3 alkyl and R4 is [ka] It is.

[0014] In some embodiments, R4 is an optionally substituted C5-C6 carbocycle or an optionally substituted C5-C6 heterocycle, and R3 is [ka] In some embodiments, the optionally substituted C5-C6 carbocycle is an optionally substituted aralkyl. In some embodiments, the optionally substituted C5-C6 heterocycle is [ka] It is.

[0015] In some embodiments, the bispecific compounds of the invention comprise Formula (II): [ka] [In the formula, [ka] represents an optionally substituted phenyl or an optionally substituted C6 heteroaryl; Xa represents NH, O, S or C(Ra)2, where each Ra independently represents H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 carbocyclyl; Xb represents C or N; Xb1 represents CRb1 or CRb3; Xb2 represents CRb2, CR4 or N; Xb3 represents N or NMe; With the proviso that when Xb is N, Xb1 is CRb1, Xb2 is CRb2, and Xb3 is N; and when Xb is C, Xb1 is CRb3, Xb2 is CR4 or N, and Xb3 is N or NMe; Rb1 is NHR b1 R b1 is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle; Rb2 is [ka] where X' is O, HNC2H4NH or NH; Rb3 is an optionally substituted C1-C3 alkyl. [ka] where n is 1, 2, 3 or 4; Rb4 is an optionally substituted C5-C6 carbocyclic ring or an optionally substituted C5-C6 heterocyclic ring; [ka] represents However, one of Rb3 and Rb4 is [ka]

[0046] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0016] Another aspect of the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a bispecific compound of Formula (I) or (II) or a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable carrier.

[0017] A further aspect of the present invention is directed to a method for making a bispecific compound of Formula (I) or (II) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0018] A further aspect of the present invention is directed to a method of treating a disease or disorder associated with abnormal (e.g., dysfunctional or dysregulated) EP300 and CBP (hereinafter "EP300 / CBP") activity, comprising administration of a therapeutically effective amount of a bispecific compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof to a subject in need of treatment for said disease or disorder.

[0019] In some embodiments, the disease or disorder is high-risk neuroblastoma (NB).

[0020] In some embodiments, the disease or disorder is a hematological cancer, such as acute myeloid leukemia (AML), multiple myeloma (MM) or diffuse large B-cell lymphoma.

[0021] In other embodiments, the disease or disorder is a solid tumor. In some embodiments, the disease or disorder is melanoma, rhabdomyosarcoma, colon cancer, rectal cancer, gastric cancer, breast cancer, or pancreatic cancer.

[0022] Without intending to be bound by any particular theory of operation, it is believed that the bispecific compounds of the present invention inhibit EP300 / CBP activity, at least in some cases, by recruiting the cellular ubiquitin / proteasome system, whose function is to routinely identify and remove damaged proteins in close proximity to EP300 / CBP as a result of binding between the bromodomain of EP300 / CPB and a targeting ligand. After degradation of EP300 or CBP molecules, the degrader is released and remains active. Thus, by engaging and utilizing the body's own natural protein processing system, the bispecific compounds of the present invention may represent a potential improvement over current small molecule inhibitors of EP300 / CBP. Thus, the effective intracellular concentration of the degrader may be significantly lower than that of small molecule inhibitors of EP300 and CBP. In summary, the bispecific compounds of the present invention may represent an advance over known EP300 / CBP inhibitors, may overcome one or more limitations associated with their use, and, at least in the case of compound 31, may also be selective in targeting EP300 and CBP.

[0023] The bispecific compounds of the present invention may be useful in the treatment of MYC-driven cancers (eg, neuroblastoma) by transcriptional silencing of MYC expression. [Brief description of the drawings]

[0024] [Figure 1A] A tree diagram of the human bromodomain family (Shortt et al., Nat. Rev. Cancer 17:160-183(2017)). [Figure 1B] FIG. 1 illustrates histone acetyltransferase p300 (EP300) and cAMP response element binding protein (CREB)-binding protein (CBP) as multidomain proteins. [Figure 1C] FIG. 1 shows the homology of the EP300 / CBP catalytic core structure (Henry et al., Biochemistry 52:5746-5759 (2013)). [Diagram 2] FIG. 1 is a graph showing relative cell proliferation following 72 hour treatment of Kelly neuroblastoma cell line with A485, lenalidomide, thalidomide, pomalidomide, and bispecific compounds 1, 2, and intermediate 2 (int-2) of the invention by ATPlite™ Luminescence Assay. [Figure 3A] FIG. 13 is an immunoblot showing EP300 degradation at 24 hours following treatment of Kelly NB cells with bispecific compounds 1, 2 and Int-2. [Figure 3B] FIG. 13 is an immunoblot showing CBP degradation at 24 hours following treatment of Kelly NB cells with bispecific compounds 1, 2 and Int-2. [Figure 3C] FIG. 13 is an immunoblot showing histone H3 and H3K27ac levels at 24 hours following treatment of Kelly NB cells with bispecific compounds 1, 2 and Int-2. [Figure 4] 1 is a graph showing relative cell proliferation following 72 hour treatment of Kelly neuroblastoma cell line with bispecific compounds 3, 4, 5, 6 and 7 by ATPlite™ Luminescence Assay. [Figure 5A] FIG. 13 is an immunoblot showing EP300 degradation after treatment of Kelly NB cells with bispecific compounds 3, 6 and 7 at 24 hours. [Figure 5B] FIG. 13 is an immunoblot showing CBP degradation after treatment of Kelly NB cells with bispecific compounds 3, 6 and 7 at 24 hours. [Figure 5C] 1 is an immunoblot showing histone H3 and H3K27ac levels after treatment of Kelly NB cells with bispecific compounds 3, 6 and 7 at 24 hours. [Figure 6] 1 is a graph showing the relative binding of bispecific compounds 1, 2 and Int-2 to the CBP bromodomain by Alpha Screen® assay. [Figure 7A]FIG. 13 is an immunoblot showing EP300 degradation at 24 hours following treatment of Kelly NB cells with bispecific compounds 8, 11 and 12. [Figure 7B] FIG. 13 is an immunoblot showing CBP degradation after treatment of Kelly NB cells with bispecific compounds 8, 11 and 12 at 24 hours. [Figure 7C] 13 is an immunoblot showing histone H3 and H3K27ac levels after treatment of Kelly NB cells with bispecific compounds 8, 11 and 12 at 24 hours. [Figure 7D] FIG. 13 is an immunoblot showing levels of bromodomain-containing protein 4 (BRD4) after treatment of Kelly NB cells with bispecific compounds 8, 11, and 12 at 24 hours. [Figure 7E] 13 is an immunoblot showing the levels of CBP, EP300 (p300), bromodomain-containing protein 2 (BRD2), BRD3, BRD4, β-actin and H3K27ac at 8 and 16 hours after treatment of Kelly NB cells with bispecific compound 31. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. As used in this specification and the appended claims, unless expressly stated to the contrary, in order to facilitate understanding of the present invention, the following terms have the meanings set forth.

[0026] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, and so forth.

[0027] Unless otherwise specified, the term "about" means within 10% (eg, within 5%, 2%, or 1%) of the particular value that is modified by the term "about."

[0028] The transitional phrase "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude further, unrecited elements or method steps. In contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to the materials or steps specified and to those materials or steps that do not "materially affect one or more basic and novel characteristics" of the claimed invention.

[0029] With respect to the compounds of the present invention, to the extent the following terms are used herein to further describe the compounds of the present invention, the following definitions apply.

[0030] As used herein, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. In one embodiment, an alkyl group is a C1-C 18 In other embodiments, the alkyl group is a C0-C6, C0-C5, C0-C3, C1-C 12, C1-C8, C1-C6, C1-C5, C1-C4 or C1-C3 groups (CO alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. In some embodiments, the alkyl group is a C1 to C3 alkyl group. In some embodiments, the alkyl group is a C1 to C2 alkyl group.

[0031] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain, such as methylene, ethylene, propylene, n-butylene, etc., that links the remainder of the molecule to a radical group, consists solely of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms. The alkylene chain can be attached to the remainder of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, the alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (C1 alkylene).

[0032] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more (eg, 1, 2, 3 or 4) halo groups.

[0033] As used herein, the term "alkenyl" refers to a straight- or branched-chain monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl includes radicals having "cis" and "trans" orientations, alternatively "E" and "Z" orientations. In one example, an alkenyl group is a C2-C 18 In another embodiment, the alkenyl group is a C2-C 12 , C2~C 10 , C2-C8, C2-C6 or C2-C3 groups. Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl.

[0034] As used herein, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one example, an alkynyl group is a C2-C 18 In another example, the alkynyl group is a C-C 12 , C2~C 10 , C2-C8, C2-C6 or C2-C3. Examples include ethynylprop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.

[0035] The term "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen group attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbyl groups covalently linked by an oxygen. Thus, the substituent of an alkyl that makes it an ether is or resembles an alkoxyl, as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0036] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0037] As used herein, the term "carbocyclic" (also referred to as "carbocyclyl"), used alone or as part of a larger moiety, refers to a group containing a saturated, partially unsaturated, or aromatic ring system having from 3 to 20 carbon atoms, alone or as part of a larger moiety (e.g., an alkcarbocyclic group). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In one embodiment, a carbocyclyl is a ring system having from 3 to 15 carbon atoms (C3-C4). 15 In one embodiment, carbocyclyl is an alkyl group having 3 to 12 carbon atoms (C 12 In another embodiment, carbocyclyl is C3-C8, C3-C 10 Or C5~C 10 In another embodiment, the carbocyclyl, as a monocyclic ring, includes C3-C8, C3-C6, or C5-C6. In some embodiments, the carbocyclyl, as a bicyclic ring, includes C7-C 12 In another embodiment, the carbocyclyl, as a spiro system, is a C5-C 12Includes. Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl, and bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spirocarbocyclyl include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, bi- or spiro-carbocycles). The term carbocyclic group also includes carbocyclic rings fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., aryl or heterocyclic rings) where the radical or point of attachment is on the carbocyclic ring.

[0038] Thus, the term carbocyclic as used herein means R c is an alkylene chain; c The term carbocyclic, as used herein, also includes carbocyclylalkyl groups, which refer to the group R -carbocyclyl. c is an alkylene chain; c Also included are carbocyclylalkoxy groups which refer to groups attached through the oxygen atom of a -carbocyclyl.

[0039] As used herein, the term "heterocyclyl" used alone or as part of a larger moiety refers to a "carbocyclyl" containing a saturated, partially unsaturated, or aromatic ring system in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In some embodiments, heterocyclyl refers to a 3- to 15-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5- to 14-membered heteroaryl ring system. The term heterocyclyl also includes C3-C8 heterocycloalkyl, which are saturated or partially unsaturated monocyclic, bicyclic or spirocyclic ring systems containing 3 to 8 carbons and one or more (1, 2, 3 or 4) heteroatoms.

[0040] In some embodiments, the heterocyclyl group contains 3-12 ring atoms, including monocyclic, bicyclic, tricyclic, and spirocyclic ring systems, where the ring atom is carbon and 1-5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl contains a 3-7 membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl contains a 4-6 membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl contains a 3 membered monocyclic ring. In some embodiments, the heterocyclyl contains a 4 membered monocyclic ring. In some embodiments, the heterocyclyl contains a 5-6 membered monocyclic ring. In some embodiments, the heterocyclyl contains 0-3 double bonds. In any of the foregoing embodiments, the heterocyclyl contains 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR4] + Cl - , [NR4] + OH -Representative examples of heterocyclyl include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinylidene aryl, hexahydropyridine ... nyl, thiazinyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo [d]imidazolyl, 1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrimidine, pyrimidine Lazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decane-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls containing a sulfur or oxygen atom and 1 to 3 nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, such as oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of 5-membered heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyls such as imidazol-2-yl, 1,3,4-triazol-5-yl; triazolyls such as 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyls such as 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclyls are benzoxazol-2-yl, benzthiazol-2-yl, and benzimidazol-2-yl. Examples of 6-membered heterocyclyls contain 1 to 3 nitrogen atoms and may contain sulfur or oxygen atoms, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, especially pyridazin-3-yl, and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide as well as pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and 1,3,4-triazin-2-yl groups are further examples of heterocyclyl groups. In some embodiments, heterocyclic groups include heterocyclic rings fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., carbocyclic or heterocyclic rings) where the radical or point of attachment is on the heterocyclic ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0041] Thus, the term heterocyclic, as used herein, includes N-heterocyclyl groups, which refer to heterocyclyl groups that contain at least one nitrogen and whose attachment point to the rest of the molecule is through a nitrogen atom in the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl. The term heterocyclic, as used herein, also includes C-heterocyclyl groups, which refer to heterocyclyl groups that contain at least one heteroatom and whose attachment point to the rest of the molecule is through a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl groups include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl and 2- or 3-pyrrolidinyl. The term heterocycle, as disclosed above, refers to R c is an alkylene chain; c The term heterocycle as used herein also includes heterocyclylalkyl groups, which refer to the group R c is an alkylene chain; c Also included are heterocyclylalkoxy groups which refer to groups attached through the oxygen atom of a -heterocyclyl.

[0042] As used herein, the term "aryl" used alone or as part of a larger moiety (e.g., "aralkyl" where the terminal carbon atom on the alkyl group is the point of attachment, e.g., a benzyl group), "aralkoxy" where an oxygen atom is the point of attachment, or "aroxyalkyl" where the point of attachment is on an aryl group) refers to groups containing monocyclic, bicyclic, or tricyclic carbocyclic ring systems, including fused rings, in which at least one ring in the system is aromatic. In some embodiments, an aralkoxy group is a benzoxy group. The term "aryl" may be used interchangeably with the term "aryl ring." In one embodiment, aryl includes groups having 6 to 18 carbon atoms. In another embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthyridinyl, and the like, which may be substituted or independently substituted by one or more substituents described herein. A particular aryl is phenyl. In some embodiments, an aryl group comprises an aryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings) where the radical or point of attachment is on the aryl ring.

[0043] Thus, the term aryl, as disclosed above, refers to R c is an alkylene chain such as methylene or ethylene; c -aryl groups, such as aralkyl groups (e.g., benzyl). In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, refers to a group of R c is an alkylene chain such as methylene or ethylene; c Also included is aralkoxy, which refers to a group bonded through the oxygen atom of an -aryl.

[0044] As used herein, the terms "heteroaryl" used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also referred to as "heteroaralkyl") or "heteroarylalkoxy" (also referred to as "heteroaralkoxy") refer to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms in which at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes a 4-6 membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen, which may be independently substituted. In another embodiment, heteroaryl includes a 5-6 membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, and the like. aryl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3- These include oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl and pyrid-2-yl N-oxide. The term "heteroaryl" also includes groups in which a heteroaryl is fused to one or more cyclic (e.g., carbocyclyl or heterocyclyl) rings, where the radical or point of attachment is on the heteroaryl ring.Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic. In some embodiments, heteroaryl groups include heteroaryl rings fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., carbocyclic or heterocyclic rings) where the radical or point of attachment is on the heteroaryl ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0045] Thus, the term heteroaryl, as used herein, encompasses N-heteroaryl groups, which refer to heteroaryl groups as defined above that contain at least one nitrogen and whose point of attachment to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl, as used herein, also encompasses C-heteroaryl groups, which refer to heteroaryl groups as defined above that contain at least one nitrogen and whose point of attachment to the remainder of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl, as disclosed above, encompasses R c is an alkylene chain as defined above; c The term heteroaryl, as used herein, also encompasses heteroarylalkyl groups, which refer to the group R c is an alkylene group as defined above; c Also included are heteroaralkoxy (or heteroarylalkoxy) groups, which refer to groups attached through the oxygen atom of a -heteroaryl.

[0046] Unless otherwise specified, any of the groups described herein may be substituted or unsubstituted to the extent not further defined for any particular group or groups. As used herein, the term "substituted" refers broadly to all permissible substituents, with the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like. Representative substituents include halogens, hydroxyl groups, and any other organic group that contains any number of carbon atoms, e.g., 1-14 carbon atoms, and may contain one or more (e.g., 1, 2, 3, or 4) heteroatoms, such as oxygen, sulfur, and nitrogen, divided into linear, branched, or cyclic structural formats.

[0047] To the extent that no other disclosure is made for any particular group or groups, representative examples of substituents include alkyl, substituted alkyl (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted ... 1), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), cyclic (e.g., C3-C 12 , C5-C6), substituted cyclic (e.g., C3-C 12 , C5-C6), carbocyclic (e.g., C3-C 12 , C5-C6), substituted carbocyclic (e.g., C3-C 12 , C5-C6), heterocyclic (e.g., C3-C 12 , C5-C6), substituted heterocyclic (e.g., C3-C 12, C5-C6), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl (e.g., pyridyl or pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C 12 , C6), substituted aryloxy (e.g., C6-C 12 , C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., C1-C6), arylthio (e.g., C6-C 12 , C6), substituted arylthio (e.g., C6-C 12 , C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid and peptide groups.

[0048] The term "binding" with respect to the interaction between a targeting ligand and a targeted protein, which in the present invention is EP300, CPB and its mutant forms (collectively referred to as "EP300 / CPB"), typically refers to an intermolecular interaction that may be preferential or substantially specific (also referred to herein as "selective"), in that, at least in one embodiment, the binding of the targeting ligand to other proteinaceous entities present in the cell is functionally insignificant (Figures 1A, 1B and 2). The bispecific compounds of the present invention may preferentially bind and recruit EP300 and CBP and their mutant forms, for example for inhibition by targeted degradation.

[0049] The term "binding" with respect to the interaction between a degron and an E3 ubiquitin ligase typically refers to an intermolecular interaction that may or may not indicate an affinity level equal to or exceeding the affinity between a targeting ligand and a target protein, but that nevertheless is sufficient to achieve recruitment of the ligase for targeted and selective degradation of the targeted protein.

[0050] Broadly, a bispecific compound comprises a moiety that binds EP300 / CBP (a targeting ligand), a degron (D) that binds an E3 ubiquitin ligase, and a linker (L) that covalently links the targeting ligand and the degron. The bispecific compound of the invention has the formula (I): [ka] [In the formula, X represents C or N, X1 is CR1 or NR3, X2 is CR2 or CR4, X3 is N, with the proviso that when X is N, X1 is CR1, X2 is CR2, and X3 is N; [ka] teeth [ka] and when X is C, X1 is NR3, X2 is CR4, and X3 is N; [ka] teeth [ka] represents; R1 is NHR 1 R 1 is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle; R2 is [ka] where X' is O, HNC2H4NH or NH; R3 is an optionally substituted C1-C3 alkyl group, [ka] represents; R4 is an optionally substituted C5-C6 carbocyclic ring, [ka] where one of R3 and R4 is [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0051] In some embodiments, when X is N, X is CR, X is CR, and X is N; [ka] teeth [ka] R1 represents NHR1, R 1 is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle, and R2 is [ka] wherein X' is O or NH, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0052] In some embodiments, when X is C, X is NR, X is CR, and X is N; [ka] teeth [ka] R3 represents an optionally substituted C1-C3 alkyl group; [ka] R4 represents an optionally substituted C5-C6 carbocyclic ring; [ka] where one of R3 and R4 is [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0053] In some embodiments, when X is N, X is CR, X is CR, and X is N; [ka] teeth [ka] and R1 is NHR 1 R 1 is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle, and R2 is [ka] and X' is HNC2H4NH, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0054] In some embodiments, when X is C, X is NR, X is CR, and X is N; [ka] teeth [ka] R3 represents an optionally substituted C1-C3 alkyl or [ka] R4 represents an optionally substituted C5-C6 carbocyclic ring or an optionally substituted C5-C6 heterocyclic ring, [ka] where one of R3 and R4 is [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0055] In some embodiments, R 1 is an optionally substituted C1-C3 alkyl.

[0056] In some embodiments, R 1 is an optionally substituted C5-C6 carbocycle. In some embodiments, the optionally substituted C5-C6 carbocycle is an optionally substituted aralkyl.

[0057] In some embodiments, R 1 is substituted with methyl or methoxy.

[0058] In some embodiments, R2 is [ka] It is.

[0059] In some embodiments, R3 is an optionally substituted C1-C3 alkyl and R4 is [ka] It is.

[0060] In some embodiments, R3 is substituted with dimethylaminyl, morpholinyl, or piperazinyl.

[0061] In some embodiments, R4 is an optionally substituted C5-C6 carbocycle and R3 is [ka] In some embodiments, the optionally substituted C5-C6 carbocycle is an optionally substituted aralkyl. In some embodiments, the optionally substituted C5-C6 heterocycle is [ka] It is.

[0062] In some embodiments, R4 is substituted with halogen, NH2, OH, or methoxy.

[0063] In some embodiments, X is N, X is CR, X is CR, and X is N, and the bispecific compound of the invention has the formula (I-1): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0064] In some embodiments, X is N, X is CR, X is CR, X is N, and R 1 is an optionally substituted C1-C3 alkyl, and R2 is [ka] and the bispecific compounds of the present invention have formulas (I-1a) to (I-1d): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0065] In some embodiments, X is N, X is CR, X is CR, X is N, and R 1 is an optionally substituted C5-C6 carbocyclic ring, and R2 is [ka] or [ka] and the bispecific compounds of the invention have formula (I-1e) or (I-1f): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0066] In some embodiments, X is N, X is CR, X is CR, X is N, and R 1 is an optionally substituted C5-C6 aralkyl, and R2 is [ka] and the bispecific compounds of the present invention have formulas (I-1g) to (I-1j): [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0067] In some embodiments, when X is C, X is NR, X is CR, and X is N, and the compound of the present invention has the formula (I-2): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0068] In some embodiments, X is C, X is NR, X is CR, X is N, R is an optionally substituted C-C alkyl, and R is [ka] or [ka] and the bispecific compounds of the present invention have formulas (I-2a) to (I-2p): [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0069] In some embodiments, X is C, X is NR, X is CR, X is N, and R is an optionally substituted C-C aralkyl or [ka] and R4 is [ka] [ka] and the compounds of the present invention are represented by formulae (I-2q) to (I-2z) and (I-2a') to (I-2k'): [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0070] In some embodiments, the bispecific compounds of the invention comprise Formula (II): [ka] [In the formula, [ka] represents an optionally substituted phenyl or C6 heteroaryl; Xa represents NH, O, S or C(Ra)2, where each Ra independently represents H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 carbocyclyl; Xb represents C or N; Xb1 represents CRb1 or CRb3; Xb2 represents CRb2, CR4 or N; Xb3 represents N or NMe; With the proviso that when Xb is N, Xb1 is CRb1, Xb2 is CRb2, and Xb3 is N; and when Xb is C, Xb1 is CRb3, Xb2 is CR4 or N, and Xb3 is N or NMe; Rb1 is NHR b1 R b1is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle; Rb2 is [ka] where X' is O, HNC2H4NH or NH; Rb3 is an optionally substituted C1-C3 alkyl. [ka] where n is 1, 2, 3 or 4; Rb4 is an optionally substituted C5-C6 carbocyclic ring or an optionally substituted C5-C6 heterocyclic ring; [ka] represents However, one of Rb3 and Rb4 is [ka] [ka]

[0046] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0071] In some embodiments, [ka] is phenyl, Xa is NH, Xb is C, X1 is CRb3, and Rb3 is [ka] wherein Xb2 is N, Xb3 is NMe, and n is 1, 2, 3 or 4; and the bispecific compound of the invention has formula (II-1) or (II-2): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof. Linker

[0072] The linker ("L") provides a covalent bond between the targeting ligand and the degron. The structure of the linker can be immaterial so long as it does not substantially interfere with the activity of the targeting ligand or the degron. In some embodiments, the linker comprises an alkylene chain (e.g., having 2-20 alkylene units). In other embodiments, the linker may comprise an alkylene chain or a divalent alkylene chain, any of which may be selected from the group consisting of -O-, -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N (R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -O S(O)2-, -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, C3~C 12 It may be interrupted and / or terminated (at one or both termini) by at least one of a carbocyclene, a 3- to 12-membered heterocyclene, a 5- to 12-membered heteroarylene, or any combination thereof, where R' is H or a C1-C6 alkyl, and the interrupting group and one or both terminating groups may be the same or different.

[0073] In some embodiments, the linker is a C1-C 12 It may comprise an alkylene chain, the nitrogen also being attached to a degron.

[0074] In some embodiments, the linker has 1 to 10 alkylene units. [ka] The alkylene chain includes an alkylene chain interrupted or terminated by:

[0075] "Carbocyclene" refers to an optionally substituted divalent carbocyclic group.

[0076] "Heterocyclene" refers to an optionally substituted divalent heterocyclyl group.

[0077] "Heteroarylene" refers to an optionally substituted divalent heteroaryl group.

[0078] Representative examples of alkylene linkers that may be suitable for use in the present invention include the following: [ka] In the formula, n is an integer of 1 to 12 (the "of" means both ends are included), for example, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, 9-10 and 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, examples of which are: [ka] Examples include; Alkylene chains terminated with various functional groups (as described above), examples of which are as follows: [ka] Alkylene chains interrupted by various functional groups (as described above), examples of which are: [ka] An alkylene chain interrupted or terminated by a heterocyclene group, for example [ka] [In the formula, m and n are independently an integer of 0 to 10], examples thereof include: [ka] Examples include; Alkylene chains interrupted by amide, heterocyclene and / or aryl groups, examples of which include: [ka] Examples include; Heterocyclene and aryl groups as well as alkylene chains interrupted by heteroatoms, examples of which include: [ka] Examples include; Alkylene chains interrupted by heteroatoms such as N, O or B, e.g. [ka] [wherein each n is independently an integer from 1 to 10, e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, 9-10, and 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and R is H or C1-C4 alkyl, examples of which are: [ka] It is.

[0079] In some embodiments, the linker is -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')- , -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2 -, -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, C 3~12 It may comprise a polyethylene glycol chain which may be terminated (at one or both ends) with at least one of a carbocyclene, a 3- to 12-membered heterocyclene, a 5- to 12-membered heteroarylene, or any combination thereof, where R' is H or a C1-C6 alkyl, and where one or both terminating groups may be the same or different.

[0080] In some embodiments, the linker has 2-8 PEG units. [ka] The polyethylene glycol chain includes a terminating

[0081] Examples of linkers containing polyethylene glycol chains include: [ka] [wherein n is an integer of 2 to 10], examples of which include: [ka] Examples include:

[0082] In some embodiments, the polyethylene glycol chain may terminate in a functional group, examples of which are as follows: [ka] .

[0083] In some embodiments, the compound of formula (I) has the structure (L10): [ka] and a linker represented by Wherein Q is CH or O; Y is CH2, CH2CH2 or absent, provided that when X is O, then Y is CH2CH2; n is an integer from 0 to 6, inclusive.

[0084] In some embodiments, the linker has the following structure: [ka] It is represented by one of the following:

[0085] Degron Degrons ("D") are functional moieties that bind E3 ubiquitin ligases.

[0086] In some embodiments, the compound of formula (I) comprises a degron that binds cereblon. Representative examples of degrons that bind cereblon and may be suitable for use in the present invention are described in U.S. Patent Application Publication No. 2018 / 0015085A1 (e.g., indolinones such as isoindolinones and isoindoline-1,3-diones encompassed by formulae IA and IA' therein, and bridged cycloalkyl compounds encompassed by formulae IB and IB' therein).

[0087] In some embodiments, the degron that binds cereblon has the structure (D1): [ka] is represented by Wherein Y is CH2 or CO; Z is NH, O or OCH2CO, and the curve ( [ka] ) represents the attachment point of the linker and the EP300 / CBP targeting moiety.

[0088] In some embodiments, the degron is Structure (D1-a) or (D1-b): [ka] It is represented by:

[0089] In some embodiments, the degron binds the von Hippel-Lindau (VHL) tumor suppressor. Representative examples of degrons that bind VHL are: [ka] [wherein Y' is a bond, N, O or C]; [ka] [wherein Z is a C5-C6 carbocyclic or C5-C6 heterocyclic group], and [ka] In some embodiments, Z is [ka] It is.

[0090] Still other degrons that bind VHL and may be suitable for use as a degron in the present invention are disclosed in U.S. Patent Application Publication No. 2017 / 0121321A1.

[0091] In some embodiments, the bispecific compound of formula (I) or (II) has the structure (1)-(46): [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharma- ceutically acceptable salts and stereoisomers thereof.

[0092] The bispecific compounds of formula (I) or (II) may be in the form of free acid or free base or pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable" with respect to salt refers to a salt of a compound that does not suppress the biological activity or properties of the compound and is relatively non-toxic, i.e., the compound in salt form can be administered to a subject without causing undesirable biological effects (such as dizziness or upset stomach) or interacting in a harmful manner with any of the other components of the composition in which the salt is contained. The term "pharmaceutically acceptable salt" refers to the product obtained by reacting a compound of the present invention with a suitable acid or base. Examples of pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate. Certain compounds of the present invention can form pharma- ceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.

[0093] The bispecific compounds of formula (I) or (II) may have at least one chiral center and therefore may be in the form of stereoisomers, where as used herein, stereoisomers encompass all isomers of individual compounds that differ only in the orientation of the atoms of the compounds in space. The term stereoisomer includes enantiomers (enantiomers containing the (R-) or (S-) configuration of the compound), mixtures of enantiomers of the compounds (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of the compounds and isomers of the compounds with more than one chiral center that are not mirror images of each other (diastereoisomers). The chiral centers of the compounds may undergo epimerization in vivo, and therefore, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Thus, the compounds of the invention can be prepared and used in the form of individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, e.g., racemic mixtures of stereoisomers.

[0094] In some embodiments, the bispecific compounds of formula (I) or (II) are isotopically derivatives in that they have at least one desired isotopic substitution of an atom that is greater than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound contains deuterium or multiple deuterium atoms. Deuterium, i.e. 2 Substitution with heavier isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous in some circumstances.

[0095] In addition to isotopic derivatives, the term "bispecific compounds of Formula (I) or (II)" encompasses N-oxides, crystalline forms (also known as polymorphs), active metabolites of the compounds having the same type of activity, tautomers, and unsolvated and solvated forms of the compounds with pharma- ceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0096] Method of synthesis In some embodiments, the present invention is directed to a method for making a bispecific compound of formula (I) or (II) or a pharma- ceutically acceptable salt or stereoisomer thereof. Broadly, the compounds of the present invention or a pharma- ceutically acceptable salt or stereoisomer thereof can be prepared by any method known to be applicable to the preparation of chemically related compounds. Representative synthetic schemes are described in the various examples, illustrating non-limiting methods by which the compounds of the present invention can be prepared.

[0097] Pharmaceutical Compositions Another aspect of the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a bispecific compound of formula (I) or (II) or a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable carrier. As known in the art, the term "pharma- ceutically acceptable carrier" refers to a pharma- ceutically acceptable material, composition, or vehicle suitable for administering the compound of the present invention to a mammal. Suitable carriers may include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), and gases that function to carry or transport the compound from one organ or part of the body to another. A carrier is "acceptable" in the sense that it is physiologically inert to the other ingredients of the formulation, is compatible with the other ingredients of the formulation, and is not harmful to the subject or patient. Depending on the type of formulation, the composition may include one or more pharma- ceutically acceptable excipients.

[0098] In general, the bispecific compounds of formula (I) or (II) can be formulated into a given type of composition according to conventional pharmaceutical practices such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration, which may include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intracerebroventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation) and topical (e.g., transdermal). In general, the most appropriate route of administration will depend on a variety of factors, including, for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may be advantageous in that the compound may be administered relatively quickly, such as in the case of single-dose treatments and / or acute conditions.

[0099] In some embodiments, the bispecific compounds of the invention are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0100] Thus, the bispecific compounds of the invention may be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups and elixirs); semi-solid compositions (e.g., gels, suspensions, and creams); and gases (e.g., propellants for aerosol compositions). The compounds may also be formulated for rapid, intermediate, or sustained release.

[0101] The solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In such solid dosage forms, active compound is mixed with carriers such as sodium citrate or dicalcium phosphate and additional carriers or excipients, such as a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, c) humectants, such as glycerol, d) disintegrants, such as crosslinked polymers (such as crosslinked polyvinylpyrrolidone (crospovidone), ), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells such as enteric coatings and other coatings. These solid dosage forms may further contain an opacifying agent.

[0102] In some embodiments, the bispecific compounds of the present invention may be formulated into hard or soft gelatin capsules. Representative excipients that may be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose, and croscarmellose sodium. The gelatin shell may contain gelatin, titanium dioxide, iron oxide, and colorants.

[0103] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups and elixirs.In addition to the compound, liquid dosage forms can contain aqueous or non-aqueous carriers (depending on the solubility of the compound) commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.Oral compositions can also contain excipients such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents and aromatic agents.

[0104] Injectable preparations may include sterile aqueous or oily suspensions. Injectable preparations may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable preparations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use. The effect of the compound can be prolonged by delaying its absorption, which can be accomplished by the use of liquid suspensions or crystalline or amorphous material with poor water solubility. Prolonged absorption of the compound from a parenterally administered formulation can also be accomplished by suspending the compound in an oil vehicle.

[0105] In certain embodiments, the bispecific compounds of formula (I) or (II) can be administered locally rather than systemically, for example, via direct injection of the conjugate into an organ, often in a depot preparation or sustained release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are made by forming microencapsule matrices of the compounds in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). The release rate of the compounds can be controlled by varying the ratio of compound to polymer and the nature of the particular polymer used. Depot injectable formulations are also prepared by encapsulating the compounds in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compounds are delivered in targeted drug delivery systems, for example liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and taken up selectively by the organ.

[0106] The bispecific compounds may be formulated for buccal or sublingual administration and examples include tablets, lozenges and gels.

[0107] The bispecific compound may be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosol, mist or powder. The pharmaceutical composition may be delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, the dosage unit of the pressurized aerosol may be determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges containing gelatin, for example, for use in an inhaler or insufflator, may be formulated containing a powder mix of the compound and a suitable powder base, for example, lactose or starch.

[0108] The bispecific compounds of formula (I) or (II) may be formulated for topical administration, which as used herein refers to intradermal administration by application of the formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

[0109] Representative examples of carriers useful for formulating compositions for topical application include solvents (e.g., alcohol, polyalcohol, water), creams, lotions, ointments, oils, bandages, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic saline or buffered saline).For example, creams can be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl or oleyl alcohol.Cream can also contain non-ionic surfactants such as polyoxy-40-stearate.

[0110] In some embodiments, topical formulations may also include excipients, examples of which are penetration enhancers. These agents can transport pharmacologically active compounds through the stratum corneum into the epidermis or dermis, preferably with little or no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in improving the rate of drug penetration through the skin. For example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (Eds. Interpharm Press Inc., Buffalo See Grove, Ill. (1997). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethyl alcohol, isopropyl alcohol, octolyphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0111] Representative examples of other excipients that may be included in topical formulations and other types of formulations (to the extent that the other excipients are compatible) include preservatives, antioxidants, moisturizers, emollients, buffers, solubilizers, skin protectants and surfactants.Suitable preservatives include alcohols, quaternary amines, organic acids, parabens and phenols.Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol and chelating agents such as EDTA and citric acid.Suitable moisturizers include glycerin, sorbitol, polyethylene glycol, urea and propylene glycol.Suitable buffers include citrate buffer, hydrochloric acid buffer and lactate buffer.Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin and polysorbate. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum and zinc oxide.

[0112] Transdermal formulations typically use transdermal delivery devices and transdermal delivery patches in which the compound is formulated in a lipophilic emulsion or buffered aqueous solution, dissolved and / or dispersed in a polymer or adhesive. Patches can be constructed for continuous, pulsatile, or on-demand delivery of drugs. Transdermal delivery of compounds can be achieved by iontophoretic patches. Transdermal patches can provide controlled delivery of compounds by using a rate-controlling membrane or by trapping the compound in a polymer matrix or gel to slow the rate of absorption. Absorption enhancers can be used to increase absorption, examples of which include absorbent pharma- ceutically acceptable solvents that aid in passing through the skin.

[0113] Ophthalmic preparations include eye drops.

[0114] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. Compositions for rectal or vaginal administration can also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients, such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity and release the compound.

[0115] Dosage As used herein, the term "therapeutically effective amount" refers to the amount of the bispecific compound of formula (I) or (II) or its pharmaceutically acceptable salt or stereoisomer that is effective in bringing about the desired therapeutic response in a particular patient suffering from a disease or disorder.Thus, the term "therapeutically effective amount" includes the amount of the compound of the present invention or its pharmaceutically acceptable salt or stereoisomer that is administered to induce beneficial changes in the disease or disorder to be treated, or to prevent the onset or progression of the disease or disorder, or to alleviate to some extent one or more of the symptoms of the disease or disorder being treated in the subject, or to simply kill or inhibit the proliferation of disease (e.g., neuroblastoma) cells, or to reduce the amount of EP300 / CBP in disease cells.

[0116] The total daily dosage of bispecific compound and its usage can be determined by the attending physician according to standard medical practice, for example, by using sound medical judgment.The specific therapeutically effective dose for any specific subject can depend on various factors, including the disease or disorder being treated and its severity (e.g., its current condition); the subject's age, weight, general health condition, sex and diet; the administration time, administration route and excretion rate of the specific active ingredient used; the duration of treatment; the drug used in combination with or simultaneously with the bispecific compound; and similar factors well known in the medical field (for example, see Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 10th Edition, A.Gilman, J.Hardman and L.Limbird, eds., McGraw-Hill Press, 155-173, 2001).

[0117] The bispecific compounds of formula (I) or (II) may be effective over a wide dosage range. In some embodiments, the total daily dosage (e.g., for an adult) may range from about 0.001 to about 1600 mg per day, 0.01 to about 1600 mg, 0.01 to about 500 mg, about 0.01 to about 100 mg, about 0.5 to about 100 mg, 1 to about 100-400 mg, about 1 to about 50 mg per day, and about 5 to about 40 mg per day, and in other embodiments, about 10 to about 30 mg per day. Individual dosages may be formulated to contain the desired dosage depending on the number of times the compound is administered per day. By way of example, capsules may be formulated with about 1 to about 200 mg of compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, the individual doses may be compounded to contain the desired dosage depending on the number of times the compound is to be administered per day.

[0118] How to use In some embodiments, the present invention is directed to a method of treating a disease or disorder associated with aberrant (e.g., dysfunctional or dysregulated) EP300 / CBP or MYC activity comprising administration of a therapeutically effective amount of a bispecific compound of Formula (I) or (II) or a pharma- ceutical acceptable salt or stereoisomer thereof to a subject in need of treating said disease or disorder.

[0119] A disease or disorder may be referred to as being characterized or mediated by abnormal (e.g., dysfunctional or dysregulated) EP300 / CBP or MYC activity (e.g., elevated levels of protein or otherwise functionally abnormal compared to a non-pathological state). A "disease" (or "symptom") is generally considered to be a state of a subject's health in which the subject is unable to maintain homeostasis and the subject's health will continue to deteriorate unless the disease is ameliorated. In contrast, a "disorder" in a subject is a state of health in which the subject is able to maintain homeostasis, but the state of the subject's health is less favorable than if the disorder were not present. If left untreated, the disorder does not necessarily cause a further deterioration of the animal's health state. In some embodiments, the bispecific compounds of formula (I) or (II) may be useful in the treatment of cell proliferative diseases and disorders (e.g., cancer or benign neoplasms). In some embodiments, the bispecific compounds of formula (I) or (II) may be useful in the treatment of MYC-driven cancers (e.g., neuroblastoma). As used herein, the term "cell proliferative disease or disorder" refers to conditions characterized by deregulated or abnormal cell proliferation, or both, including non-cancerous conditions such as neoplasms, precancerous conditions, benign tumors, and cancers.

[0120] The term "subject" (or "patient") as used herein includes all members of the animal kingdom susceptible to or afflicted with the indicated disease or disorder. In some embodiments, the subject is a mammal, e.g., a human or non-human mammal. The method is applicable to pet animals such as dogs and cats, as well as domestic animals such as cows, horses, sheep, goats, pigs, and other domestic and wild animals. A subject "in need" of treatment may be suffering from or suspected of suffering from a particular disease or disorder, may have been diagnosed as positive, or otherwise exhibits a sufficient number of risk factors or a sufficient number or combination of signs or symptoms to allow a medical professional to diagnose or suspect that the subject suffers from a disease or disorder. Thus, subjects suspected of suffering from a particular disease or disorder as opposed to subjects suffering from a particular disease or disorder are not necessarily two distinct groups.

[0121] Exemplary types of non-cancerous (e.g., cell proliferative) diseases or disorders that may be amenable to treatment with the compounds of the invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, cardiac diseases, viral diseases, chronic and acute kidney disease or injury, metabolic diseases, and allergic and genetic diseases.

[0122] Representative examples of specific non-cancerous diseases and disorders include rheumatoid arthritis, alopecia areata, lymphoproliferative conditions, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, anhidrotic ectodermal dysplasia, pure red cell aplasia, and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryopyrin-associated periodic syndrome (CAPS), endotoxic shock, endometritis, gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, adult respiratory distress. syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, chronic transplant rejection, hidradenitis suppurativa, inflammatory bowel disease, Crohn's disease, Behçet's syndrome, systemic lupus erythematosus, glomerulonephritis, multiple sclerosis, early-onset diabetes mellitus, autoimmune uveitis, autoimmune vasculitis, thyroiditis, Addison's disease, lichen planus, appendicitis, bullous pemphigus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, myasthenia gravis, immunoglobulin A nephropathy, Hashimoto's disease, Sjögren's syndrome, vitiligo, Wegener's granulomatosis, granulomatous orchitis, autoimmune oophoritis, rheumatic carditis, ankylosing spondylitis, Graves' disease, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, eczema, dermatitis herpetiformis, ulcerative colitis, pancreatic fibrosis, hepatitis, liver fibrosis, CD14 mediated sepsis, non-CD14 mediated sepsis, acute and chronic kidney disease, irritable bowel syndrome, pyresis, restenosis, cervicitis, stroke and ischemic injury, neurotrauma, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndrome, cachexia, malaria, Leprosy, Leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendonitis, tenosynovitis, herniated, ruptured or prolapsed disc syndrome, osteopetrosis, sinusitis, thrombosis, silicosis, pulmonary sarcosis, bone resorption diseases such as osteoporosis, fibromyalgia, AIDS and other viral diseases such as shingles, herpes simplex type I or II, influenza virus and cytomegalovirus, diabetes mellitus type I and II, obesity, insulin resistance and diabetic retinopathy, 22q11.2 deletion syndrome, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, color blindness, cricketing, Down syndrome, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Klinefleter's syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome, urea cycle disorders, thalassemia, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, interstitial pneumonia, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, atherosclerosis, arteriosclerosis, amyotrophic lateral sclerosis, asociality, varicose veins, vaginitis, depression, and sudden infant death syndrome.

[0123] In other embodiments, the method relates to treating a subject with cancer. Broadly, the bispecific compounds of the present invention may be effective in treating carcinomas (solid tumors, including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers affecting the blood, including lymphocytes, bone marrow, and / or lymph nodes), such as leukemia, lymphoma, and multiple myeloma. Adult tumors / cancers and pediatric tumors / cancers are included. Cancers may be vascularized, or may not yet be substantially vascularized, or may be non-vascularized tumors.

[0124] Representative examples of cancer include adrenal cortical carcinoma, AIDS-related cancer (e.g., Kaposi's and AIDS-related lymphoma), appendix cancer, childhood cancer (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, bladder cancer, brain cancer (e.g., glioma and glioblastoma, e.g., brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, etc.), and tumor necrosis factor receptor agonist (TnR) ... cystic cyst, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumor, visual pathway and hypothalamic glioma), breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, nervous system cancer (e.g., central nervous system cancer, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorder, colorectal cancer (e.g., colon cancer, rectal cancer), lymphoid neoplasm, mycosis fungoidesfungoides), Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., gastric cancer, small intestine cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST)), cholangiocarcinoma, germ cell tumors, ovarian germ cell tumors, head and neck cancer, neuroendocrine tumors, Hodgkin's lymphoma, Ann Arbor stage III and stage IV childhood non-Hodgkin's lymphoma, R OS1-positive refractory non-Hodgkin's lymphoma, leukemia, lymphoma, multiple myeloma, hypopharyngeal carcinoma, intraocular melanoma, eye cancer, pancreatic islet cell tumors (endocrine pancreas), kidney cancer (e.g., Wilms' tumor, renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), ALK-positive anaplastic large cell lymphoma, ALK-positive advanced malignant solid neoplasms, Waldenstrom's hypergammaglobulinemia, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, mesothelioma, primary site unknown metastatic squamous cell neck cancer, multiple endocrine neoplasms (MEN), myelodysplastic syndromes, myelodysplastic / myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer (e.g., cancer of the mouth, cancer of the lip, cancer of the oral cavity, cancer of the tongue, cancer of the oropharynx, cancer of the throat, cancer of the larynx), ovarian cancer (e.g., ovarian epithelial carcinoma, ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pheoblastoma, metastatic anaplastic thyroid cancer, undifferentiated thyroid cancer, These include differentiated thyroid carcinoma, papillary thyroid carcinoma, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial carcinoma, uterine sarcoma, endometrial carcinoma), squamous cell carcinoma, testicular cancer, thymoma, thymic carcinoma, thyroid carcinoma, juvenile xanthogranuloma, transitional cell carcinoma of the renal pelvis and ureter and other urinary tracts, urethral carcinoma, gestational trophoblastic neoplasm, vaginal carcinoma, vulvar carcinoma, hepatoblastoma, rhabdoid tumor, and Wilms' tumor.

[0125] Sarcomas that may be treatable with the compounds of the invention include both soft tissue and bone cancers as well, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelioma or mesothelioma (lining the membranes of the body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (fatty tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), mesenchymous or mixed mesodermal tumor (mixed connective tissue type), and histiocytic sarcoma (immune cancer).

[0126] In some embodiments, the methods of the invention involve treatment of subjects with cell proliferative diseases or disorders of the blood system, liver, brain, lung, colon, pancreas, prostate, ovaries, breast, skin and endometrium.

[0127] As used herein, "cell proliferative diseases or disorders of the blood system" includes lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, chronic myelogenous leukemia, primary myelofibrosis and essential thrombocythemia. Thus, representative examples of hematological cancers include multiple myeloma, lymphomas (T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and ALK+ anaplastic large cell lymphoma (e.g. diffuse large B-cell lymphoma (e.g. germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma), Burkitt's lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / Waldenström lymphoma, lymphoplasmacytic lymphoma / Waldenström lymphoma, lymphoplasmocy ... and B-cell non-Hodgkin's lymphoma selected from refractory B-cell non-Hodgkin's lymphoma and relapsed B-cell non-Hodgkin's lymphoma), childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin, including, for example, small lymphocytic lymphoma), childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia, myeloid neoplasms and mast cell neoplasms.

[0128] As used herein, "hepatic cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect the liver.Hepatic cell proliferation disorder can include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma and hepatoblastoma), precancerous or precancerous conditions of the liver, benign growth or lesion of the liver, and malignant growth or lesion of the liver, as well as metastatic lesions in tissues and organs in the body other than the liver.Hepatic cell proliferation disorder can include liver hyperplasia, metaplasia and dysplasia.

[0129] As used herein, "brain cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect the brain.Brain cell proliferation disorder can include brain cancer (e.g., glioma, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma and primitive neuroectodermal tumor (medulloblastoma)), brain precancer or precancerous condition, brain benign growth or lesion, and brain malignant growth or lesion, and metastatic lesion in body tissue and organ other than brain.Brain cell proliferation disorder can include brain hyperplasia, metaplasia and dysplasia.

[0130] As used herein, "pulmonary cell proliferative disease or disorder" includes all forms of cell proliferative disorders that affect lung cells. Pulmonary cell proliferative disorders include lung cancer, pre-cancer and pre-cancerous conditions of the lung, benign lung growths or lesions, lung hyperplasia, metaplasia and dysplasia, and metastatic lesions in tissues and organs of the body other than the lung. Lung cancer includes all forms of lung cancer, such as malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors and atypical carcinoid tumors. Lung cancer includes small cell lung cancer ("SLCL"), non-small cell lung cancer ("NSCLC"), adenocarcinoma, small cell carcinoma, large cell carcinoma, squamous cell carcinoma and mesothelioma. Lung cancer can include "scar carcinoma", bronchioloalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma and large cell neuroendocrine carcinoma. Lung cancer also includes lung neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell types). In some embodiments, the compounds of the invention can be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC with ROS1 rearrangements, lung adenocarcinoma, and squamous cell lung carcinoma).

[0131] As used herein, "cell proliferative diseases or disorders of the colon" includes all forms of cell proliferative disorders affecting colon cells, including colon cancer, precancer or precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. Colon cancer includes sporadic and hereditary colon cancer, malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colon cancer may be associated with genetic syndromes such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MYH-associated polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis. Cell proliferative disorders of the colon may also be characterized by colonic hyperplasia, metaplasia, or dysplasia.

[0132] As used herein, "pancreatic cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect pancreatic cells.Pancreatic cell proliferation disorder can include pancreatic cancer, pancreatic precancer or precancerous condition, pancreatic hyperplasia, pancreatic dysplasia, pancreatic benign growth or lesion, and pancreatic malignant growth or lesion, as well as metastatic lesion in body tissues and organs other than pancreas.Pancreatic cancer includes all forms of cancer of pancreas, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatic blastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, serous cystadenoma, and pancreatic neoplasm with histological and ultrastructural heterogeneity (e.g., mixed cell type).

[0133] As used herein, "prostate cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect the prostate.Prostate cell proliferation disorder can include prostate cancer, prostate pre-cancer or pre-cancerous condition, benign prostate growth or lesion, and malignant prostate growth or lesion, as well as metastatic lesion in body tissues and organs other than the prostate.Prostate cell proliferation disorder can include prostate hyperplasia, metaplasia, and dysplasia.

[0134] As used herein, "cell proliferative disease or disorder of the ovary" includes all forms of cell proliferative disorders that affect cells of the ovary. Cell proliferative disorders of the ovary may include precancer or precancerous conditions of the ovary, benign growths or lesions of the ovary, ovarian cancer, and metastatic lesions in tissues and organs of the body other than the ovary. Cell proliferative disorders of the ovary may include ovarian hyperplasia, metaplasia, and dysplasia.

[0135] As used herein, "cell proliferative disease or disorder of the breast" includes all forms of cell proliferative disorders that affect breast cells. Cell proliferative disorders of the breast can include breast cancer, precancer or precancerous conditions of the ovary, benign growths or lesions of the breast, and metastatic lesions in tissues and organs of the body other than the breast. Cell proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

[0136] As used herein, "cell proliferative disease or disorder of the skin" includes all forms of cell proliferative disorders that affect skin cells. Cell proliferative disorders of the skin may include precancerous or precancerous conditions of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma or other malignant growths or lesions of the skin, and metastatic lesions in tissues and organs of the body other than the skin. Cell proliferative disorders of the skin may include hyperplasia, metaplasia, and dysplasia of the skin.

[0137] As used herein, "endometrial cell proliferative disease or disorder" includes all forms of cell proliferative disorder that affect endometrial cells.Endometrial cell proliferative disorder can include endometrial precancer or precancerous conditions, endometrial benign proliferation or lesions, endometrial cancer, and metastatic lesions in body tissues and organs other than endometrium.Endometrial cell proliferative disorder can include endometrial hyperplasia, metaplasia, and dysplasia.

[0138] In some embodiments, the disease or disorder is high-risk neuroblastoma (NB).

[0139] In some embodiments, the disease or disorder is acute myeloid leukemia (AML), multiple myeloma (MM), melanoma, rhabdomyosarcoma, or diffuse large B-cell lymphoma. In other embodiments, the disease or disorder is small solid tumor. In other embodiments, the disease or disorder is colon cancer, rectal cancer, gastric cancer, breast cancer, or pancreatic cancer.

[0140] The bispecific compounds of formula (I) or (II) may be administered to patients, e.g., cancer patients, as monotherapy or in combination therapy. The treatment may be performed as "first-line / primary", i.e., as an initial treatment in patients who have not previously received an anti-cancer treatment regimen, alone or in combination with other treatments; or as "second-line", "quaternary", etc., treatment, alone or in combination with other treatments. The treatment may also be performed to patients who have received previous treatments that were unsuccessful or partially successful, but who have become unresponsive or intolerant to the treatment. The treatment may also be given as adjuvant treatment, i.e., to prevent recurrence of cancer in patients who currently have no detectable disease or after surgical removal of a tumor. Thus, in some embodiments, the compounds may be administered to patients who have received another treatment, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy, or any combination thereof.

[0141] The method of the present invention may include administration of a bispecific compound of formula (I) or a pharmaceutical composition thereof to a patient in a single dose or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the frequency of administration may range from once a day to about once every 8 weeks. In some embodiments, the frequency of administration ranges from about once a day for 1, 2, 3, 4, 5 or 6 weeks, and in other embodiments, includes at least one 28-day cycle including daily administration for 3 weeks (21 days) followed by a 7-day "off" period. In other embodiments, the bispecific compound may be administered twice a day (BID) for 2 1 / 2 days (a total of 5 doses) or once a day (QD) for 2 days (a total of 2 doses). In other embodiments, the bispecific compound may be administered once a day (QD) for 5 days.

[0142] Combination therapy The bispecific compounds of formula (I) or (II) may be used in combination or simultaneously with at least one other active agent, such as an anti-cancer agent or regimen, in treating diseases and disorders. The terms "in combination" and "simultaneously" in this context mean that the agents are administered simultaneously, including substantially simultaneous administration by the same or separate dosage forms and by the same or different modes of administration, or sequential administration, such as as part of the same treatment regimen or by a continuous treatment regimen. Thus, when given sequentially, at the start of administration of the second compound, the first of the two compounds may still be detectable at effective concentrations at the site of treatment, in some cases. The order and time intervals may be determined so that the compounds can act together (e.g., synergistically to provide increased benefits over when the compounds are otherwise administered). For example, the therapeutic agents may be administered simultaneously or sequentially at different times in any order, but when not administered simultaneously, the therapeutic agents may be administered close enough in time to provide the desired therapeutic effect, which may be in a synergistic manner. Thus, these terms are not limited to administering the active agents exactly at the same time.

[0143] In some embodiments, the treatment regimen may include administration of the bispecific compound of formula (I) or (II) in combination with one or more additional therapeutic agents known for use in treating a disease or condition (e.g., cancer). The dosage of the additional anti-cancer therapeutic agent may be the same as or lower than the known or recommended dose. See Hardman et al., eds., Goodman&Gilman's The Pharmacological Basis Of Basis Of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference 60th ed., 2006. For example, anti-cancer agents that may be suitable for use in combination with the bispecific compounds of the present invention are known in the art. See, for example, U.S. Pat. No. 9,101,622 (section 5.2 thereof) and U.S. Pat. No. 9,345,705 B2 (columns 12-18 thereof). Representative examples of additional active agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., antimitotic agents, angiogenesis inhibitors, antihormonal agents, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, antiandrogen agents, signal transduction pathway inhibitors, antimicrotubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulatory agents, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and chimeric antigen receptor T cell (CAR-T) therapy.

[0144] In some embodiments, a bispecific compound of Formula (I) or (II) and an additional anticancer therapeutic agent may be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 to about 3 hours apart, about 3 to about 4 hours apart, about 4 to about 5 hours apart, about 5 to about 6 hours apart, about 6 to about 7 hours apart, about 7 to about 8 hours apart, about 8 to about 9 hours apart, about 9 to about 10 hours apart, about 10 to about 11 hours apart, about 11 to about 12 hours apart, about 12 to 18 hours apart, 18 to 24 hours apart, 24 to 36 hours apart, 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours apart, 84 to 96 hours apart, or 96 to 120 hours apart. Two or more anti-cancer therapeutics may be administered within the same patient visit.

[0145] In some embodiments involving cancer treatment, the bispecific compound of formula (I) or (II) and the additional anti-cancer or therapeutic agent are administered cyclically. Cycle therapy includes administering one anti-cancer therapeutic agent for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time, and repeating this sequential administration, i.e., cycle, to reduce the occurrence of resistance to one or both of the anti-cancer therapeutic agents, to avoid or reduce the side effects of one or both of the anti-cancer therapeutic agents, and / or to improve the efficacy of the treatment. In one example, cycle therapy includes administering a first anti-cancer therapeutic agent for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time, followed by administering a third anti-cancer therapeutic agent for a period of time, and so on, to reduce the occurrence of resistance to one of the anti-cancer therapeutic agents, to avoid or reduce the side effects of one of the anti-cancer therapeutic agents, and / or to improve the efficacy of the anti-cancer therapeutic agents.

[0146] In some embodiments, the bispecific compounds of the invention can be used in combination with other anti-NB or anti-cancer agents, examples of which include dinutuximab (Unituxin®) (e.g., for NB), cyclophosphamide (e.g., for NB), busulfan + melphalan hydrochloride, carboplatin + etoposide phosphate and melphalan hydrochloride, doxorubicin hydrochloride, vincristine sulfate, entrectinib (e.g., for brain cancer, central nervous system (CNS) cancer), Hu3F8+ donated natural killer cells (e.g., for persistent or recurrent NB), Hu3F8+ granulocyte-macrophage colony-stimulating factor (GM-CSF) (e.g., for relapsed / refractory NB, Hu These include 3F8 / GM-CSF immunotherapy plus isotretinoin (e.g., for consolidation of first remission in patients with NB), venetoclax® (e.g., for persistent or recurrent cancers including NB, leukemia and non-Hodgkin's lymphoma), oral beta-glucan (e.g., for NB), trametinib (e.g., for germ cell tumors, liver cancer, kidney cancer, NB, pediatric brain tumors, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, soft tissue sarcoma, Wilms' tumor), cobimetinib (e.g., for melanoma, pediatric brain tumors and soft tissue sarcomas), and bivalent vaccines with immune adjuvant OPT-821 in combination with intrathecal radioimmunotherapy with 131I-8H9 (e.g., for primary brain tumors, brain cancer, NB and CNS cancers).

[0147] Pharmaceutical Kits The compositions of the present invention can be assembled into kits or pharmaceutical systems. The kits or pharmaceutical systems according to this aspect of the present invention include a carrier or package such as a box, carton, tube, etc., in which is secured one or more containers, such as vials, tubes, ampoules, or bottles, containing the bispecific compounds of formula (I) or (II) or pharmaceutical compositions thereof. The kits or pharmaceutical systems of the present invention can also include printed instructions for using the compounds and compositions.

[0148] These and other aspects of the present invention will be further understood upon consideration of the following examples, which are intended to illustrate certain embodiments of the invention and are not intended to limit the scope of the invention as defined by the claims. EXAMPLES

[0149] Example 1: Synthesis of 5-((12-(4-(4-(3-(cyclohexylamino)-6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-12-oxododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1) [ka] Scheme 1. Synthesis of intermediate 1 (Int-1). [ka]

[0150] A mixture of SM-1 (300 mg, 1.73 mmol), SM-2 (425 mg, 1.9 mmol), BrettPhos Pd G3 catalyst (78 mg, 0.086 mmol) and K2CO3 (478 mg, 3.46 mmol) in 4:1 dioxane / HO (5 mL) was stirred at 100 °C under N2 atmosphere in a 25 mL flask for 16 hours (h). After the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by ISCO chromatography (regular 12 g column, DCM / MeOH=20 / 1) to give Int-a (130 mg, 40% yield).

[0151] C 10 H 11 MS(ESI) calculated for N3O: 189.09, found: 190.58, 191.19. [ka]

[0152] A mixture of Int-a (77 mg, 0.407 mmol), SM-3 (48 mg, 0.407 mmol), SM-4 (118 mg, 0.407 mmol) and Sc(OTf)3 (20 mg, 0.0407 mmol) in DMSO (2 mL) in a 10 mL flask was stirred at 100 °C for 16 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by ISCO chromatography (regular 4 g column, ethyl acetate / hexane = 5 / 1) to give Int-b (83 mg, 35% yield). [ka]

[0153] To Int-b (83 mg, 0.14 mmol) in a 10 mL flask was added HCl / dioxane (2 mL, 4 M) at 0° C. The resulting mixture was warmed to 25° C. and stirred for 8 h. After the reaction was completed, the mixture was filtered. The resulting filter cake was washed with ethyl acetate (2 mL×3 times) and then dried under reduced pressure to give compound Int-b (70 mg, nearly quantitative yield).

[0154] 1 H NMR(500 MHz,DMSO-d6)δ 9.37(s,2H),8.71(d,J=7.0 Hz,1H),7.96(d,J=8.9 Hz,2H),7.83(d,J=1.4 Hz,1H),7.51(dd,J=7.0,1.7 Hz,1H),7.33-7.23(m,5H),7.21-7.16(m,2H),4.17(s,2H),3.56(t,J=5.3 Hz,4H),3.23(q,J=5.0 Hz,4H),2.54(s,3H),2.34(s,3H).

[0155] C 29 H 30 MS(ESI) calculated for NO: 478.25, found: 261.07, 479.26. [ka]

[0156] Intermediate 2 (Int-2) was prepared in a similar manner to compound Int-1 in Scheme 1 as a yellow powder (51 mg, quantitative yield).

[0157] 1 H NMR(500 MHz,DMSO-d6)δ 9.12(s,2H),8.74(d,J=5.0 Hz,1H),8.04(d,J=8.3 Hz,2H),7.95(dd,J=11.3,7.4 Hz,2H),7.22-7.19(m,2H),5.35(s,1H),3.54(t,J=5.2 Hz,4H),3.25(s,4H),2.89(s,1H),2.50(s,3H),2.31(s,4H),1.80(d,J=12.3 Hz,2H),1.66-1.62(m,2H),1.29(d,J=11.3 Hz,2H),1.10-1.07(m,2H).

[0158] C 28 H 34 MS(ESI) calculated for NO: 470.28, found: 256.81 and 471.31. [ka]

[0159] Intermediate 3 (Int-3) was prepared in a similar manner to compound Int-1 in Scheme 1 as a yellow powder (492 mg, quantitative yield).

[0160] H NMR(500 MHz,acetone-d6)δ 8.41(d,J=7.1 Hz,1H),7.82(s,1H),7.21(d,J=8.2 Hz,2H),7.12(d,J=7.3 Hz,1H),6.60(d,J=8.3 Hz,2H),3.11(q,J=3.3 Hz,4H),2.91(m,1H),2.54(s,3H),2.36(s,3H),1.93-1.87(m,2H),1.77-1.72(m,2H),1.36-1.19(m,6H). [ka]

[0161] Intermediates Int-4, Int-5, Int-6 and Int-7 were prepared according to Hay et al., J. Am. Chem. Soc. 136:9308-9319 (2014) and WO 2018 / 073586. [ka]

[0162] Intermediate Int-8 was prepared according to Taylor et al., ACS Med Chem Lett. 7:531-536 (2016). [ka] Scheme 2. Synthesis of compound 1. [ka]

[0163] In a 10 mL flask, a mixture of Int-2 (1 eq.) and immunomodulatory imide drug (IMiD) acid 1 (1 eq.) in DMF was treated with N,N-diisopropylethylamine (DIPEA) (2 eq.) and 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (2 equiv.) was added. The reaction was stirred at 25 °C until completion (5-16 h). After the reaction was complete, the mixture was purified through preparative HPLC to give compound 1 as a pale yellow powder (3.8 mg, 21% yield).

[0164] C 53 H 65 MS(ESI) calculated for N9O6: 923.51, found: 463.18, 924.93 and 925.92.

[0165] Example 2: Synthesis of 4-((2-(2-(2-(3-(4-(4-(3-(cyclohexylamino)-6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2) [ka]

[0166] Compound 2 was prepared in a similar manner to compound 1 in Example 1 using Int-2 and the appropriate IMiD acid as a yellow powder (5.5 mg, 30% yield).

[0167] 1 H NMR(500 MHz,DMSO-d6)δ 11.10(s,1H),8.69(s,1H),7.98-7.88(m,4H),7.61-7.53(m,1H),7.14(t,J=8.3 Hz,3H),7.03(d,J=7.0 Hz,1H),6.59(t,J=5.9 Hz,1H),5.26(s,1H),5.06(dd,J=12.7,5.4 Hz,1H),3.68-3.51(m,24H),2.88(ddd,J=16.9,13.5,5.4 Hz,2H),2.64-2.53(m,4H),2.50(s,3H),2.31(s,3H),2.06-1.99(m,1H),1.79(d,J=12.1 Hz,2H),1.67-1.59(m,2H),1.28(dd,J=11.8,3.9 Hz,2H),1.09(d,J=7.9 Hz,2H).

[0168] C 50 H 59 MS(ESI) calculated for N9O9: 929.44, found: 465.87, 466.52, 930.90 and 931.85.

[0169] Example 3 Synthesis of 4-((21-(4-(4-(3-(cyclohexylamino)-6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-21-oxo-3,6,9,12,15,18-hexaoxahenicosyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3) [ka]

[0170] Compound 3 was prepared in a similar manner to compound 1 in Example 1 using Int-2 and the appropriate IMiD acid as a yellow powder (4.7 mg, 45% yield).

[0171] C 56 H 71 N9O 12 MS(ESI) calculated for: 1061.52, found: 531.77, 532.80, 1063.00 and 1063.95.

[0172] Example 4: Synthesis of N-(2-(2-(2-(3-(4-(4-(3-(cyclohexylamino)-6-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (4) [ka]

[0173] Compound 4 was prepared in a similar manner to compound 1 in Example 1 using Int-2 and the appropriate IMiD acid as a yellow powder (3.7 mg, 38% yield).

[0174] C 52 H 61 N9O 11MS(ESI) calculated for: 987.45, found: 495.18, 988.85 and 989.80.

[0175] Example 5 Synthesis of 4-((21-(4-(4-(3-(benzylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-21-oxo-3,6,9,12,15,18-hexaoxahenicosyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5) [ka]

[0176] Compound 5 was prepared as a yellow powder (3.9 mg, 37% yield) in a similar manner to compound 1 in Example 1 using Int-1 and the appropriate IMiD acid.

[0177] 1 H NMR(500 MHz,DMSO-d6)δ 11.09(s,1H),8.65(d,J=7.1 Hz,1H),7.86(d,J=8.7 Hz,2H),7.76(s,1H),7.60-7.56(m,1H),7.50(d,J=7.0 Hz,1H),7.35-7.22(m,5H),7.14(dd,J=8.8,3.2 Hz,3H),7.04(d,J=7.0 Hz,1H),6.60(s,1H),5.91(s,1H),5.05(dd,J=12.8,5.4 Hz,1H),4.16(d,J=3.2 Hz,2H),3.68-3.59(m,10H),3.57-3.49(m,21H),3.35-3.26(m,6H),2.88(ddd,J=16.9,13.8,5.4 Hz,1H),2.65(d,J=6.5 Hz,4H),2.54(s,3H),2.34(s,3H),2.05-1.99(m,1H).

[0178] C 57 H 67 N9O 12MS(ESI) calculated for: 1069.49, found: 536.10, 1070.94 and 1071.89.

[0179] Example 6: Synthesis of 4-((2-(2-(2-(3-(4-(4-(3-(benzylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (6) [ka]

[0180] Compound 6 was prepared as a yellow powder (6.9 mg, 72% yield) in a similar manner to compound 1 in Example 1 using Int-1 and the appropriate IMiD acid.

[0181] 1 H NMR(500 MHz,DMSO-d6)δ 11.10(s,1H),8.65(d,J=7.1 Hz,1H),7.86(d,J=8.7 Hz,2H),7.78(s,1H),7.60-7.54(m,1H),7.51(d,J=6.9 Hz,1H),7.35-7.23(m,5H),7.13(dd,J=8.7,5.4 Hz,3H),7.03(d,J=7.1 Hz,1H),6.59(s,1H),5.92(s,1H),5.05(dd,J=12.7,5.5 Hz,1H),4.16(s,2H),3.48-3.25(m,22H),2.88(ddd,J=16.9,13.8,5.4 Hz,1H),2.66-2.55(m,4H),2.54(s,3H),2.35(s,3H),2.02(ddd,J=12.8,5.8,3.0 Hz,1H).

[0182] C 53 H 59 N9O 10 MS(ESI) calculated for: 937.41, found: 469.79, 470.51, 938.80 and 939.75.

[0183] Example 7: Synthesis of 4-(2-(4-(4-(3-(benzylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)phenyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (7) [ka]

[0184] Compound 7 was prepared as a yellow powder (4.9 mg, 63% yield) in a similar manner to compound 1 in Example 1 using Int-1 and the appropriate IMiD acid.

[0185] C 44 H 40 MS(ESI) calculated for N8O7: 792.30, found: 793.64, 794.59.

[0186] Example 8: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide (8) [ka]

[0187] Compound 8 was prepared in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid as a yellow powder (12 mg, 73% yield).

[0188] 1H NMR(500 MHz,acetone-d6)δ 10.16(s,1H),9.11(s,1H),8.50(d,J=7.0 Hz,1H),7.67(s,1H),7.61-7.50(m,4H),7.24-7.19(m,1H),7.16(d,J=8.1 Hz,2H),7.11(d,J=8.5 Hz,1H),7.04(d,J=7.0 Hz,1H),6.60(t,J=5.7 Hz,1H),5.09(dd,J=12.6,5.4 Hz,1H),3.79(t,J=6.0 Hz,2H),3.72(t,J=5.4 Hz,3H),3.63(d,J=4.2 Hz,8H),3.52-3.49(m,2H),3.15(dd,J=8.7,6.3 Hz,2H),3.07(t,J=7.6 Hz,2H),2.99-2.93(m,1H),2.87(q,J=4.7,4.1 Hz,1H),2.80-2.75(m,2H),2.57(t,J=6.0 Hz,2H),2.52(s,3H),2.33(s,3H),2.22(dddd,J=10.2,7.5,5.4,2.5 Hz,1H),1.87(d,J=11.8 Hz,2H),1.74-1.69(m,2H),1.35-1.21(m,6H).

[0189] Example 9: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecanamide (9) [ka]

[0190] Compound 9 was prepared in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid as a yellow powder (15 mg, 92% yield).

[0191] 1H NMR(500 MHz,acetone-d6)δ 10.15(s,1H),9.05(s,1H),8.22(dd,J=7.0,1.0 Hz,1H),7.62-7.56(m,3H),7.40(t,J=1.3 Hz,1H),7.15(d,J=8.5 Hz,2H),7.09(d,J=8.5 Hz,1H),7.04(d,J=7.0 Hz,1H),6.85(dd,J=7.0,1.8 Hz,1H),6.42(t,J=5.8 Hz,1H),5.08(dd,J=12.6,5.4 Hz,1H),3.38(ddd,J=7.0,3.0,1.3 Hz,2H),3.08-3.00(m,4H),2.99-2.93(m,2H),2.89(s,3H),2.83-2.74(m,4H),2.49(s,3H),2.32(s,3H),2.22(dddd,J=10.3,5.3,3.2,1.5 Hz,1H),2.16(t,J=7.5 Hz,1H),1.86-1.78(m,2H),1.70(td,J=10.5,8.7,5.6 Hz,6H),1.62-1.54(m,2H),1.46-1.43(m,2H),1.33(s,12H).

[0192] C 51 H 62 MS(ESI) calculated for N8O6: 882.48, found: 883.39[M+1], 884.37, 884.94.

[0193] Example 10: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-12-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide)dodecanamide (10) [ka]

[0194] Compound 10 was prepared as a white powder (16 mg, 81% yield) in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid.

[0195] C 53 H 64 MS(ESI) calculated for N8O8: 940.48, found: 941.75[M+1], 942.70.

[0196] Example 11: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide (11) [ka]

[0197] Compound 11 was prepared in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid as a yellow powder (14 mg, 94% yield).

[0198] 1H NMR(500 MHz,acetone-d6)δ 9.92(s,1H),9.09(s,1H),8.72(dd,J=7.2,1.0 Hz,1H),7.91(dd,J=1.7,0.9 Hz,1H),7.58(ddd,J=8.6,4.5,2.8 Hz,3H),7.52(dd,J=7.1,1.7 Hz,1H),7.22-7.15(m,2H),7.10(d,J=8.5 Hz,1H),7.03(d,J=7.0 Hz,1H),6.43(t,J=5.9 Hz,1H),5.08(dd,J=12.6,5.4 Hz,1H),3.43-3.38(m,2H),3.27(dd,J=8.3,7.0 Hz,2H),3.13(dd,J=8.5,6.8 Hz,2H),3.02-2.93(m,1H),2.92-2.85(m,1H),2.83-2.73(m,2H),2.55(s,3H),2.40(t,J=7.4 Hz,2H),2.35(s,3H),2.25-2.17(m,1H),1.93-1.86(m,2H),1.74(ddd,J=20.5,11.6,6.7 Hz,6H),1.51(q,J=6.7 Hz,4H),1.31(dd,J=10.8,3.1 Hz,2H),1.23-1.17(m,2H).

[0199] C 45 H 50 MS(ESI) calculated for N8O6: 798.39, found: 799.29[M+1], 800.28, 800.85.

[0200] Example 12: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (12) [ka]

[0201] Compound 12 was prepared as a pale yellow powder (16 mg, 90% yield) in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid.

[0202] 9%).

[0203] 1 H NMR(500 MHz, acetone-d6)δ 9.99(s,1H),9.53(s,1H),8.75-8.72(m,1H),8.42(dd,J=8.4,1.4 Hz,1H),7.97-7.89(m,2H),7.74-7.67(m,2H),7.60(dd,J=16.7,7.9 Hz,2H),7.56-7.45(m,2H),7.27(d,J=8.2 Hz,2H),5.21(dd,J=12.5,5.4 Hz,1H),4.95(s,2H),3.30(t,J=7.6 Hz,2H),3.17(t,J=7.6 Hz,2H),3.02(dd,J=5.3,3.3 Hz,1H),2.87-2.77(m,2H),2.56(s,3H),2.36(s,3H),2.30(ddd,J=10.4,6.8,4.3 Hz,1H),1.91(dd,J=12.8,3.8 Hz,2H),1.72(dt,J=13.4,3.2 Hz,2H),1.50(t,J=6.3 Hz,3H),1.36-1.29(m,2H),1.22(ddd,J=12.0,8.9,2.6 Hz,2H).

[0204] C 41 H 41 MS (ESI) calculated for N7O7: 743.31, found: 744.27 [M+1], 744.80, 745.52.

[0205] Example 13: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanamide (13) [ka]

[0206] Compound 13 was prepared in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid as a yellow powder (20 mg, 99% yield).

[0207] C 47 H 54 MS(ESI) calculated for N8O6: 826.42, found: 827.68[M+1], 828.63.

[0208] Example 14: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanamide (14) [ka]

[0209] Compound 14 was prepared in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid as a yellow powder (20 mg, 99% yield).

[0210] 1H NMR(500 MHz,acetone-d6)δ 9.97(s,1H),9.09(s,1H),8.64(dd,J=7.1,0.9 Hz,1H),7.83(t,J=1.3 Hz,1H),7.56(dd,J=8.4,5.9 Hz,3H),7.42-7.39(m,1H),7.20-7.15(m,2H),7.01(d,J=2.2 Hz,1H),6.92(dd,J=8.4,2.2 Hz,1H),6.34(t,J=5.5 Hz,1H),5.06(dd,J=12.6,5.4 Hz,1H),3.34-3.28(m,2H),3.23(dd,J=8.3,6.5 Hz,2H),3.11(dd,J=8.6,6.7 Hz,2H),3.02-2.92(m,1H),2.83-2.74(m,2H),2.54(s,3H),2.39(t,J=7.3 Hz,2H),2.34(s,3H),2.18(dddd,J=12.7,7.6,5.5,2.5 Hz,1H),1.91-1.84(m,2H),1.73(dq,J=10.4,6.9,6.4 Hz,6H),1.55-1.49(m,2H),1.32-1.26(m,5H),1.21-1.15(m,2H).

[0211] C 45 H 50 MS(ESI) calculated for N8O6: 798.39, found: 799.63[M+1], 800.62.

[0212] Example 15: Synthesis of N1-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-N4-((R)-13-((2R,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)succinamide (15) [ka]

[0213] Compound 15 was prepared in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid as a yellow powder (2.64 mg, 18% yield).

[0214] 1 H NMR(500 MHz,acetone-d6)δ 9.49(s,1H),8.85(s,1H),8.55(dd,J=4.4,1.4 Hz,1H),8.32-8.26(m,2H),7.69(d,J=8.3 Hz,2H),7.57(dd,J=12.1,3.7 Hz,2H),7.49(d,J=8.2 Hz,2H),7.43-7.41(m,2H),7.36(dd,J=8.4,4.4 Hz,2H),6.94-6.87(m,1H),4.75-4.68(m,2H),4.61-4.55(m,2H),4.38(dd,J=15.4,5.1 Hz,1H),4.03(d,J=3.8 Hz,2H),3.88(d,J=10.7 Hz,1H),3.81(dd,J=10.8,4.1 Hz,1H),3.73-3.67(m,4H),3.65-3.60(m,4H),3.54-3.50(m,2H),3.35(t,J=5.0 Hz,2H),3.16(q,J=7.3 Hz,2H),2.68-2.65(m,2H),2.58(dd,J=6.5,2.1 Hz,2H),2.53(s,3H),2.48(s,3H),2.35(s,3H),1.78(d,J=10.3 Hz,2H),1.62(d,J=11.3 Hz,2H),1.35-1.28(m,10H),1.04(s,9H).

[0215] C 60 H 78 N 10 O 10 MS(ESI) calculated for S: 1130.56, found: 1129.82, 1130.81[M+1].

[0216] Example 16: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15,18-hexaoxahenicosan-21-amide (16) [ka]

[0217] Compound 16 was prepared in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid as a yellow powder (10 mg, 85% yield).

[0218] 1 H NMR(500 MHz,acetone-d6)δ 9.15(s,1H),8.35(dd,J=7.0,0.9 Hz,1H),7.61-7.56(m,3H),7.54-7.51(m,1H),7.21-7.17(m,2H),7.13(d,J=8.5 Hz,1H),7.07(dd,J=12.4,7.8 Hz,2H),7.02(dd,J=7.0,1.8 Hz,1H),6.62(t,J=5.7 Hz,1H),5.09(dd,J=12.7,5.5 Hz,1H),3.80(t,J=5.9 Hz,2H),3.76(t,J=5.3 Hz,2H),3.67-3.55(m,28H),2.99-2.93(m,2H),2.80(d,J=4.4 Hz,2H),2.61(t,J=5.9 Hz,2H),2.51(s,3H),2.33(s,3H),2.25-2.20(m,1H),1.87-1.83(m,2H),1.74-1.70(m,2H),1.51(d,J=6.6 Hz,4H).

[0219] C 54 H 68 N8O 12 MS(ESI) calculated for: 1020.50, found: 1021.90[M+1], 1022.85.

[0220] Example 17: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carboxamide (17) [ka]

[0221] Compound 17 was prepared in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid as a yellow powder (7.2 mg, 64% yield).

[0222] Example 18: Synthesis of N-(4-(2-(3-(cyclohexylamino)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2-a]pyridin-2-yl)ethyl)phenyl)-4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzamide (18) [ka]

[0223] Compound 18 was prepared as a yellow powder (4.2 mg, 32% yield) in a similar manner to compound 1 in Example 1 using Int-3 and the appropriate IMiD acid.

[0224] 1H NMR(500 MHz,acetone-d6)δ 9.99(s,1H),9.46(s,1H),8.25(dd,J=7.0,1.0 Hz,1H),7.99-7.94(m,2H),7.77-7.72(m,2H),7.60-7.51(m,3H),7.41(dd,J=1.7,1.0 Hz,1H),7.25-7.21(m,2H),7.10(dd,J=14.2,6.7 Hz,2H),7.02(d,J=8.5 Hz,1H),6.88(dd,J=7.0,1.7 Hz,1H),5.11(dd,J=12.6,5.4 Hz,1H),4.77(d,J=5.8 Hz,2H),3.08(ddd,J=15.1,6.3,2.4 Hz,4H),2.85-2.76(m,4H),2.50(s,3H),2.33(s,3H),2.28-2.20(m,1H),1.87-1.83(m,2H),1.75-1.67(m,2H),1.33-1.21(m,6H).

[0225] C 47 H 46 MS(ESI) calculated for N8O6: 818.35, found: 819.66[M+1], 820.61.

[0226] Example 19: Synthesis of 5-((2-(2-(2-(3-(4-((S)-1-(2-(3-chloro-4-methoxyphenethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)propan-2-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (19) [ka]

[0227] Compound 19 was prepared in a similar manner to compound 1 in Example 1 using Int-4 and the appropriate IMiD acid as a yellow powder (5 mg, 33% yield).

[0228] 1H NMR(500 MHz,acetone-d6)δ 10.03(s,1H),7.61-7.54(m,3H),7.41(d,J=2.2 Hz,1H),7.27(dd,J=8.4,2.2 Hz,1H),7.19(dd,J=8.3,1.7 Hz,1H),7.13(d,J=8.6 Hz,1H),7.04(t,J=7.5 Hz,2H),6.63(t,J=5.6 Hz,1H),5.08(dd,J=12.7,5.4 Hz,1H),4.36(dd,J=14.9,7.6 Hz,1H),4.10(dd,J=14.9,6.2 Hz,1H),3.87(s,3H),3.74(d,J=5.3 Hz,2H),3.69(t,J=6.7 Hz,2H),3.66-3.60(m,4H),3.57-3.52(m,4H),3.41(s,4H),3.27(t,J=3.5 Hz,4H),3.14(q,J=6.9 Hz,1H),3.01-2.94(m,2H),2.80(dd,J=4.3,1.7 Hz,2H),2.77-2.75(m,2H),2.54(t,J=6.7 Hz,2H),2.43(s,3H),2.39(d,J=5.7 Hz,1H),2.27(s,3H),2.21(ddd,J=9.4,4.7,2.6 Hz,1H),1.30(d,J=1.8 Hz,2H),1.04(d,J=6.8 Hz,3H).

[0229] C 50 H 59 ClNO 10 MS(ESI) calculated for: 966.40, found: 967.33[M+1], 969.61, 970.41.

[0230] Example 20: Synthesis of 5-((10-(4-((S)-1-(2-(3-chloro-4-methoxyphenethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)propan-2-yl)piperazin-1-yl)-10-oxodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20) [ka]

[0231] Compound 20 was prepared in a similar manner to compound 1 in Example 1 using Int-4 and the appropriate IMiD acid as a yellow powder (14 mg, 96% yield).

[0232] C 51 H 61 MS (ESI) calculated for ClN8O7: 932.44, found: 933.55 [M+1], 935.52.

[0233] Example 21: Synthesis of 5-((6-(4-((S)-1-(2-(3-chloro-4-methoxyphenethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)propan-2-yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21) [ka]

[0234] Compound 21 was prepared in a similar manner to compound 1 in Example 1 using Int-4 and the appropriate IMiD acid as a yellow powder (11 mg, 80% yield).

[0235] 1H NMR(500 MHz,acetone-d6)δ 10.01(s,1H),7.59(ddd,J=4.3,2.1,1.2 Hz,2H),7.57-7.54(m,1H),7.41(d,J=2.1 Hz,1H),7.27(dd,J=8.4,2.3 Hz,1H),7.19(dd,J=8.3,1.7 Hz,1H),7.10(d,J=8.5 Hz,1H),7.05-7.01(m,2H),6.42(t,J=5.9 Hz,1H),5.08(dd,J=12.6,5.4 Hz,1H),4.36(dd,J=14.9,7.6 Hz,1H),4.11(dd,J=14.9,6.1 Hz,1H),3.87(s,3H),3.45(d,J=6.3 Hz,1H),3.40-3.37(m,4H),3.29-3.24(m,4H),3.15-3.12(m,1H),3.01-2.9 2(m,2H),2.83-2.78(m,2H),2.77-2.67(m,4H),2.43(s,3H),2.34(t,J=7.4 Hz,2H),2.26(s,3H),2.24-2.19(m,1H),1.75-1.69(m,2H),1.66-1.61(m,2H),1.48(td,J=8.4,4.2 Hz,2H),1.04(d,J=6.8 Hz,3H).

[0236] C 47 H 53 MS (ESI) calculated for ClN8O7: 876.37, found: 877.46 [M+1], 878.37, 879.43.

[0237] Example 22: Synthesis of N-(4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazol-2-yl)ethyl)phenyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide (22) [ka]

[0238] Compound 22 was prepared in a similar manner to compound 1 in Example 1 using Int-5 and the appropriate IMiD acid as a yellow powder (3.7 mg, 23% yield).

[0239] 1 H NMR(500 MHz,acetone-d6)δ 10.09(s,1H),9.08(s,1H),7.62-7.57(m,5H),7.26(d,J=8.5 Hz,2H),7.20(dd,J=8.2,1.6 Hz,1H),7.11(d,J=8.5 Hz,1H),7.04(d,J=7.0 Hz,1H),6.61(t,J=5.5 Hz,1H),5.08(dd,J=12.6,5.5 Hz,1H),4.34(t,J=6.5 Hz,2H),3.79(t,J=6.0 Hz,2H),3.72(t,J=5.2 Hz,2H),3.63(h,J=2.1 Hz,8H),3.57(t,J=4.6 Hz,4H),3.52-3.49(m,2H),3.30-3.23(m,4H),2.97-2.94(m,2H),2.80-2.77(m,2H),2.68(t,J=6.5 Hz,2H),2.57(t,J=6.0 Hz,2H),2.48(s,2H),2.43(s,3H),2.26(s,3H),2.24-2.20(m,1H).

[0240] C 48 H 56 N8O 10 MS(ESI) calculated for: 904.41, found: 905.65[M+1], 906.60.

[0241] Example 23: Synthesis of N-(4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazol-2-yl)ethyl)phenyl)-12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecanamide (23) [ka]

[0242] Compound 23 was prepared in a similar manner to compound 1 in Example 1 using Int-5 and the appropriate IMiD acid as a yellow powder (3.2 mg, 34% yield).

[0243] 1 H NMR(500 MHz,acetone-d6)δ 9.96(s,1H),9.03(s,1H),7.62-7.57(m,5H),7.28-7.24(m,2H),7.21(dd,J=8.2,1.6 Hz,1H),7.10(d,J=8.5 Hz,1H),7.04(d,J=7.1 Hz,1H),6.43(t,J=5.7 Hz,1H),5.08(dd,J=12.6,5.4 Hz,1H),4.37(t,J=6.4 Hz,2H),4.03(p,J=6.6 Hz,2H),3.58(t,J=4.6 Hz,4H),3.51(q,J=7.3 Hz,2H),3.41-3.37(m,2H),3.33-3.28(m,2H),3.27-3.23(m,2H),2.99-2.95(m,2H),2.80-2.76(m,2H),2.70(t,J=6.4 Hz,2H),2.43(s,3H),2.35(t,J=7.4 Hz,2H),2.26(s,3H),2.22(ddt,J=13.0,5.6,2.8 Hz,1H),1.70(dt,J=3.9,7.0 Hz,4H),1.51(t,J=6.5 Hz,11H),1.48-1.42(m,3H).

[0244] C 51 H 62 MS(ESI) calculated for N8O7: 898.47, found: 899.73[M+1], 900.64.

[0245] Example 24: Synthesis of N-(4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazol-2-yl)ethyl)phenyl)-12-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide)dodecanamide (24) [ka]

[0246] Compound 24 was prepared in a similar manner to compound 1 in Example 1 using Int-5 and the appropriate IMiD acid as a yellow powder (4.1 mg, 24% yield).

[0247] C 53 H 64 MS(ESI) calculated for N8O9: 956.48, found: 957.71[M+1], 958.66.

[0248] Example 25: Synthesis of N-(4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinopropyl)-1H-benzo[d]imidazol-2-yl)ethyl)phenyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide (25) [ka]

[0249] Compound 25 was prepared in a similar manner to compound 1 in Example 1 using Int-6 and the appropriate IMiD acid as a yellow powder (10.7 mg, 59% yield).

[0250] 1H NMR(500 MHz,acetone-d6)δ 10.01(s,1H),9.09(s,1H),7.63-7.56(m,5H),7.29-7.24(m,2H),7.23(dd,J=8.3,1.6 Hz,1H),7.10(d,J=8.5 Hz,1H),7.03(d,J=7.0 Hz,1H),6.44(t,J=5.9 Hz,1H),5.08(dd,J=12.6,5.4 Hz,1H),4.39(dd,J=14.9,7.5 Hz,1H),4.12(dd,J=14.9,6.3 Hz,1H),3.53(t,J=4.6 Hz,4H),3.43-3.38(m,2H),3.36-3.30(m,2H),3.30-3.25(m,2H),3.06(q,J=6.8 Hz,1H),3.01-2.92(m,1H),2.81-2.78(m,1H),2.78-2.71(m,3H),2.46(t,J=5.3 Hz,1H),2.42(s,3H),2.40(t,J=7.3 Hz,2H),2.26(s,3H),2.24-2.18(m,1H),1.75(ddd,J=14.6,11.6,7.3 Hz,4H),1.56-1.48(m,3H),1.07(d,J=6.8 Hz,3H).

[0251] C 46 H 52 MS(ESI) calculated for N8O7: 828.40, found: 829.62[M+1], 830.53.

[0252] Example 26: Synthesis of N-(4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinopropyl)-1H-benzo[d]imidazol-2-yl)ethyl)phenyl)-8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanamide (26) [ka]

[0253] Compound 26 was prepared in a similar manner to compound 1 in Example 1 using Int-6 and the appropriate IMiD acid as a yellow powder (13.4 mg, 72% yield).

[0254] C 48 H 56 MS(ESI) calculated for N8O7: 856.43, found: 857.66[M+1], 858.65.

[0255] Example 27: Synthesis of N-(4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinopropyl)-1H-benzo[d]imidazol-2-yl)ethyl)phenyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide (27) [ka]

[0256] Compound 27 was prepared in a similar manner to compound 1 in Example 1 using Int-6 and the appropriate IMiD acid as a yellow powder (14 mg, 70% yield).

[0257] 1H NMR(500 MHz,acetone-d6)δ 10.05(s,1H),9.14(s,1H),7.74-7.67(m,2H),7.57(td,J=7.2,3.6 Hz,3H),7.31(dd,J=8.4,1.5 Hz,1H),7.25(d,J=8.1 Hz,2H),7.10(d,J=8.6 Hz,1H),7.03(d,J=7.1 Hz,1H),6.60(s,1H),5.08(dd,J=12.7,5.4 Hz,1H),4.50(dd,J=14.8,7.5 Hz,1H),4.25(dd,J=14.8,6.5 Hz,1H),3.80(t,J=6.0 Hz,2H),3.72(t,J=5.3 Hz,2H),3.63(s,8H),3.58(s,4H),3.50(q,J=5.4 Hz,2H),3.44-3.39(m,2H),3.28(t,J=7.7 Hz,2H),3.17(q,J=6.8 Hz,1H),3.00-2.91(m,1H),2.88-2.81(m,2H),2.80-2.73(m,2H),2.58(t,J=5.9 Hz,4H),2.43(s,3H),2.26(s,3H),2.23-2.19(m,1H),1.12(d,J=6.8 Hz,3H).

[0258] C 49 H 58 N8O 10 MS(ESI) calculated for: 918.43, found: 919.68[M+1], 920.85.

[0259] Example 28: Synthesis of N-(2-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinopropyl)-1H-benzo[d]imidazol-2-yl)ethyl)phenyl)amino)ethyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide (28) [ka]

[0260] Compound 28 was prepared as a yellow powder (5.9 mg, 34% yield) in a similar manner to compound 1 in Example 1 using Int-6 and the appropriate IMiD acid.

[0261] 1 H NMR(500 MHz,acetone-d6)δ 10.06(s,1H),7.61-7.56(m,2H),7.54(d,J=8.2 Hz,1H),7.27-7.21(m,1H),7.17(dd,J=8.2,1.6 Hz,1H),7.09-7.02(m,4H),6.57(d,J=8.4 Hz,2H),6.41(t,J=5.8 Hz,1H),5.07(dd,J=12.6,5.5 Hz,1H),4.29(dd,J=14.9,7.2 Hz,1H),4.03(dd,J=14.9,6.4 Hz,1H),3.54(t,J=4.6 Hz,4H),3.42(q,J=6.3 Hz,2H),3.37-3.33(m,2H),3.24-3.15(m,4H),3.14-3.10(m,2H),3.02(q,J=6.8 Hz,1H),2.97-2.92(m,1H),2.80-2.75(m,2H),2.70(dt,J=11.2,4.6 Hz,2H),2.46(d,J=4.6 Hz,1H),2.43(s,3H),2.27(s,3H),2.24-2.16(m,4H),1.69(dt,J=9.1,7.3 Hz,4H),1.46(tt,J=7.0,1.9 Hz,2H),1.03(d,J=6.8 Hz,3H).

[0262] C 48 H 57 MS(ESI) calculated for N9O7: 871.44, found: 872.63[M+1], 873.58.

[0263] Example 29: Synthesis of N-((1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexyl)-10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decanamide (29) [ka]

[0264] Compound 29 was prepared in a similar manner to compound 1 in Example 1 using Int-7 and the appropriate IMiD acid as a yellow powder (12 mg, 44% yield).

[0265] C 52 H 58 MS(ESI) calculated for F2N8O7: 944.44, found: 945.55[M+1], 946.54.

[0266] Example 30: Synthesis of N-((1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide (30) [ka]

[0267] Compound 30 was prepared in a similar manner to compound 1 in Example 1 using Int-7 and the appropriate IMiD acid as a yellow powder (15 mg, 59% yield).

[0268] C 48 H 50 MS(ESI) calculated for F2N8O7: 888.38, found: 889.50[M+1], 890.38.

[0269] Example 31: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-((10-(4-(1-methyl-5-((R)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-6-yl)-1H-indazol-3-yl)-1H-pyrazol-1-yl)-10-oxodecyl)amino)isoindoline-1,3-dione (31) [ka]

[0270] Compound 31 was prepared as a yellow powder (5.32 mg, 17% yield) in a similar manner to compound 1 in Example 1 using Int-8 and the appropriate IMiD acid. 44 H 47 MS(ESI) calculated for N9O6: 797.36, found: 798.46[M+1], 799.37.

[0271] Example 32: Cytolysis Assay with Compounds of the Invention (ATPlite™)

[0272] Kelly neuroblastoma cells were seeded at 1,000 cells / well in 384-well white plates and treated in a dose-dependent manner for 72 hours. Cells were assessed for viability as a measure of cellular luminescence using the ATPlite™ Luminescence Assay System (Perkin Elmer, Cat. No. 6016943), normalized to DMSO-treated control cells.

[0273] The results shown in Figure 2 show that bispecific compound 2 killed Kelly neuroblastoma cells in a dose-dependent and more potent manner at 72 hours compared to A485, a histone acetyltransferase (HAT) p300 inhibitor, and cereblon binders lenalidomide, thalidomide and pomalidomide. IC of bispecific compound 2 50 was approximately 10-fold more potent than A485 (Table 1). [Table 1]

[0274] The results shown in Figure 4 indicate that bispecific compounds 3, 6 and 7 were potent inhibitors of Kelly neuroblastoma cell proliferation at 72 hours. The IC 50 Values ​​were in the micromolar and submicromolar range (Table 2). [Table 2]

[0275] IC of bispecific compounds 1–31 50 A summary is shown in Table 3 below. [Table 3]

[0276] Example 33: CBP (bromodomain) AlphaScreen® assay.

[0277] The assay was performed with minimal modifications from the manufacturer's protocol (PerkinElmer®, USA). All reagents were diluted in 50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 150 mM NaCl, 0.1% w / v bovine serum albumin (BSA), 0.01% w / v Tween® 20, pH 7.5 and equilibrated to room temperature before addition to the plate. After addition of AlphaScreen® Acceptor Beads to the master solution, all subsequent steps were performed under low light conditions. 10 μL of 2× solutions of components with final concentrations of 40 nM CBP bromodomain, 10 μg / ml Ni-coated Acceptor Beads and 7.2 nM biotinylated Int-2 were added to a 384-well plate (AlphaPlate-384, PerkinElmer®, USA). The plate was spun down at 150×g and 100 nL of compound in dimethylsulfoxide (DMSO) from a stock plate was added by pin transfer using a Janus® Workstation (PerkinElmer®, USA). Streptavidin-coated donor beads (final 10 μg / ml) were added in a volume of 2×10 μL as in the previous solution. After this addition, the plate was sealed with foil to prevent light exposure and evaporation. The plate was spun down again at 150×g. The plate was incubated at room temperature for 1 hour and then read on a 2104 EnVision® Multilabel Plate Reader (PerkinElmer®, USA) using the manufacturer's protocol.

[0278] The results shown in Figure 6 indicate that bispecific compounds 1, 2 and int-2 bound to CBP (bromodomain) in the range of 10 μM. The IC 50 The values ​​are shown in Table 4. [Table 4]

[0279] Example 34: Western blot for E300 / CBP degradation by compounds of the present invention

[0280] Kelly neuroblastoma cells were seeded at 1,000,000 cells / well in 6-well plates and treated in a dose-dependent manner for 24 hours. Whole cell lysates were collected using ice-cold lysis buffer [300 mM NaCl, 50 mM Tris-HCl, pH 7.5, 0.5% Triton X-100, 1% sodium dodecyl sulfate (SDS), 1 mM dithiothreitol (DTT) (Invitrogen™), cOmplete™ protease inhibitor cocktail from Roche® (1:000), 25 units / mL Benzonase®] and blotted at a protein concentration of 30 μg for EP300 and CBP, and 10 μg for histone H3 and H3K27ac. Lysates were also blotted for bromodomain-containing protein 4 (BRD4). Lysates were separated on NuPAGE™ 3-8% Tris-Acetate polyacrylamide gels (EA03785BOX, Invitrogen™) for EP300 and CBP, and on Bolt 4-12% Bis-Tris polyacrylamide gels (NW04125BOX, Invitrogen™) for H3 and H3K27ac, and then transferred to nitrocellulose membranes (LC2001, Invitrogen™). Primary and secondary antibodies used included anti-p300 (ab10485, Abcam®) at 1:500 dilution, anti-CBP (D6C5, Cell Signaling Technology®) at 1:500 dilution, anti-actin (3700S, Cell Signaling Technology®) at 1:5000 dilution, anti-H3 (4499S, Cell Signaling Technology®) at 1:1000 dilution, anti-H3K27ac (ab4729, Abcam®) at 1:1000 dilution, IRDye®800 goat anti-rabbit (926-32211, LiCor® Biosciences) at 1:5000 dilution, and IRDye®680 goat anti-mouse (926-68070, LiCor®) at 1:5000 dilution. Visualization was performed with an Odyssey infrared imaging system (LiCor® Biosciences).

[0281] The results shown in Figures 3A-C indicated that bispecific compound 2 was a potent degrader of both EP300 and CBP with a clear reduction in H2K27ac. However, Int 2, the targeting ligand in bispecific compound 2, appeared to have general cytotoxicity. Bispecific compound 1 showed no detectable degradation of EP300 and CBP, but there was a reduction in H3K27ac, indicating that bispecific compound 1 likely acted as an inhibitor rather than a degrader.

[0282] The results shown in Figures 5A-C indicate that bispecific compound 7 was a potent degrader of both P300 and CBP with significant degradation and a slight decrease in acetylation levels at 1 μM. Bispecific compound 3 showed some degradation at 10 μM, whereas bispecific compound 6 showed little to no degradation.

[0283] The results shown in Figures 7A-7D indicate that bispecific compounds 8 and 11 were potent degraders of both P300 and CBP with significant degradation and reduced acetylation levels at 1 μM. Bispecific compound 12 showed significant degradation and reduced acetylation levels of P300 at 1 μM. BRD4 degradation was observed with bispecific compounds 8, 11, and 12 at 1 μM at 24 hours. The results in Figure 7E indicate that bispecific compound 31 was a potent and selective degrader of P300 and CBP over BRD2 / 3 / 4 with significant degradation at 3 μM.

[0284] All patent and non-patent publications are indicative of the level of skill of those skilled in the art. All such publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0285] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims. The present invention includes the following embodiments. [1] 1. A bispecific compound comprising a targeting ligand that binds histone acetyltransferase p300 (EP300) and cAMP response element binding protein-binding protein (CBP), a degron (D) that binds an E3 ubiquitin ligase, and a linker (L) that covalently links the targeting ligand and the degron, the compound having formula (I): [ka] [In the formula, X represents C or N, X 1 CR 1 or NR 3 and X 2 CR 2 or CR 4 and X 3 is N, except that if X is N, then X 1 is CR 1 and X 2 is CR 2 and X 3 is N, [ka] teeth [ka] If X is C, then X 1 is NR 3 and X 2 is CR 4 and X 3 is N, [ka] teeth [ka] represents; R 1 NHR 1 R 1 is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle; R 2 teeth,

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[10] R 3 is an optionally substituted C1-C3 alkyl, and R 4 but,

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[11] R 3 is substituted with dimethylaminyl, morpholinyl, or piperazinyl.

[12] R 4 is an optionally substituted C5-C6 carbocyclic ring or an optionally substituted C5-C6 heterocyclic ring, and R 3 but,

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[13] The bispecific compound according to

[12] , wherein the optionally substituted C5-C6 carbocyclic group is an optionally substituted aralkyl.

[14] The optionally substituted C5-C6 heterocyclic group is

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[12] ,

[15] R 4 But halogen, NH 2 , OH or methoxy.

[16] If X is N, then X 1 is CR 1 and X 2 is CR 2 and X 3 is N, and the formula (I-1):

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[17] R 1 is an optionally substituted C1-C3 alkyl, and R 2 but,

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[18] R 1 is an optionally substituted C5-C6 carbocyclic ring, and R 2 but,

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[19] R 1 is an optionally substituted C5-C6 aralkyl, and R 2 but,

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[20] X is C and X 1 NR 3 and X 2 CR4 and X 3 is N, and the formula (I-2):

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[21] R 3 is an optionally substituted C1-C3 alkyl, and R 4 but,

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[22] R 3 is an optionally substituted C5-C6 aralkyl or

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[23] Formula (II):

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[24]

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[25] The linker is structure:

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[23] , wherein the bispecific compound is represented by any one of the following:

[26] The bispecific compound of [1] or

[23] , wherein the degron binds cereblon (CRBRN).

[27] The degron is Structure (D1):

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[26] , wherein the compound is CO.

[28] The degron is Structure (D1-a) or (D1-b):

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[27] , wherein the bispecific compound is represented by

[29] The bispecific compound of [1] or

[23] , wherein the degron binds VHL.

[30] The degron has the formula (D2-a) to (D2-e):

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[29] , having a structure represented by any one of the following:

[31] Z,

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[30] ,

[32] Structures (1)-(46):

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[33] A pharmaceutical composition comprising a therapeutically effective amount of a bispecific compound of formula (I) according to [1] or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[34] The pharmaceutical composition described in

[33] , which is in the form of a tablet.

[35] The pharmaceutical composition described in

[33] , which is in the form of a capsule.

[36] A method for treating a disease or disorder associated with abnormal EP-300 / CBP activity, comprising administering a therapeutically effective amount of a bispecific compound described in [1] or a pharma- ceutically acceptable salt or stereoisomer thereof to a subject in need of treatment for a disease or disorder associated with abnormal EP-300 / CBP activity.

[37] The method according to

[36] , wherein the disease or disorder is EP300 / CPB-dependent and MYC-induced cancer.

[38] The method according to

[36] , wherein the disease or disorder is neuroblastoma (NB).

[39] The method according to

[36] , wherein the disease or disorder is blood cancer.

[40] The method of claim 39, wherein the blood cancer is acute myeloid leukemia (AML), multiple myeloma (MM) or diffuse large B-cell lymphoma.

[41] The method according to

[36] , wherein the disease or disorder is a solid tumor.

[42] The method according to

[41] , wherein the solid tumor is melanoma, rhabdomyosarcoma, colon cancer, rectal cancer, gastric cancer, breast cancer or pancreatic cancer.

[43] The method of

[38] , further comprising administering to the subject the therapeutically effective amount of the bispecific compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof in combination with a therapeutically effective amount of an additional anti-NB agent.

[44] 36. The method of claim 35, wherein the therapeutically effective amount of the bispecific compound of Formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof, is orally administered to a subject in the form of a tablet comprising the therapeutically effective amount of the bispecific compound of Formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[45] 36. The method of claim 35, wherein the therapeutically effective amount of the bispecific compound of Formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof, is orally administered to the subject in the form of a capsule comprising the therapeutically effective amount of the bispecific compound of Formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[46] The method of

[36] , wherein the therapeutically effective amount of the bispecific compound of Formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof, is parenterally administered to the subject in the form of a liquid comprising the therapeutically effective amount of the bispecific compound of Formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[47] The method according to

[36] , wherein the compound of formula (I) is administered to the subject in the form of a salt.

[48] The method according to

[36] , wherein the subject is a human.

[49] A pharmaceutical composition comprising a therapeutically effective amount of a bispecific compound according to

[23] or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[50] The pharmaceutical composition described in

[49] , which is in the form of a tablet.

[51] The pharmaceutical composition described in

[49] , which is in the form of a capsule.

[52] A method for treating a disease or disorder associated with abnormal EP-300 / CBP activity, comprising administering a therapeutically effective amount of a bispecific compound described in

[23] or a pharma- ceutically acceptable salt or stereoisomer thereof to a subject in need of treatment for a disease or disorder associated with abnormal EP-300 / CBP activity.

[53] The method according to

[52] , wherein the disease or disorder is EP300 / CPB-dependent and MYC-driven cancer.

[54] The method according to

[49] , wherein the disease or disorder is neuroblastoma (NB).

[55] The method according to

[49] , wherein the disease or disorder is blood cancer.

[56] The method according to

[55] , wherein the blood cancer is acute myeloid leukemia (AML), multiple myeloma (MM) or diffuse large B-cell lymphoma.

[57] The method according to

[52] , wherein the disease or disorder is a solid tumor.

[58] The method according to

[57] , wherein the solid tumor is melanoma, rhabdomyosarcoma, colon cancer, rectal cancer, gastric cancer, breast cancer or pancreatic cancer.

[59] The method of

[54] , further comprising administering to the subject the therapeutically effective amount of the bispecific compound of formula (II) or a pharma- ceutically acceptable salt or stereoisomer thereof in combination with a therapeutically effective amount of an additional anti-NB agent.

[60] 52. The method of claim 52, wherein the therapeutically effective amount of the bispecific compound of Formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, is orally administered to a subject in the form of a tablet comprising the therapeutically effective amount of the bispecific compound of Formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[61] 52. The method of claim 52, wherein the therapeutically effective amount of the bispecific compound of Formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, is orally administered to the subject in the form of a capsule comprising the therapeutically effective amount of the bispecific compound of Formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[62] 52. The method of claim 52, wherein the therapeutically effective amount of the bispecific compound of Formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, is parenterally administered to the subject in the form of a liquid comprising the therapeutically effective amount of the bispecific compound of Formula (II), or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[63] The method according to

[52] , wherein the compound of formula (II) is administered to the subject in the form of a salt.

[64] The method according to

[52] , wherein the subject is a human.

Claims

1. 1. A bispecific compound comprising a targeting ligand that binds histone acetyltransferase p300 (EP300) and cAMP response element binding protein-binding protein (CBP), a degron (D) that binds an E3 ubiquitin ligase, and a linker (L) that covalently links the targeting ligand and the degron, said compound having formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt or stereoisomer thereof, In the formula, X represents C or N, X １ is CR １ Or N.R. ３ and X ２ is CR ２ or CR ４ and X ３ is N, provided that if X is N, then X １ is CR １ And X ２ is CR ２ And X ３ is N, 【Chemistry 2】 teeth 【Chemistry 3】 When X is C, X １ is NR ３ And X ２ is CR ４ And X ３ is N, 【Chemistry 4】 teeth 【Chemistry 5】 represents; R １ is NHR １ represents R １ is an optionally substituted C1-C3 alkyl, an optionally substituted C5-C6 carbocycle, or an optionally substituted C7-C8 aralkyl; R ２ teeth, 【Chemistry 6】 [wherein X′ is O, HNC ２ H ４ NH or NH; R ３ is optionally substituted C1-C3 alkyl, 【Chemistry 7】 represents R ４ is an optionally substituted C5-C6 carbocyclic ring or an optionally substituted C5-C6 heterocyclic ring; 【Chemistry 8】 represents However, R ３ and R ４ One of them is 【Chemistry 9】 and The degron has the structure (D1): 【Chemistry 62】 [Wherein, Y is CH ２ or CO, Z is NH, O or OCH ２ CO; or The degron has the formula (D2-a) to (D2-e): 【Chemistry 64】 wherein Y′ is a bond, N, O or C; 【Chemistry 65】 wherein Z is a C5-C6 carbocyclic or C5-C6 heterocyclic group, and optionally Z is 【Chemistry 67】 is], and 【Chemistry 66】 wherein the substituents of the optionally substituted groups when substituted are (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkoxy, haloalkyl, (C 3 -C 12 ) carbocyclic, (C 3 -C 12 ) heterocyclic, aryl, heteroaryl, halo, hydroxyl, cyano, carboxyl, amino, (C 1 -C 8 ) alkylamino or di(C 1 -C 8 ) alkylamino; or a pharma- ceutically acceptable salt or stereoisomer thereof.

2. When X is N, X １ is CR １ And X ２ is CR ２ And X ３ is N, 【Chemistry 10】 teeth 【Chemistry 11】 represents R １ NHR １ represents R １ is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle; R ２ but, 【Chemistry 12】 wherein X′ is O or NH; or If X is C, then X １ is NR ３ And X ２ is CR ４ And X ３ is N, 【Chemistry 13】 teeth 【Chemistry 14】 represents R ３ is optionally substituted C1-C3 alkyl, 【Chemistry 15】 represents R ４ is an optionally substituted C5-C6 carbocyclic ring; 【Chemistry 16】 where R ３ and R ４ One of them is 【Chemistry 17】 or When X is N, X １ is CR １ And X ２ is CR ２ And X ３ is N, 【Chemistry 18】 teeth 【Chemistry 19】 represents R １ is NHR １ represents R １ is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle; R ２ teeth, 【Chemistry 20】 [In the formula, X′ is NHC ２ H ４ NH; or If X is C, then X １ is NR ３ And X ２ is CR ４ and X ３ is N, 【Chemistry 21】 teeth 【Chemical 22】 represents R ３ is optionally substituted C1-C3 alkyl or 【Chemistry 23】 represents R ４ is an optionally substituted C5-C6 carbocyclic group or an optionally substituted C5-C6 heterocyclic group, or 【Chemistry 24】 where R ３ and R ４ One of them is, 【Chemistry 25】 That is, 2. The bispecific compound of claim 1, or a pharma- ceutically acceptable salt or stereoisomer thereof.

3. R １ 2. The bispecific compound of claim 1, wherein is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle.

4. R １ 2. The bispecific compound of claim 1 , wherein is substituted with methyl or methoxy.

5. R ３ is an optionally substituted C1-C3 alkyl, R ４ but, 【Chemistry 26】 and optionally, R ３ 2. The bispecific compound of claim 1 , wherein is substituted with dimethylaminyl, morpholinyl, or piperazinyl.

6. R ４ is an optionally substituted C5-C6 carbocycle or an optionally substituted C5-C6 heterocycle; R ３ but, 【Chemistry 27】 2. The bispecific compound of claim 1 , wherein

7. The optionally substituted C5-C6 heterocyclic group, 【Chemistry 28】 or The optionally substituted C5-C6 carbocyclic group is selected from the group consisting of halogen, NH ２ 7. The bispecific compound of claim 6, wherein said N-substituted aryl group is substituted with , OH or methoxy.

8. When X is N, X １ is CR １ And X ２ is CR ２ And X ３ is N, and the formula (I-1): 【Chemical 29】 or having a structure represented by If X is C, then X １ is NR ３ And X ２ is CR ４ And X ３ is N, and the compound represented by formula (I-2): 【Chemical 37】 2. The bispecific compound of claim 1 having a structure represented by:

9. R １ is an optionally substituted C1-C3 alkyl, R ２ but, 【Chemistry 30】 and represented by formulas (I-1a) to (I-1d): 【Chemistry 31】 【Chemistry 32】 or R １ is an optionally substituted C5-C6 carbocyclic ring, R ２ but, 【Chemical 33】 and having the formula (I-1e) or (I-1f): 【Chemical Formula 34】 or having a structure represented by R １ is an optionally substituted C7-C8 aralkyl, R ２ but, 【Chemistry 35】 and represented by the formulas (I-1g) to (I-1j): 【Chemical 36】 9. The bispecific compound of claim 8 having a structure represented by any one of:

10. R ３ is an optionally substituted C1-C3 alkyl, R ４ but, 【Chemical 38】 and Formulae (I-2a) to (I-2p): 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 or R ３ is an optionally substituted C5-C6 aralkyl or 【Chemistry 43】 and R ４ but, 【Chemistry 44】 and represented by formulas (I-2q) to (I-2z) and (I-2a′) to (I-2k′): 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 9. The bispecific compound of claim 8 having a structure represented by any one of:

11. Formula (II): 【Chemistry 51】 or a pharma- ceutically acceptable salt or stereoisomer thereof, During the ceremony, 【Chemistry 52】 represents an optionally substituted phenyl or an optionally substituted C6 heteroaryl; Xa is NH, O, S or C(Ra) ２ wherein each Ra independently represents H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 carbocyclyl; Xb represents C or N; Xb １ is CRb １ or CRb ３ represents Xb ２ is CRb ２ , C.R. ４ or N, Xb ３ represents N or NMe, However, when Xb is N, Xb １ is CRb １ and Xb ２ is CRb ２ and Xb ３ is N, and if Xb is C, then Xb １ is CRb ３ and Xb ２ is CR ４ or N, Xb ３ is N or NMe; Rb １ is NHR ｂ１ represents R ｂ１ is an optionally substituted C1-C3 alkyl or an optionally substituted C5-C6 carbocycle; Rb ２ teeth, 【Chemistry 53】 X' represents O, HNC ２ H ４ NH or NH; Rb ３ is optionally substituted C1-C3 alkyl, 【Chemical 54】 [wherein n is 1, 2, 3 or 4]; Rb ４ is an optionally substituted C5-C6 carbocyclic ring or an optionally substituted C5-C6 heterocyclic ring; 【Chemistry 55】 represents However, Rb ３ and Rb ４ One of them is, 【Chemistry 56】 【Chemistry 57】 and L represents a linker covalently linking the targeting ligand and the degron; The degron has the structure (D1): 【Chemistry 62】 and Y is CH ２ or CO, Z is NH, O or OCH ２ CO, or The degron has the formula (D2-a) to (D2-e): 【Chemistry 64】 wherein Y′ is a bond, N, O or C; 【Chemistry 65】 [Wherein, Z is a C5-C6 carbocyclic or C5-C6 heterocyclic group, optionally Z is 【Chemistry 67】 is], and 【Chemistry 66】 wherein the substituents of the optionally substituted groups when substituted are (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkoxy, haloalkyl, (C 3 -C 12 ) carbocyclic, (C 3 -C 12 ) heterocyclic, aryl, heteroaryl, halo, hydroxyl, cyano, carboxyl, amino, (C 1 -C 8 ) alkylamino or di(C 1 -C 8 ) alkylamino; or a pharma- ceutically acceptable salt or stereoisomer thereof.

12. 【Chemical 58】 is phenyl, Xa is NH, Xb is C, and X １ is CRb ３ and Rb ３ but 【Chemistry 59】 and Xb ２ is N, and Xb ３ is NMe, n is 1, 2, 3 or 4, and the compound represented by formula (II-1) or (II-2): 【Chemistry 60】 12. The bispecific compound of claim 11 having a structure represented by:

13. The linker comprises an alkylene chain or a polyethylene glycol (PEG) chain, any one of which is -O-, -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR') and / or may be interrupted (at one or both termini) by at least one of: -NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, C3-C12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene, or any combination thereof; R' is H or C １ ~C ６ 12. The bispecific compound of claim 1 or 11, wherein said interrupting group and said one or both terminating groups are alkyl and may be the same or different.

14. the alkylene chain has 1 to 10 alkylene units; 【Chemistry 87】 has been interrupted or terminated by, or the PEG chain has 2-8 PEG units; 【Chemistry 98】 14. The bispecific compound of claim 13, which terminates with:

15. The linker is structure: 【Chemistry 61】 2. The bispecific compound of claim 1, represented by any one of:

16. The degron is Represented by structure (D1), optionally The degron has the structure (D1-a) or (D1-b): 【Chemistry 63】 12. The bispecific compound of claim 1 or 11, represented by:

17. 12. The bispecific compound of claim 1 or 11, wherein the degron has a structure represented by any one of formulas (D2-a) to (D2-e).

18. Structures (1) to (46): 【Chemistry 68】 【Chemistry 69】 【Chemistry 70】 【Chemistry 71】 【Chemical 72】 【Chemical Formula 73】 【Chemical 74】 【Chemistry 75】 【Chemical 76】 【Chemical 77】 【Chemical 78】 【Chemical Formula 79】 【Chemistry 80】 【Chemistry 81】 or a pharma- ceutically acceptable salt or stereoisomer thereof.

19. 20. A pharmaceutical composition comprising a therapeutically effective amount of a bispecific compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier, optionally wherein the composition is in the form of a tablet or capsule.

20. 20. A pharmaceutical composition for treating a disease or disorder associated with aberrant EP-300 / CBP activity comprising administering a therapeutically effective amount of a bispecific compound according to any one of claims 1 to 18, wherein said disease or disorder is an EP300 / CPB-dependent and MYC-driven cancer, optionally wherein said cancer is a hematological cancer or a solid tumor, optionally wherein said hematological cancer is acute myeloid leukemia (AML), multiple myeloma (MM) or diffuse large B-cell lymphoma, and optionally wherein said solid tumor is neuroblastoma (NB), melanoma, rhabdomyosarcoma, colon cancer, rectal cancer, gastric cancer, breast cancer or pancreatic cancer.

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