CBP / p300 heterobifunctional conditional inhibitors

Abstract

Described herein are heterobifunctional small molecules, methods of making, pharmaceutical compositions and medicaments comprising such heterobifunctional small molecules, and methods of using such heterobifunctional small molecules are described herein, in the conditional inhibition of the activity of CREB-binding protein (CBP) / p300 in cells expressing the androgen receptor.

Description

Attorney Docket No.: P60303-WO-1CBP / p300 HETEROBIFUNCTIONAL CONDITIONAL INHIBITORSCLAIM OF PRIORITY

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 748,595, filed on January 23, 2025, and U. S. Provisional Application Serial No. 63 / 789,847, filed on April 16, 2025, which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] Described herein are heterobifunctional small molecules, methods of making, pharmaceutical compositions and medicaments comprising such heterobifunctional small molecules, and methods of using such heterobifunctional small molecules are described herein, in the selective and conditional inhibition of the activity of CREB-binding protein (CBP) / p300 in cells also expressing the androgen receptor, and the use of such compounds in the treatment of diseases and conditions.BACKGROUND OF THE INVENTION

[0003] Cellular homeostasis, a key hallmark of living organisms, arises from interactions between biomolecules, such as protein (e.g., enzyme) and substrate interactions, within and outside the cell. Conventionally, the function of a particular protein in a particular disease state has been investigated and controlled through the use of monofunctional molecules (e.g., an inhibitor), which occupy the active site of the disease protein, thereby forming binary complexes that inhibit or downregulate activity of the disease proteins. Such monofunctional molecules have provided a conceptual pathway toward many FDA-approved drugs as a means for treating the disease state.

[0004] However, many monofunctional molecules lack specificity for the disease proteins in question leading to undesired toxicities or lack of efficacy, or the disease proteins adapts to the monofunctional molecules thereby leading to resistance. An alternative approach with monofunctional molecules is to target the coregulator or coactivator proteins of the disease proteins. However, such coregulator or coactivator proteins are typically present in every cell, healthy or diseased, and inhibiting their activity typically leads to narrower therapeutic indices.

[0005] Described herein are heterobifunctional small molecules that engage the androgen receptor (AR) and CBP / p300, thereby forming ternary complexes only in the disease cells that express both proteins and lead to loss of function of CBP / p300 in such cells. The heterobifunctional small molecules described herein comprise at least one silent binder to CBP / p300 and at least one binder to AR. Such heterobifunctional small molecules offer a new means for treatment of diseases or conditions, such as AR positive prostate cancers, with a wider therapeutic index.Attorney Docket No.: P60303-WO-1SUMMARY OF THE INVENTION

[0006] In some embodiments, disclosed herein is a heterobifunctional conditional inhibitor compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human E1A-binding protein p300 (p300) (CBP / p300);L is an optional linker; wherein L is covalently attached at a position of SB-CBP / p300 that is solvent exposed when SB binds to CBP / p300;B-AR is a binder of the androgen receptor (AR), wherein the B-AR comprises option 1) option 2), or option 3):1) a head group that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety is covalently attached to the core moiety; wherein the head group is:Attorney Docket No.: P60303-WO-1wherein:each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4;2) a head group that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety covalently attached to the core moiety; wherein the head group is:Attorney Docket No.: P60303-WO-1moiety;the optional tail moiety comprises a ring D that is covalently attached to the core, wherein ring D is a 5-, 6-, 8-, 9- or 10-membered aryl or a 5-, 6-, 8-, 9- or 10-membered heteroaryl that is optionally substituted with w R3; w is 1, 2, 3, or 4;Z is -O- or -NR5-;each X1is independently -CR1- or -N-;Attorney Docket No.: P60303-WO-1X4is -CRd- or -N-;each R1is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -OR4, OC(=O)R4, -OC(=O)N(R5)2, -OC(=O)OR5, -OC(=O)NR5, -SH, -SR4, - S(=O)R4, -S(=O)2R5, -S(=O)2OR4, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, - NR5C(=O)OR5, -NR5S(=O)2R5, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlais hydrogen, halogen, -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -NO2, -C(=O)R5, -C(=O)OR5, - C(=O)N(R5)2,-OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;Rldis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4;each R2is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, - OH, -OR4, OC(=O)R4, -S(=O)R4, -S(=O)2R5, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, - NR5C(=O)R4, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; ortwo R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, - OR4, or -N(R5)2.each R4is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two R5on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; andwherein L is covalently attached to the core moiety at position (*) if the optional tail moiety is absent, or L is covalently attached to the tail moiety if present.Attorney Docket No.: P60303-WO-1

[0007] In some embodiments, disclosed herein is a heterobifunctional conditional inhibitor compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human E1A-binding protein p300 (p300) (CBP / p300);L is an optional linker; wherein L is covalently attached at a position of SB-CBP / p300 that is solvent exposed when SB binds to CBP / p300;B-AR is a binder of the androgen receptor (AR), wherein the B-AR comprises option 1), option 2), or option 3):option 1) a head group A3that occupies the ligand-binding domain (LBD) of AR, and an optional tail moiety (ring D) is covalently attached to the core moiety; wherein the core comprises an optionally substituted cycloalkyl and the core and head group A3have the structure of Formula (A):'zs ' 2(R )m, Formula (A);wherein each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4; andR1Attorney Docket No.: P60303-WO-1option 2) a head group A3that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety (ring D) is covalently attached to the core moiety; wherein the core and head group A3have one of the following structures:Attorney Docket No.: P60303-WO-1, and an optional tail moiety (ring D) is covalently attached to the core moiety;Attorney Docket No.: P60303-WO-1the optional tail moiety of option 1), option 2), and option 3) comprises a ring D that is covalently attached to the core, wherein ring D is a 5-, 6-, 8-, 9- or 10-membered aryl or a 5-, 6-, 8-, 9- or 10-membered heteroaryl that is optionally substituted with w R3; w is 1, 2, 3, 4;Z is -O- or -NR5-;each X1is independently -CR1- or -N-;X4is -CRd- or -N-;each R1is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -OR4, OC(=O)R4, -OC(=O)N(R5)2, -OC(=O)OR5, -OC(=O)NR5, -SH, -SR4, - S(=O)R4, -S(=O)2R5, -S(=O)2OR4, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, - NR5C(=O)OR5, -NR5S(=O)2R5, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlais hydrogen, halogen, -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -NO2, -C(=O)R5, -C(=O)OR5, - C(=O)N(R5)2, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;Rldis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4;each R2is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - OR4, OC(=O)R4, -S(=O)R4, -S(=O)2R5, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, - C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; ortwo R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -OR4, or - N(R5)2;each R4is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;Attorney Docket No.: P60303-WO-1or two R5on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; andwherein L is covalently attached to the core moiety at position (*) if the optional tail moiety is absent, or L is covalently attached to the tail moiety if present.

[0008] In some embodiments, described herein is a heterobifunctional conditional inhibitor of CBP / p300 having the structure of Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), or Formula (X), or a pharmaceutically acceptable salt or solvate thereof:Formula (IV), R28 (R35)mFormula (V),Formula (VI),Formula (VIII),Attorney Docket No.: P60303-WO-1Formula (X), wherein,each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4;Z is -O- or -NR5-;Attorney Docket No.: P60303-WO-1each X1is independently -CR1- or -N-;X4is -CRld- or -N-;each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4;Rlais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, or -CN;Rldis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4;or Rlband Rldare taken together with the intervening carbon atoms between Rlband Rldto form a phenyl, pyridinyl, pyridazinyl, or pyrimidinyl optionally substituted with 1 or 2 R1; each X is independently -CR3- or -N-;each R2is independently hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl; or two R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;each R3is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -OR4, or -N(R5)2. each R4is independently Ci-C4alkyl, Ci-C4deuteroalkyl, or Ci-C4fluoroalkyl;each R5is independently hydrogen, Ci-C4alkyl, Ci-C4deuteroalkyl, or Ci-C4fluoroalkyl; R28is -C(=O)CH3, -C(=O)CD3, -C(=O)CF3, -C(=O)CH2F, -C(=O)CHF2, -C(=O)CH2CH3, - C(=O)CD2CH3, -C(=O)CH2CD3, -C(=O)CD2CD3, -C(=O)CH2CF3, -C(=O)CF2CF3, - C(=O)CH2CH2F, -C(=O)CH2CHF2, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CD3), - C(=O)NH(CF3), -C(=O)NH(CH2F), -C(=O)NH(CHF2), -C(=O)NH(CH3), - C(=O)NH(CH2CH3), -C(=O)NH(CD2CD3), -C(=O)NH(CH2CF3), -C(=O)NH(CF2CF3), - C(=O)NH(CH2CH2F), or -C(=O)NH(CH2CHF2);each X2is independently -CR30- or -N- provided that at most two X2are -N-;Z1is -NRC- or -O-; Rcis hydrogen or C1-C6alkyl;R26is hydrogen, substituted or unsubstituted Ci-C4alkyl, Ci-C4deuteroalkyl, Ci- C4fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;X3is -CR27- or -N-;Attorney Docket No.: P60303-WO-1R27is hydrogen, halogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci-C4fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CN, -OH, -ORa, -N(Rb)2, -NRbC(=O)Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;each R30is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, -CN, -OH, or -ORa;each R35is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl;m is 0, 1, or 2; p is 0, 1, 2, or 3;each of A1and A2is independently absent, substituted or unsubstituted monocyclic C3-C10cycloalkyl, substituted or unsubstituted spiro bicyclic C5-C12cycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, or substituted or unsubstituted spiro bicyclic 5- to 12-membered heterocycloalkyl, wherein each A is independently unsubstituted or substituted with x R2b;R2aAttorney Docket No.: P60303-WO-1each R2ais independently hydrogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci-C4fluoroalkyl, or substituted or unsubstituted C3-C6cycloalkyl:each R2bis independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;each Rais independently C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each Rbis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle

[0009] Also described herein is a pharmaceutical composition comprising a heterobifunctional compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration, intravenous administration, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, or a suspension.

[0010] In one aspect, the heterobifunctional compounds described herein, or a pharmaceutically acceptable salt, or solvate thereof, are used in the treatment of diseases or conditions, such as cancer, autoimmune diseases, and inflammatory diseases. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer comprises altered AR expression levels. In some embodiments, the cancer comprises altered androgen receptor expression levels. In some embodiments, altered AR expression levels comprises overexpressed AR, overactive AR, amplified AR, or combinations thereof.Attorney Docket No.: P60303-WO-1

[0011] In some embodiments, described herein is a stable ternary complex comprising: CBP / p300; Androgen Receptor (AR); and a heterobifunctional conditional inhibitor compound described herein. In some embodiments, described herein is a stable ternary complex comprising: CBP / p300; Androgen Receptor (AR); and a heterobifunctional conditional inhibitor compound described herein, wherein CBP / p300 and DP are present in a prostate cancer cell.

[0012] In some embodiments, described herein is a method of selectively inhibiting the activity of CREB-binding protein (CBP) / p300 in a cell expressing the androgen receptor of a mammal comprising administering a heterobifunctional compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a heterobifunctional compound described herein, or a pharmaceutically acceptable salt or solvate thereof, inhibits the activity of CBP / p300 in the cell but does not inhibit the activity of the CBP / p300 in cells not expressing the AR. In some embodiments, the AR is overexpressed, overactive or both overexpressed and overactive in the COI.

[0013] In some embodiments, described herein is a method of treating an androgen receptor dependent or androgen receptor mediated disease or condition in mammal comprising administering to the mammal a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the androgen receptor dependent or androgen receptor mediated disease or condition is selected from benign prostate hyperplasia, hirsutism, adenomas and neoplasms of the prostate, benign or malignant tumor cells containing the androgen receptor, prostate cancer, breast cancer, endometrial cancer, and uterine cancer.

[0014] In some embodiments, described herein is a method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is an androgen dependent cancer. In some embodiments, the cancer is prostate cancer.

[0015] In any of the embodiments disclosed herein, the mammal is a human. In some embodiments, compounds disclosed herein are orally administered to a human.

[0016] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.Attorney Docket No.: P60303-WO-1DETAILED DESCRIPTION OF THE INVENTION

[0017] Normally, human cells grow and multiply through cell division to form new cells as the body needs them. Every cell in humans includes a collection of genes and proteins, many of which are required for survival and proliferation, and impairment of these genes and proteins leads to loss of fitness or cell death.

[0018] When cells grow old or become damaged, they die and new cells take their place.Sometimes this orderly process breaks down, and abnormal or damaged cells grow and multiply when they shouldn’t. In the context of disease states, such as cancerous, autoimmune, or inflammatory states, certain proteins drive the disorderly growth and multiplication of abnormal or damaged cells.

[0019] Conventional monofunctional molecules (e.g., activators, inhibitors) form binary complexes with a target protein. In these binary complexes, the activators or inhibitors target a functional site, either orthosterically or allosterically, to modulate the target protein.

[0020] Many desired cellular changes cannot be accomplished through inhibition alone. Another class of molecules, i.e., bifunctional molecules, have been developed that operate by inducing proximity between the target proteins to form ternary complexes, which evokes a number of functions beyond inhibition.

[0021] Bifunctional molecules have primarily been utilized for their potential to simultaneously engage two macromolecular targets to form ternary complexes that in turn result in new and unique biological and cellular activities. The bifunctional molecules have seen promise in the applications of chemical induced dimerization, the inhibition of protein-protein interactions (PPIs), the degradation of target proteins, the simultaneous catalysis of two or more enzymatic processes, and the promotion or inhibition of protein aggregation. However, bifunctional molecules are not limited to the simultaneous engagement of targets. These molecules can be rationally designed from two functional chemical moieties for various dual functions such as the dual inhibition of synergistic proteins in diseases, targeted drug delivery, and activity-based profiling. Such applications have been proposed to replace combination therapies.

[0022] In ternary complexes, the bifunctional molecules can bind to various sites, including active or allosteric sites. While conventional inhibitors are occupancy driven, bifunctional molecules are often event driven. As a result, conventional inhibitors are stoichiometric, while bifunctional molecules can be sub-stoichiometric and catalytic. Furthermore, conventional inhibitors require strong binding affinities, whereas bifunctional molecules may exhibit low-to-moderate binding affinities to targeted proteins, as some ternary complexes rely on cooperativity. Compared with protein inhibitors, which can globally affect protein targets, these bifunctional molecules can be used to localize enzymatic activity to a given target. In addition, binary complexes have a saturation binding effect, where at high concentrations, the binding site is occupied. In contrast, ternary complexes can exhibit a hook effect, where high concentrations of the small molecule can saturate the two binding partnersAttorney Docket No.: P60303-WO-1into individual binary complexes, resulting in loss of efficacy at a higher dose. Mathematical frameworks to describe the three-body equilibria have been developed to support experimental and theoretical findings of these ternary complexes (E. F. Douglass Jr., et al., A comprehensive mathematical model for three-body binding equilibria, J. Am. Chem. Soc., 135 (2013), pp. 6092-6099).

[0023] Cancer cells show extensive alterations in protein expression levels, which are drivers of their malignant transformation. Proteins with altered expression levels in cancer are involved in protein synthesis and degradation, signaling and metabolic pathways, DNA repair, apoptosis, and other cellular processes, whose alterations cause tumor development and progression.

[0024] A key component of successful drug development is the assessment of the therapeutic index (TI), the ratio of the dose or exposure of a drug required to elicit the desired therapeutic effect compared with the dose or exposure at which toxicity becomes limiting. While drugs with a high TI effectively kill cancer cells with manageable toxicities, drugs with a low TI cause significant side effects at or below efficacious doses. Cytotoxic chemotherapies, which typically target proliferating cells, generally have low TIs.The modulation of androgen receptor protein levels is an effective anticancer target in androgen receptor positive cancers, which is achieved by targeting of up-regulated androgen receptors. Described herein is a novel treatment modality for treating androgen receptor positive cancers. The novel heterobifunctional compounds described herein comprise at least two different monofunctional compounds / ligands, one that targets androgen receptors and the other that targets a CBP / p300, with an optional linker connecting the two together. When the binder of the androgen receptor binds to its target and the CBP / p300 binder simultaneously binds with its target, inhibition of CBP / p300 is the result. The novel heterobifunctional compounds described herein are therapeutics with a high TI. For example, CBP / p300 inhibition with monofunctional inhibitors of CBP / p300 (e.g., CCS1477, GNE-781) have an impact on platelets and have shown to reduce platelet counts and cause thrombopoiesis inhibition. In some embodiments, this impact on platelets is not observed with the heterobifunctional CBP / p300 conditional inhibitors described herein.

[0025] In some embodiments disclosed herein is a heterobifunctional inhibitor. In some embodiments, the heterobifunctional inhibitor is a heterobifunctional conditional inhibitor. In some embodiments disclosed herein is a heterobifunctional inhibitor of CBP / p300. In some embodiments, the heterobifunctional inhibitor is a heterobifunctional conditional inhibitor of CBP / p300.

[0026] In some embodiments, wherein the silent binder of CBP / p300 binds to CBP / p300 and inhibits the activity of CBP / p300 in the COI if the binder of AR simultaneously binds to the AR and the relative abundance of AR in the COI is greater than the CBP / p300 in the COI.Attorney Docket No.: P60303-WO-1

[0027] In some embodiments, CBP / p300 and AR are both expressed in a cell of interest (COI).

[0028] In some embodiments, the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI. In some embodiments, the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI by a factor of at least about 2, at least about 5, at least about 10, at least about 50, at least about 100, or about least about 250. In some embodiments, the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI by a factor of at least about 100. In some embodiments, the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI. In some embodiments, the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI by a factor of at least about 2, at least about 5, at least about 10, at least about 50, at least about 100, or about least about 250. In some embodiments, the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI by a factor of at least about 100. In some embodiments, the relative abundance of AR in the COI is greater than the relative abundance of the CBP / p300 in the COI. In some embodiments, the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI by a factor of at least about 2, at least about 5, at least about 10, at least about 50, at least about 100, or about least about 250. In some embodiments, the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI by a factor of at least about 100.

[0029] In some embodiments, the COI is a diseased cell, and AR is overexpressed, overactive, or both overexpressed and overactive, or amplified in the diseased cell as compared to when the COI is a non-diseased cell. In some embodiments, the COI is a diseased cell, and AR is overexpressed in the diseased cell as compared to when the COI is a non-diseased cell. In some embodiments, the COI is a diseased cell, and AR is overactive in the diseased cell as compared to when the COI is a nondiseased cell. In some embodiments, the COI is a diseased cell, and AR is overexpressed and overactive in the diseased cell as compared to when the COI is a non-diseased cell. In some embodiments, the COI is a diseased cell, and AR is amplified in the diseased cell as compared to when the COI is a non-diseased cell. In some embodiments, COI is a diseased cell, and AR is overexpressed, overactive, or both overexpressed and overactive, or amplified in the diseased cell as compared to when the COI is a non-diseased cell.

[0030] In some embodiments, the activity of CBP / p300 is reduced or inhibited by the compound of Formula (I) when CBP / p300 and AR are both expressed in the same COI and the relative abundance of the AR in the COI is greater than the relative abundance of CBP / p300 in the COI. In some embodiments, the activity of CBP / p300 is reduced by the compound of Formula (I) when CBP / p300 and AR are both expressed in the same COI and the relative abundance of the AR in the COI is greater than the relative abundance of CBP / p300 in the COI. In some embodiments, the activity of CBP / p300 is inhibited by the compound of Formula (I)when CBP / p300 and AR are bothAttorney Docket No.: P60303-WO-1expressed in the same COI and the relative abundance of the AR in the COI is greater than the relative abundance of CBP / p300 in the COI.

[0031] In some embodiments, the activity of the CBP / p300 is unaltered by the compound of Formula (I) when CBP / p300 and AR are not both expressed in the same COI and / or the relative abundance of the AR in the COI is not greater than the relative abundance of CBP / p300 in the COI.Cell of Interest (COI)

[0032] In some embodiments, the COI is a diseased cell where inhibition of CBP / p300 is desirable. In some embodiments, the COI is a diseased cell overexpressing the androgen receptor. In some embodiments, the cell of interest is a cancer cell. In some embodiments, the cancer cell is associated with a carcinoma, sarcoma, leukemia, lymphoma, myeloma, or the central nervous system. In some embodiments, the cancer cell is associated with a carcinoma, for example, squamous cell carcinoma, adenocarcinoma, transitional cell carcinoma, or basal cell carcinoma. In some embodiments, the cancer cell is an epithelial cell, for example, a squamous cell, adenomatous cell, transitional cell, or basal cell. In some embodiments, the cancer cell is associated with a sarcoma, for example, bone sarcoma or soft tissue sarcoma. In some embodiments, the cancer cell is a bone cell, cartilage cell, or muscle cell. In some embodiments, the cancer cell is associated with a leukemia. In some embodiments, the cancer cell is a white blood cell. In some embodiments, the cancer cell is associated with a lymphoma or myeloma. In some embodiments, the cancer cell is a white blood cell or plasma cell. In some embodiments, the cancer cell is associated with the central nervous system, for example, the brain or spinal cord. In some embodiments, the cancer cell is a glial cell.

[0033] In some embodiments, the COI is a cell associated with head and neck cancer, laryngeal and hypopharyngeal cancer, nasal cavity and paranasal sinuses cancer, nasopharyngeal cancer, oral cavity (mouth) and oropharyngeal (throat) cancer, or salivary gland cancer. In some embodiments, the COI is a cell associated with anal cancer, bile duct cancer, colorectal cancer, esophagus cancer, gallbladder cancer, gastrointestinal neuroendocrine tumors, gastrointestinal stromal tumor, liver cancer pancreatic cancer, pancreatic neuroendocrine tumor, small intestine cancer, or stomach cancer. In some embodiments, the COI is a cell associated with associated with bladder cancer, kidney cancer, or Wilms tumor. In some embodiments, the COI is a cell associated with lung cancer, lung carcinoid tumor, or malignant mesothelioma. In some embodiments, the COI is a cell associated with breast cancer. In some embodiments, the COI is a cell associated with cervical cancer, endometrial cancer, ovarian cancer, penile cancer, prostate cancer, testicular cancer, uterine sarcoma, vaginal cancer, or vulvar cancer. In some embodiments, the COI is a cell associated with adrenal cancer, gastrointestinal neuroendocrine tumors, lung carcinoid tumor, pancreatic neuroendocrine tumor, pituitary tumors, or thyroid cancer. In some embodiments, the COI is a cell associated with skin cancer, basal and squamous cell skin cancer, Kaposi sarcoma, lymphoma of the skin, melanoma skin cancer, or Merkel cell skin cancer. In some embodiments, the COI is a cell associated with boneAttorney Docket No.: P60303-WO-1cancer, Ewing family of tumors, osteosarcoma, rhabdomyosarcoma, or soft tissue sarcoma. In some embodiments, the COI is a cell associated with eye cancer or retinoblastoma. In some embodiments, the COI is a cell associated with brain and spinal cord tumors or neuroblastoma. In some embodiments, the COI is a cell associated with leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, lymphoma, non-Hodgkin lymphoma, Hodgkin-lymphoma, multiple myeloma, myelodysplastic syndromes, thymus cancer, or Waldenstrom macroglobulinemia.

[0034] In some embodiments, the COI is a cell associated with prostate cancer or breast cancer. In some embodiments, the COI is a cell associated with prostate cancer, luminal breast cancer, and luminal androgen receptor triple-negative breast cancer.CBP / p300

[0035] CBP / p300 is an AR coactivator or coregulator. Androgens, functioning through the AR, are essential for the normal development and maintenance of the prostate. Androgen-bound AR functions as a transcription factor to regulate genes involved in an array of physiological processes. The transcriptional activity of AR is affected by coregulators that influence a number of functional properties of AR, including ligand selectivity and DNA binding capacity. As the promoter of target genes, coregulators participate in DNA modification, either directly through modification of histones or indirectly by the recruitment of chromatin-modifying complexes, as well as functioning in the recruitment of the basal transcriptional machinery. Aberrant coregulator activity due to mutation or altered expression levels may be a contributing factor in the progression of diseases related to AR activity, such as prostate cancer.

[0036] The progression of prostate cancer is also sensitive to androgens. Surgical and / or pharmacological androgen ablation remain the predominant form of treatment for advanced prostate cancer. Androgen ablation therapy is often combined with treatment with nonsteroidal antiandrogens, such as hydroxyflutamide, to block residual adrenal androgen action. While 70–80% of patients initially respond to androgen ablation therapy, tumors ultimately become resistant and may, in fact, proliferate in response to antiandrogens. Because AR is generally expressed in prostate tumors and their metastases, aberrant regulation of AR activity by coregulators may contribute to prostate cancer progression or the acquired agonist effect of antiandrogens.

[0037] In addition, androgen-independent activation of the AR is a well-known phenomenon and can occur via several different mechanisms, including activation by interleukins. For example, interleukin-6 (IL-6) has been shown to activate AR-dependent gene expression in the absence of androgens. Activation of the AR and AR target gene expression by IL-6 requires p300 and its HAT activity. Similar to IL-6, interleukin-4 (IL-4) activates the AR, increases CBP / p300 protein expression, and enhances the interaction of CBP / p300 with the AR at the KLK3 promoter. Therefore,Attorney Docket No.: P60303-WO-1CBP / p300 appears to be crucial for AR transcriptional activity in both the presence and absence of androgens.Silent Binder of CBP / p300

[0038] “Silent-binder” refers to a compound (or fragment of a heterobifunctional compound) that binds to a target protein (e.g., CBP / p300) and does not substantially alter protein function. In some embodiments, a silent binder does not result in functional activation or inhibition of the target protein (e.g., CBP / p300).

[0039] It is understood that some silent binders may, upon binding to a target protein, result in or induce some measurable or detectable effect on protein function. However, in such instances the measurable altered protein function is not detrimental to the ordinary functioning of the target protein at concentrations relevant for inducing inhibition of the target protein.

[0040] It is also understood that the silent binder to a target protein (e.g., CBP / p300) does not substantially alter protein function when it is incorporated into the heterobifunctional conditional inhibitor compounds disclosed herein unless the B-AR component of the heterobifunctional conditional inhibitor compound also simultaneously binds to AR in the same cell.

[0041] In some embodiments, a silent binder may be silent because it binds to a domain of a target protein that is not a relevant domain for the activity of the target protein. In other embodiments, a silent binder may be silent because it an allosteric binder of the target protein. In other embodiments, a silent binder may be silent because its incorporation into a heterobifunctional compound reduces the activity of the binder as compared to when it is not incorporated into a heterobifunctional compound. For example, a compound may be a modulator of a target protein (e.g., CBP / p300) when it is not a component of a heterobifunctional compound but becomes a silent binder of the target protein by virtue of its incorporation into a heterobifunctional compounds disclosed herein.

[0042] “Binder of androgen receptor” or “B-AR” refers to a compound (or fragment of a heterobifunctional compound) that binds to AR and: 1) does not substantially alter AR protein function; or 2) substantially alters AR protein function. In some embodiments, B-AR when incorporated into the heterobifunctional compounds disclosed herein does not substantially alter AR protein function of AR. In some embodiments, B-AR when incorporated into the heterobifunctional compounds disclosed herein does not substantially alter AR protein function of AR unless the silent binder of CBP / p300 component of the heterobifunctional conditional compound also simultaneously binds to CBP / p300 in the same cell.

[0043] Silent Antagonist is a drug that attenuates the effects of agonists or inverse agonists, producing a functional reduction in signal transduction. Affects only ligand-dependent receptor activation and displays no intrinsic activity itself. Also known as a neutral antagonist.Attorney Docket No.: P60303-WO-1

[0044] Agonist is a drug that binds to and activates a receptor. Can be full, partial or inverse. A full agonist has high efficacy, producing a full response while occupying a relatively low proportion of receptors. A partial agonist has lower efficacy than a full agonist. It produces sub-maximal activation even when occupying the total receptor population, therefore cannot produce the maximal response, irrespective of the concentration applied. An inverse agonist produces an effect opposite to that of an agonist yet binds to the same receptor binding-site as an agonist.

[0045] Allosteric Modulator is a drug that binds to a receptor at a site distinct from the active site. Induces a conformational change in the receptor, which alters the affinity of the receptor for the endogenous ligand. Positive allosteric modulators increase the affinity, whilst negative allosteric modulators decrease the affinity.

[0046] Antagonist is a drug that attenuates the effect of an agonist. Can be competitive or noncompetitive, each of which can be reversible or irreversible. A competitive antagonist binds to the same site as the agonist but does not activate it, thus blocks the agonist’s action. A non-competitive antagonist binds to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor. A reversible antagonist binds non-covalently to the receptor, therefore can be “washed out”. An irreversible antagonist binds covalently to the receptor and cannot be displaced by either competing ligands or washing.

[0047] Efficacy describes the way that agonists vary in the response they produce when they occupy the same number of receptors. High efficacy agonists produce their maximal response while occupying a relatively low proportion of the total receptor population. Lower efficacy agonists do not activate receptors to the same degree and may not be able to produce the maximal response (see Agonist, Partial).

[0048] In some embodiments, the silent binder of CBP / p300 is a CBP / p300 bromodomain binder. In some embodiments, the silent binder of CBP / p300 is a CBP / p300 histone acetyltransferase (HAT) domain binder. In some embodiments, the silent binder of CBP / p300 is a CBP / p300 bromodomain binder comprising a benzimidazole, piperidine, benzodiazepinone, indole, oxazolidinedione, barbituric skeleton, thiobarbituric skeleton, or alkaloid. In some embodiments, the silent binder of CBP / p300 is a CBP / p300 binder as described in Zhang-Xu He, et al., European Journal of Medicinal Chemistry, Volume 209, 2021, 112861, which is incorporated by reference for such CBP / p300 binder. In some embodiments, the silent binder of CBP / p300 is a CBP / p300 binder as any one of compounds 1 to 75 as described in Zhang-Xu He, et al., European Journal of Medicinal Chemistry, Volume 209, 2021, 112861, which is incorporated by reference for such CBP / p300 binders.Attorney Docket No.: P60303-WO-1

[0049] In some embodiments, the silent binder of CBP / p300 has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Compounds

[0050] Described herein is a heterobifunctional conditional inhibitor compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:SB-CBP / p300 — L |— B-AR^>wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human E1A-binding protein p300 (p300) (CBP / p300);L is an optional linker; wherein L is covalently attached at a position of SB-CBP / p300 that is solvent exposed when SB binds to CBP / p300;B-AR is a binder of the androgen receptor (AR), wherein the B-AR comprises option 1), option 2), or option 3):1) a head group A3that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety is covalently attached to the core moiety; wherein the head group A3is:Attorney Docket No.: P60303-WO-1wherein the core comprises an optionally substituted cycloalkyl having the structure of Formula (A):, Formula (A);wherein:each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4;2) a head group A3that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety is covalently attached to the core moiety; wherein the head group A3is:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1, and an optional tail moiety is covalently attached to the core moiety; the optional tail moiety of option 1), option 2), and option 3) comprises a ring D that is covalently attached to the core, wherein ring D is a 5-, 6-, 8-, 9- or 10-membered aryl or a 5-, 6-, 8-, 9- or 10-membered heteroaryl that is optionally substituted with w R3; w is 1, 2, 3, 4;Z is -O- or -NR5-;each X1is independently -CR1- or -N-;X4is -CRd- or -N-;each R1is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -OR4, OC(=O)R4, -OC(=O)N(R5)2, -OC(=O)OR5, -OC(=O)NR5, -SH, -SR4, - S(=O)R4, -S(=O)2R5, -S(=O)2OR4, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, - NR5C(=O)OR5, -NR5S(=O)2R5, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlais hydrogen, halogen, -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -NO2, -C(=O)R5, -C(=O)OR5, - C(=O)N(R5)2, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;Rldis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4;each R2is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - OR4, OC(=O)R4, -S(=O)R4, -S(=O)2R5, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, - C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; ortwo R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -OR4, or - N(R5)2;each R4is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;Attorney Docket No.: P60303-WO-1each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two R5on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; andwherein L is covalently attached to the core moiety at position (*) if the optional tail moiety is absent, or L is covalently attached to the tail moiety if present.

[0051] In some embodiments, described herein is a heterobifunctional conditional inhibitor compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human E1A-binding protein p300 (p300) (CBP / p300);L is an optional linker; wherein L is covalently attached at a position of SB-CBP / p300 that is solvent exposed when SB binds to CBP / p300;B-AR is a binder of the androgen receptor (AR), wherein the B-AR comprises option 1), option 2), option 3):1) a head group that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety is covalently attached to the core moiety; wherein the head group is:Attorney Docket No.: P60303-WO-1the structure of Formula (A):, Formula (A); wherein:each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4;2) a head group that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety is covalently attached to the core moiety; wherein the head group is:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1and an optional tail moiety is covalently attached to the core moiety;the optional tail moiety comprises a ring D that is covalently attached to the core, wherein ring D is a 5-, 6-, 8-, 9- or 10-membered aryl or a 5-, 6-, 8-, 9- or 10-membered heteroaryl that is optionally substituted with w R3; w is 1, 2, 3, or 4;Z is -O- or -NR5-;each X1is independently -CR1- or -N-;X4is -CRd- or -N-;each R1is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Cs-C. cycloalkyl. substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -OR4, OC(=O)R4, -OC(=O)N(R5)2, - OC(=O)OR5, -OC(=O)NR5, -SH, -SR4, -S(=O)R4, -S(=O)2R5, -S(=O)2OR4, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, -NR5C(=O)OR5, -NR5S(=O)2R5, -C(=O)R5, - C(=O)OR5, or -C(=O)N(R5)2;Rlais hydrogen, halogen, -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -NO2, -C(=O)R5, -C(=O)OR5, - C(=O)N(R5)2, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;Rldis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4;each R2is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Csheteroalkyl, -CN, -NO2, -OH, -OR4, OC(=O)R4, -S(=O)R4, -S(=O)2R5, -S(=O)2N(R5)2, - N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; or two R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each R3is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, -CN, -OH, -OR4, or -N(R5)2.each R4is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-Attorney Docket No.: P60303-WO-1membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two R5on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; andwherein L is covalently attached to the core moiety at position (*) if the optional tail moiety is absent, or L is covalently attached to the tail moiety if present.

[0052] In some embodiments, the binder of CBP / p300 binds in the acetyl-lysine (Kac) binding site of the bromodomain CBP / p300. In some embodiments, the binder of CBP / p300 comprises an acetyllysine mimetic moiety that binds in the acetyl-lysine (KAc) binding site of the bromodomain of human CREB-binding protein (CBP) or human ElA-binding protein p300 (p300) (CBP / p300).

[0053] In some embodiments, the optional linker is covalently attached at a position of a) that is solvent exposed when a) binds the KAc binding site of the bromodomain of CBP / p300.

[0054] In some embodiments, the moiety comprising an acetyl-lysine mimetic makes or mimics a hydrogen bond interaction to Asnl 168 in the Asn-binding pocket of the bromodomain of CBP, or makes or mimics a hydrogen bond interaction to Asnl 132 in the Asn-binding pocket of the bromodomain of p300.

[0055] In some embodiments, a) further comprises a moiety that interacts with Arg 1173 in the bromodomain of CBP or Asnl 137 in the bromodomain of p300.

[0056] In some embodiments, wherein a) further comprises:1) a moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300;or2) a moiety that occupies the BC Loop region of the bromodomain of CBP / p300; or3) both 1) and 2).

[0057] In some embodiments, wherein the moiety comprising an acetyl-lysine mimetic comprises a moiety selected from pyrrolidonyl, phenyl, pyridinyl, pyridinonyl, triazolyl, pyrrolyl, isoxazolyl, pyrazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolonyl, quinazolinyl, dihydroquinazolinonyl, imidazo [4,5 -c] quinolinyl fused to a dimethylisoxazolyl, triazolophthalazinyl, indolizinyl, benzoimidazolyl, isoxazole-indolizinyl, thienodiazepine-indolizinyl, benzodiazepine-indolizinyl, 5 -isoxazolylbenzimidazolyl, 6-isoxazolylbenzimidazolyl, 7 -isoxazolo-quinolinyl, diazobenzyl, triazolophthalazinyl, isoxazoloquinolinyl, 2-thiazolidinonyl, triazolopyrimidinyl, thienodiazepinyl, benzodiazepinyl, benzotriazepinyl, triazolobenzodiazepinyl, triazolothienodiazepinyl, triazolothienodiazepinyl, and isoxazole-azepinyl.

[0058] In some embodiments, the optional linker of c) is covalently attached to a) on: the acetyl-lysine mimetic moiety; or the moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300, if present; or the moiety that occupies the BC Loop region of the bromodomain of CBP / p300, if present; wherein the optional linker of c) is covalently attached to a) atAttorney Docket No.: P60303-WO-1a position that does not interfere with the binding of the acetyl-lysine mimetic moiety in the acetylated lysine (KAc) binding site of CBP / p300.

[0059] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprises a moiety selected from:Attorney Docket No.: P60303-WO-1each R32is independently an optional moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300;or each R32is independently an optional moiety that occupies the BC Loop region of the bromodomain of CBP / p300;H is the point of attachment to the optional linker that covalently connects a) to b);or -I is R32and the optional linker that covalently connects a) to b) is attached to R32;each R28is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;each R34is independently hydrogen or substituted or unsubstituted Ci-Cealkyl;each R35is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -OH, -ORa, or -N(Rb)2;m is 0, 1, 2, 3, or 4;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, - NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;Y is -C(R30)2- or C(=O);each R30is independently hydrogen, halogen, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- C6heteroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, - S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, - NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;q is 0, 1, 2, 3, or 4;each R31is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2; each R36is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;Ring B is a fused substituted or unsubstituted 5 or 6 membered heterocycloalkyl;Attorney Docket No.: P60303-WO-1each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0060] In some embodiments, the moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300 is R32, wherein:R32is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2-Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Cncycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;y is 1 or 2;Z is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted Ci-Cealkyl;R26is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each X is independently -CR27- or -N-;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -Attorney Docket No.: P60303-WO-1S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen or substituted or unsubstituted Ci-Cealkyl;R29is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;Y is -C(R30)2- or -N(R28)-;each R30is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, - OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, - NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;q is 0, 1, 2, 3, or 4;or R32is -L-C;L is substituted or unsubstituted Ci-Cealkyl or substituted or unsubstituted Ci-Ceheteroalkyl; C is substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted G- Gcycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0061] In some embodiments, the moiety that occupies the BC Loop region of the bromodomain of CBP / p300 is R32, wherein:Attorney Docket No.: P60303-WO-1each of which is substituted or unsubstituted.

[0062] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprisesIn some embodiments, the moiety comprising an acetyl-lysine mimetic comprisesIn some embodiments, the moiety comprising an acetyl-lysine mimetic comprises

[0063] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprisesIn some embodiments, the moietyAttorney Docket No.: P60303-WO-1comprising an acetyl-lysine mimetic comprises

[0064] In some embodiments, the moiety comprising an acetyl-lysine mimetic compriseswherein:each R28is independently hydrogen or substituted or unsubstituted Ci-Cealkyl;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, - C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2.

[0065] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprisesAttorney Docket No.: P60303-WO-1

[0066] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprises

[0067] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprisesembodiments, the moiety comprising an acetyl-lysine mimetic comprises the moiety comprising anacetyl-lysine mimetic comprises

[0068] In some embodiments,

[0069] In some embodiments, the moiety comprising an acetyl-lysine mimetic compriseswherein:each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;R33is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, or substituted or unsubstituted Ci-Ceheteroalkyl;R34is hydrogen or substituted or unsubstituted Ci-Cealkyl;each R38is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Cs-Cscycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, - CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -Attorney Docket No.: P60303-WO-1NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;r is 0, 1, 2, 3, or 4;Y X>'R26ZJGC.

[0070] In some embodiments, R32is ™J~~,, or^^X R27(R27)PX JC X—J —; each R27is independently hydrogen, substituted or unsubstituted Ci- Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Cscycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OH, or -ORa; and each Rais independently substituted or unsubstituted C1-C6alkyl.

[0071] In some embodiments, R32is

[0072] In some embodiments, each R27is independently hydrogen, -CH₃, -CH2CH3, -F, -CHF2, -CF₃, -CN, -OH, -OCH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrazolyl, 1 -methyl pyrazolyl, pyridinyl, or pyrimidinyl.Attorney Docket No.: P60303-WO-1N'N N-N N-N

[0074] In some embodiments, R32is d- O’, orAttorney Docket No.: P60303-WO-1

[0075] O-N

[0077] In some embodiments, R32is O-N N HN-N 'N In some embodiments, R32is

[0078] In some embodiments, SB-CBP / p300 has the structure of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof:Formula (IIIb)Attorney Docket No.: P60303-WO-1wherein:each X is independently -CR27- or -N-;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Cecycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, - OC(=O)N(Rb)2, -OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Ra, -S(=O)2Rb, -S(=O)2ORa, - S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)NRb, -N RbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Rb, - C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;y is 1 or 2;each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0079] In some embodiments, SB-CBP / p300 has the structure of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein:each X is independently -CR27- or -N-;each R27is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, - N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, - C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;Attorney Docket No.: P60303-WO-1R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;y is 1 or 2;each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C’s-Cecycloalkyl. substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Ci-Cecycloalkyl. substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0080] In some embodiments, SB-CBP / p300 has the structure of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof:Formula (IIIc)wherein:R6is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Ra, -S(=O)2Rb, -S(=O)2ORa, -S(=O)2N(Rb)2, - N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;Z is -NRC-, -O-, or -S-;Attorney Docket No.: P60303-WO-1Rcis hydrogen or substituted or unsubstituted Ci-Cealkyl;each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0081] In some embodiments, SB-CBP / p300 has the structure of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein:R26is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; each R27is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, - N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, - C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Ra, or -C(=O)N(Rb)2;Z is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted Ci-Cealkyl;each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substitutedAttorney Docket No.: P60303-WO-1or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0082] In some embodiments, SB-CBP / p300 has the structure of Formula (IIId-1) or (IIId-2), or awherein:R6is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Cs-Cscycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Rb, -S(=O)2Rb, - S(=O)2ORa, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, - NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R9is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R10is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Rb, -S(=O)2Rb, - S(=O)2ORa, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, - NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;q is 0, 1, 2, 3, or 4;each R11is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2ORa, -S(=O)2N(Rb)2, -Attorney Docket No.: P60303-WO-1N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;Y is -C(R10)2- or C(=O);each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0083] In some embodiments, SB-CBP / p300 has the structure of Formula (IIId-1) or (IIId-2), or a pharmaceutically acceptable salt or solvate thereof, wherein:R26is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, - S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R29is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R30is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, - OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, - NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;q is 0, 1, 2, 3, or 4;Attorney Docket No.: P60303-WO-1each R31is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, - NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or - C(=O)N(Rb)2;Y is -C(R30)2- or C(=O);each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0084] In some embodiments, SB-CBP / p300 has the structure of Formula (Hie), or a pharmaceutically acceptable salt or solvate thereof:Formula (IIIe)wherein:X is -CR27- or -N-;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Rb, -S(=O)2Rb, - S(=O)2ORa, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, - NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;Attorney Docket No.: P60303-WO-1R12is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;Ring A is absent or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0085] In some embodiments, SB-CBP / p300 has the structure of Formula (Hie), or a pharmaceutically acceptable salt or solvate thereof, wherein:X is -CR27- or -N-;each R27is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, - N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, - C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;R32is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; Ring A is absent or substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted orAttorney Docket No.: P60303-WO-1unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0086] In some embodiments, SB-CBP / p300 has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0087] In some embodiments, SB-CBP / p300 has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0088] In some embodiments, SB-CBP / p300 has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

[0089] In some embodiments, the silent binder of CBP / p300 has one of the following structures:Binder of the Androgen Receptor (AR) Component of the Heterobifunctional CBP / p300 Conditional Inhibitors

[0090] In some embodiments, B-AR comprises option 1) and a tail moiety that is covalently attached to the core, wherein the tail moiety comprises a ring D and the core and tail moiety have the structure:Attorney Docket No.: P60303-WO-1

[0092] In some embodiments, B-AR comprises option 1) and(R2)I; each R2is independently hydrogen, -CH₃, -CH₂F, -CHF₂, or -CF3

[0093] In some embodiments, B-AR comprises option 1) and or

[0094] In some embodiments, B-AR comprises option 1) and

[0095] In some embodiments, B-AR comprises option 1) and

[0096] In some embodiments, B-AR comprises option 1) and Z is -O-, -NH-. or -N(CH3)-.

[0097] In some embodiments, B-AR comprises option 1) and Z is -O- or -N(CH3)-.

[0098] In some embodiments, B-AR comprises option 1) and Z is -O-.Attorney Docket No.: P60303-WO-1

[0099] In some embodiments, B-AR comprises option 1) and A3is

[0100] In some embodiments, B-AR comprises option 1) and A3is

[0101] In some embodiments, B-AR comprises option 1) and A3isR1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1L T

[0104] In some embodiments, B-AR comprises option 1) and A3is

[0105] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:

[0106] In some embodiments, wherein B-AR comprises option 1) and the head group is:In some embodiments, wherein B-AR comprises option 1) and theAttorney Docket No.: P60303-WO-1

[0107] In some embodiments, wherein B-AR comprises option 1) and the head group is:

[0108] In some embodiments, each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, - CH2CFS, -OH, -OCF3, -OCH3, -OCD3, -OCH2CH3, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CD3).

[0109] In some embodiments, A3is:Attorney Docket No.: P60303-WO-1

[0110] In some embodiments, B-AR comprises option 1) and the head group is:

[0112] In some embodiments, B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1R1', R^R1^AO RI^A0^ Ug:R1or R1

[0113] In some embodiments, B-AR comprises option 1) and has the structure:Rl, RlR1, R1lxCNlor R^, R^0K^ o“Axr o ^V / A NHR1' °,0A?1orAttorney Docket No.: P60303-WO-1

[0114] In some embodiments, B-AR comprises option 1) and has the structure:

[0115] In some embodiments, wherein: each R1is independently hydrogen, F, Cl, Br, I, -CH3, - CD3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, -OCD3, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CD3).

[0116] In some embodiments, B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1

[0117] In some embodiments, B-AR comprises option 1) and has the structure:

[0118] In some embodiments, B-AR comprises option 1) and has the structure:

[0119] In some embodiments, B-AR comprises option 1) and has the structureAttorney Docket No.: P60303-WO-1

[0120] In some embodiments, B-AR comprises option 1) and has the structure

[0121] In some embodiments, B-AR comprises option 1) and has the structure:

[0122] In some embodiments, ring D is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl, wherein each ring D is optionally substituted with w R3.CR3- or -N-.

[0125] In some embodiments, each R3is independently hydrogen, F, Cl, Br, I, -CH₃, -CH₂CH₃, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OH, -OCF3, -OCH3, -OCH2CH3, -CN, -C(=O)NH2, or -C(=O)NH(CH3).

[0126] In some embodiments, each R3is independently hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or -CN.Attorney Docket No.: P60303-WO-1

[0128] In some embodiments, B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0129] In some embodiments, B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0130] In some embodiments, B-AR comprises option 1) and has the structure:

[0131] In some embodiments, B-AR comprises option 1) and has the structure:

[0132] In some embodiments, each R1is independently hydrogen, F, Cl, Br, I, -CH₃, -CD3, - -CH₂CH₃, -CH2F, -CHF2, -CFS, -OH, -OCF3, -OCH3, -OCD3, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CDs).

[0133] In some embodiments, B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1

[0134] In some embodiments, B-AR comprises option 1) and has the structure:. In some embodiments, B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1

[0135] In some embodiments, B-AR comprises option 1) and has the structure:

[0136] In some embodiments, each R1is independently hydrogen, F, Cl, Br, I, -CH₃, -CD3, - -CH₂CH₃, -CH2F, -CHF2, -CFS, -OH, -OCF3, -OCH3, -OCD3, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CDs).Attorney Docket No.: P60303-WO-1

[0137] In some embodiments, B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1

[0138] In some embodiments, B-AR comprises option 1) and has the structure:

[0140] In some embodiments, B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0142] In some embodiments, B-AR comprises option 2) and the core comprises:Attorney Docket No.: P60303-WO-10 0 0 0

[0143] In some embodiments, B-AR comprises option 2) and the core comprises:

[0144] In some embodiments, B-AR comprises option 2) and the core comprises:

[0145] In some embodiments, B-AR comprises option 2) and the core comprises:In some embodiments, the core comprises:Attorney Docket No.: P60303-WO-1In some embodiments, the core comprises:

[0146] In some embodiments, B-AR comprises option 2) and the core comprises:embodiments, the core comprises:. In some embodiments, the core comprises:. In someAttorney Docket No.: P60303-WO-1embodiments, the core comprises:In some embodiments, the core comprises:In some embodiments, the core comprises:. In some embodiments, the core comprises:In some embodiments, the core comprises:

[0148] In some embodiments, B-AR comprises option 2) and the core comprises:embodiments, the core comprises:. In some embodiments, the core comprises:. In some embodiments, the core comprises:

[0149] In some embodiments, B-AR comprises option 2) and the core comprises:Attorney Docket No.: P60303-WO-1

[0150] In some embodiments, B-AR comprises option 2) and the core comprises:

[0151] In some embodiments, B-AR comprises option 2) and the core comprises:Attorney Docket No.: P60303-WO-1

[0152] In some embodiments, B-AR comprises option 2) and the core comprises:Attorney Docket No.: P60303-WO-1

[0153] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0154] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0155] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1

[0156] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0157] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1

[0158] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1O, or O

[0159] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0160] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0161] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1

[0162] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0163] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0164] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0165] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0166] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:

[0167] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1

[0168] In some embodiments, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

[0169] In some embodiments, or a pharmaceutically acceptable salt or solvate thereof, wherein B-pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core

[0170] The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, whereinB-AR comprises option 2) and the core and tail moiety comprises:

[0171] In some embodiments, B-AR comprises option 2) and A3is selected from:Attorney Docket No.: P60303-WO-1each X1is independently -CR1- or -N-;Rlais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;each R1is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4; each R4is independently Ci-C4alkyl, or Ci-C4fluoroalkyl;each R5is independently hydrogen, Ci-C4alkyl, or Ci-C4fluoroalkyl.

[0172] In some embodiments, B-AR comprises option 2) and A3is selected from:Attorney Docket No.: P60303-WO-1eachX1is independently -CR1- or -N-; Rlais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;each R1is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4; each R4is independently Ci-C4alkyl, or Ci-C4fluoroalkyl;each R5is independently hydrogen, Ci-C4alkyl, or Ci-C4fluoroalkyl.

[0173] In some embodiments, Rlais -CN, -NO2, -C(=O)NH2 or -C(=O)NH(CH3);Rlbis hydrogen, F, Cl, Br, I, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or -CN;each Rlcis hydrogen, F, Cl, Br, -CH3, -CH₂F, -CHF₂, or -CF3;each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CH₂F, -CHF₂, -CF₃, -OH, -OCF3, or - OCH3.

[0174] In some embodiments, A3is selected from:Attorney Docket No.: P60303-WO-1

[0175] Attorney Docket No.: P60303-WO-1

[0176] In some embodiments, A3is selected from:ON,Or GN

[0177] In some embodiments, A3isxr xiCNxxCN

[0178] In some embodiments, A3is MM Aj MJ, JM^CN xxAttorney Docket No.: P60303-WO-1

[0179] In some embodiments, A3is

[0181] In some embodiments, B-AR comprises a head group A3and an optional core, wherein A3is selected from:

[0182] In some embodiments, B-AR comprises option 2) and the core and tail moiety comprises:CNAttorney Docket No.: P60303-WO-1

[0183] In some embodiments, ring D that is phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, napthyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, or benzotriazolyl; wherein ring D is optionally substituted with w R3; w is 1, 2, 3 or 4; each R3is independently hydrogen, F, Cl, Br, I, -CH3, -CH₂CH₃, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, - CH2CF3, -OH, -OCF3, -OCH3, -OCH2CH3, -CN, -C(=O)NH2or -C(=O)NH(CH3). In some embodiments, w is 1, 2, or 3. In some embodiments, w is 1 or 2. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.

[0184] In some embodiments, wherein ring D is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl, wherein each ring D is optionally substituted with w R3.CR3- or -N-.

[0187] In some embodiments, each R3is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, - CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, - CH2CF3, -OH, -OCF3, -OCH3, -OCH2CH3, -CN, - C(=O)NH2, or -C(=O)NH(CH3).X.HX. N

[0188] In some embodiments,Attorney Docket No.: P60303-WO-1

[0189] In some embodiments, B-AR has one of the following structures

[0190] In some embodiments, B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0192] In some embodiments, B-AR has one of the following structures:

[0193] In some embodiments, B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1

[0194] In some embodiments, B-AR has one of the following structures:

[0195] In some embodiments, B-AR has one of the following structures:

[0196] In some embodiments, B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1N-NAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0200] In some embodiments, B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0204] In some embodiments, the linker is absent.

[0205] In some embodiments, the linker has a prescribed length thereby linking the silent binder of CBP / p300 and the binder of AR while allowing an appropriate distance therebetween.

[0206] In some embodiments, the linker is flexible. In some embodiments, the linker is rigid.

[0207] In some embodiments, the linker comprises a linear structure. In some embodiments, the linker comprises a non-linear structure. In some embodiments, the linker comprises a branched structure. In some embodiments, the linker comprises a cyclic structure.

[0208] In some embodiments, the use of trivalent linkers allow for the preparation of heterotrifunctional compounds comprising one silent binder to a DDP and two binders to a disease protein, or two silent binders to a DDP and one binder to a disease protein, thereby simultaneously binding a disease protein and a DDP and forming a productive ternary complex. In some embodiments, such heterotrifunctional compounds would result in more sustained and more potent anticancer activity.

[0209] In some embodiments, the linker comprises one or more linear structures, one or more nonlinear structures, one or more branched structures, one or more cyclic structures, one or more flexible moieties, one or more rigid moieties, or combinations thereof.

[0210] In some embodiments, the linker comprises one or more amino acid residues. In some embodiments, the linker comprises 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. In some embodiments, one or more amino acids of the linker are unnatural amino acids. In some embodiments, the linker comprises a peptide linkage. The peptide linkage comprises L-amino acids and / or D-amino acids.

[0211] In some embodiments, the linker has 1 to 100 atoms, 1 to 50 atoms, 1 to 30 atoms, 1 to 20 atoms, 1 to 15 atoms, 1 to 10 atoms, or 1 to 5 atoms in length. In some embodiments, the linker has 1 to 10 atoms in length. In some embodiments, the linker has 1 to 20 atoms in length.

[0212] In some embodiments, the linker comprises flexible and / or rigid regions.Attorney Docket No.: P60303-WO-1

[0214] In some embodiments, L comprises substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or combinations thereof.I — TA)— (L1)n-

[0215] In some embodiments, L is absent or TA) — I'v—, wherein: each A is independently absent, substituted or unsubstituted monocyclic Cs-Ciocycloalkyl, substituted or unsubstituted bridged bicyclic Cs-Ciocycloalkyl, substituted or unsubstituted fused bicyclic C3-Ciocycloalkyl, substituted or unsubstituted spiro bicyclic Cs-Ciocycloalkyl, substituted or unsubstituted monocyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted bridged bicyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted fused bicyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted spiro bicyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein each A is independently unsubstituted or substituted with x R2b;wherein each L1is independently unsubstituted or substituted with x R2b;n is 1, 2, 3, 4, 5, or 6;each x is independently 1, 2, 3, 4, 5, 6, 7, or 8;each R2ais independently hydrogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci-C4fluoroalkyl, or substituted or unsubstituted Cs-Cecycloalkyl; andeach R2bis independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Cs-Cscycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, - OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -Attorney Docket No.: P60303-WO-1C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0216] In some embodiments, each A is independently absent,Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1n is 1, 2, or 3;each x is independently 1, 2, 3, 4, 5, or 6;each Rais independently hydrogen or substituted or unsubstituted C1-C6alkyl; andeach Rbis independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl.

[0218] In some embodiments, each A is independently absent, absent,Attorney Docket No.: P60303-WO-1embodiments, each A is independently. Insome embodiments, each A is independently absent,Rbx RiN[002191 In some embodiments, each absent,RiaNn is 1, 2, or 3;each x is independently 1, 2, 3, 4, 5, or 6;each Rais independently hydrogen or substituted or unsubstituted C1-C6alkyl; andeach Rbis independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl.

[0220] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0221] In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6.

[0222] In some embodiments, Rais hydrogen. In some embodiments, each Rais independently substituted or unsubstituted C1-C6alkyl. In some embodiments, each Rais independently hydrogen, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl. In some embodiments, each Rais independently hydrogen or methyl. In some embodiments, Rais methyl.

[0223] In some embodiments, Rbis hydrogen. In some embodiments, each Rbis independently substituted or unsubstituted Ci-Cealkyl. In some embodiments, each Rbis independently hydrogen, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl. In some embodiments, each Rbis independently hydrogen or methyl. In some embodiments, Rbis methyl.

[0224] In some embodiments, (L’)nis absent, (L’)nis absent,Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1thereof.

[0227] In some embodiments, L isAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1or a pharmaceutically acceptable salt or solvate thereof.

[0228] In some embodiments, SB-CBP / p300 has the structure of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof:Formula (IIIb)wherein:each X is independently -CR27- or -N-;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Cecycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, - OC(=O)N(Rb)2, -OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Ra, -S(=O)2Rb, -S(=O)2ORa, - S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)NRb, -N RbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Rb, - C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;y is 1 or 2;each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;Attorney Docket No.: P60303-WO-1or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0229] In some embodiments, SB-CBP / p300 has the structure of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof, wherein:each X is independently -CR27- or -N-;each R27is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, - C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;y is 1 or 2;each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0230] In some embodiments, SB-CBP / p300 has the structure of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof:.28NNFormula (IIIc)-BlAttorney Docket No.: P60303-WO-1wherein:R6is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted -Cefluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Ra, -S(=O)2Rb, -S(=O)2ORa, -S(=O)2N(Rb)2, - N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;Z is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted Ci-Cealkyl;each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted G-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0231] In some embodiments, SB-CBP / p300 has the structure of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof, wherein:R26is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; each R27is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -Attorney Docket No.: P60303-WO-1N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, - C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Ra, or -C(=O)N(Rb)2;Z is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted Ci-Cealkyl;each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C’s-Cecycloalkyl. substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0232] In some embodiments, SB-CBP / p300 has the structure of Formula (IIId-1) or (IIId-2), or a pharmaceutically acceptable salt or solvate thereof:wherein:R6is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Rb, -S(=O)2Rb, - S(=O)2ORa, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, - NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;Attorney Docket No.: P60303-WO-1p is 0, 1, 2, or 3;R9is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R10is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Rb, -S(=O)2Rb, - S(=O)2ORa, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, - NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;q is 0, 1, 2, 3, or 4;each R11is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2ORa, -S(=O)2N(Rb)2, - N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;Y is -C(R10)2- or C(=O);each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0233] In some embodiments, SB-CBP / p300 has the structure of Formula (IIId-1) or (IIId-2), or a pharmaceutically acceptable salt or solvate thereof, wherein:R26is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R27is independently hydrogen, halogen, substituted or unsubstituted G-Cealkyl, substituted or unsubstituted G-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Attorney Docket No.: P60303-WO-1CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, - S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R29is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each R30is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, - OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, - NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;q is 0, 1, 2, 3, or 4;each R31is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, - NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or - C(=O)N(Rb)2;Y is -C(R30)2- or C(=O);each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.Attorney Docket No.: P60303-WO-1

[0234] In some embodiments, SB-CBP / p300 has the structure of Formula (Hie), or a pharmaceutically acceptable salt or solvate thereof:Formula (IIIe)wherein:X is -CR27- or -N-;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORb, -OC(=O)NRb, -SH, -SRa, -S(=O)Rb, -S(=O)2Rb, - S(=O)2ORa, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORb, - NRbS(=O)2Rb, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;R12is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;Ring A is absent or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0235] In some embodiments, SB-CBP / p300 has the structure of Formula (IIIe), or a pharmaceutically acceptable salt or solvate thereof, wherein:X is -CR27- or -N-;Attorney Docket No.: P60303-WO-1each R27is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted G-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, - N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, - C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;R32is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; Ring A is absent or substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each Rais independently substituted or unsubstituted G-Galky!, substituted or unsubstituted G-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted G-Galkyl, substituted or unsubstituted G-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0236] In some embodiments, SB-CBP / p300 has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0237] In some embodiments, SB-CBP / p300 has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0238] In some embodiments, SB-CBP / p300 has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

[0239] In some embodiments, a compound described herein is a heterobifunctional conditional inhibitor of CBP / p300 having the structure of Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), or Formula (X), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.: P60303-WO-1Formula (X), wherein, A3or A4isAttorney Docket No.: P60303-WO-1each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4;Z is -O- or -NR5-;each X1is independently -CR1- or -N-;X4is -CRld- or -N-;each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4;Rlais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, or -CN;Rldis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4;or Rlband Rldare taken together with the intervening carbon atoms between Rlband Rldto form a phenyl, pyridinyl, pyridazinyl, or pyrimidinyl optionally substituted with 1 or 2 R1; each X is independently -CR3- or -N-;each R2is independently hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl; or two R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;Attorney Docket No.: P60303-WO-1each R3is independently hydrogen, halogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci- C4fluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, -CN, -OH, -OR4, or -N(R5)2. each R4is independently Ci-C4alkyl, Ci-C4deuteroalkyl, or Ci-C4fluoroalkyl;each R5is independently hydrogen, Ci-C4alkyl, Ci-C4deuteroalkyl, or Ci-C4fluoroalkyl; R28is -C(=O)CH3, -C(=O)CD3, -C(=O)CF3, -C(=O)CH2F, -C(=O)CHF2, -C(=O)CH2CH3, - C(=O)CD2CH3, -C(=O)CH2CD3, -C(=O)CD2CD3, -C(=O)CH2CF3, -C(=O)CF2CF3, - C(=O)CH2CH2F, -C(=O)CH2CHF2, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CD3), - C(=O)NH(CF3), -C(=O)NH(CH2F), -C(=O)NH(CHF2), -C(=O)NH(CH3), - C(=O)NH(CH2CH3), -C(=O)NH(CD2CD3), -C(=O)NH(CH2CF3), -C(=O)NH(CF2CF3), - C(=O)NH(CH2CH2F), or -C(=O)NH(CH2CHF2);each X2is independently -CR30- or -N- provided that at most two X2are -N-;Z1is -NRC- or -O-; Rcis hydrogen or C1-C6alkyl;R26is hydrogen, substituted or unsubstituted Ci-C4alkyl, Ci-C4deuteroalkyl, Ci- C4fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;X3is -CR27- or -N-;R27is hydrogen, halogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci-C4fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CN, -OH, -ORa, -N(Rb)2, -NRbC(=O)Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;each R30is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, -CN, -OH, or -ORa;each R35is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl;m is 0, 1, or 2; p is 0, 1, 2, or 3;Attorney Docket No.: P60303-WO-1each of A1and A2is independently absent, substituted or unsubstituted monocyclic C3- Ciocycloalkyl, substituted or unsubstituted spiro bicyclic Cs-Cncycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, or substituted or unsubstituted spiro bicyclic 5- to 12-membered heterocycloalkyl, wherein each A is independently unsubstituted or substituted with x R2b;each R2ais independently hydrogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci-C4fluoroalkyl, or substituted or unsubstituted C3-C6cycloalkyl:each R2bis independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;each Rais independently Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cefluoroalkyl, Ci-Attorney Docket No.: P60303-WO-1Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0240] As described herein, substructures of, including, and L2align with the orientation of the formulas from which they depend (left-to-right orientation).

[0241] In some embodiments, the compound has the following structure:Formula (IVa),Formula (Va),Formula (Vb),Formula (Vc),Attorney Docket No.: P60303-WO-1Formula (Via),Formula (Vila), o Formula (Villa), Formula (IX),Attorney Docket No.: P60303-WO-1

[0242] In some embodiments, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0243] In some embodiments, or a pharmaceutically acceptable salt or solvate thereof, wherein: each X1is -CR1- or -N-, provided that at most 2 X1are -N-;Rlais -CN;Rlbis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; each Rlcis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, or -CF3;Rldis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3;or Rlband Rldare taken together with the intervening carbon atoms between Rlband Rldto form a phenyl or pyridinyl optionally substituted with 1 or 2 R1;each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, -CH2CF3, -OH, -OCF3, -OCH3, or -OCH2CH3.

[0244] In some embodiments, or a pharmaceutically acceptable salt or solvate thereof, wherein A4Attorney Docket No.: P60303-WO-1’ ° -Attorney Docket No.: P60303-WO-1; and each R3is independently hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OH, -OCF3, -OCH3, -OCH2CH3OCD3, -OCH2CD3, -CN, -NH2, -NH(CH3), -NH(CH3)2, -NH(CD3) or -N(CD3)2; and each R3is independently hydrogen, F, Cl, -CH3, - CD3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, -OCD3, or -CN.Attorney Docket No.: P60303-WO-1

[0247] In some embodiments, the compound has the structure of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:

[0248] In some embodiments, the compound has the structure of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:Formula (Va),Attorney Docket No.: P60303-WO-1F

[0249] In some embodiments, the compound has the structure of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.: P60303-WO-1

[0250] In some embodiments, the compound has the structure of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof:A4A4A4A4I I I IA4A4A4I I IAttorney Docket No.: P60303-WO-1

[0251] In some embodiments, the compound has the structure of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.: P60303-WO-1

[0252] In some embodiments, the compound has the structure of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Cl, Br, I, -CH₃, -CD₃, -CF3, -CH2F, -CHF2, -CH₂CH₃, -CD₂CH₃, -CH₂CD₃, -CD₂CD₃, -CH₂CF₃ -CF₂CF₃, -CH₂CH₂F, -CH₂CHF₂, -OCH₃, -OCD₃, -OCF₃, -OCH₂F, -OCHF₂, -OCH₂CH₃, -OCD₂CH₃ -OCH₂CD₃, -OCD₂CD₃, -OCH₂CF₃, -O-CF₂CF₃, -OCH₂CH₂F, -OCH₂CHF₂, or -CN.Attorney Docket No.: P60303-WO-1

[0255] In some embodiments, R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, - ORa, -N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -Attorney Docket No.: P60303-WO-1R26

[0256] In some embodiments, R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, -yR26N-N0Ra, -N(Rb)2, -C(=O)Rb, or -C(=O)N(Rb)2; or R27ishydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -(CH3)3, -CD3, -CD2CH3, -CH2CD3, -CD2CD3, -CF₃, -CH2F, -CHF2, -CH2CF3, -CF2CF3, -CH2CH2F, -CH2CHF2, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0257] In some embodiments, R27is hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, - CH2CF3, -OH, -OCF3, -OCH3, -OCH2CH3, -OCD3, -OCH2CD3, -CN, -NH2, -NH(CH3), -NH(CH3)2, -NH(CD3) or -N(CD3)2, -C(=O)CH3, -C(=O)CD3, -C(=O)CF3, -C(=O)CH2F, -C(=O)CHF2, -C(=O)CH2CH3, -C(=O)CD2CD3, -C(=O)CH2CF3, -C(=O)CF2CF3, -C(=O)CH2CH2F, -C(=O)CH2CHF2, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CD3), -C(=O)NH(CF3), -C(=O)NH(CH2F), -C(=O)NH(CHF2), -C(=O)NH(CH3), -C(=O)NH(CH2CH3), -C(=O)NH(CD2CD3), -C(=O)NH(CH2CF3), -C(=O)NH(CF2CF3), -C(=O)NH(CH2CH2F), or -C(=O)NH(CH2CHF2); or R27ishydrogen, -CH3, -CH2CH3, -CH2(CH3)2, -(CH₃)₃, -CD3, -CF₃, -CH2F, -CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0258] In some embodiments, R30is hydrogen, -CH3, -CD3, -CF₃, -CH2F, -CHF2, or -CN.

[0259] In some embodiments, R32aisAttorney Docket No.: P60303-WO-1j LA A it _A A. x r IJ5M, i'T,Attorney Docket No.: P60303-WO-1

[0260] In some embodiments,cyclopropyl;Attorney Docket No.: P60303-WO-1substituted with one or more D, F, Cl, -CH3, -CD3, -CF3, -CH₂F, -CHF₂, -OH, -OCH3, -OCD3, -OCF3, -OCH2F, or -OCHF2; -CH₂CH₃, -CH(CH3)2, or cyclopropyl.Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-11f1i < VH \ | V IAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1, or a pharmaceutically acceptable salt or solvate thereof.

[0267] In some embodiments,Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0271] In some embodiments,, each Rdis independently hydrogen, or -CH3; each R2ais independently hydrogen, -CH3, -CH₂CH₃, -CH(CH3)2, -CF₃, -CH₂F, -CHF₂, or cyclopropyl; and each R2bis independently hydrogen, F, Cl, -CH3, -CF₃, -CH₂F, -CHF₂, -OH, -OCH3, -OCD3, -OCF3, -OCH₂F, -OCHF₂, -CN or cyclopropyl. In some embodiments, each Rdis independently hydrogen; each R2ais independently hydrogen, -CH3, -CH₂CH₃, -CH(CH3)2, or cyclopropyl; and each R2bis independently hydrogen, F, -CH3, -CF₃, -CH₂F, -CHF₂, -OH, or -OCH3. In some embodiments, each Rdis independently hydrogen; each R2ais independently hydrogen, -CH3, -CH₂CH₃, -CH(CH3)2, or cyclopropyl; and each R2bis independently hydrogen, F, -CH3, -OH, or -OCH3.Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1or a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1solvate thereof.Attorney Docket No.: P60303-WO-1oAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1pharmaceutically acceptable salt or solvate thereof.

[0289] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof:Table 1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1^ \O.AAO_ / / \z1xzs

[0290] In some embodiments, the compound is a compound of Table 1A, or a pharmaceutically acceptable salt or solvate thereof:z oTable 1ACmpd. StructurezJ100 zFcr? \101F y OAooAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Numbered Embodiments

[0291] Embodiment 1. A heterobifunctional conditional inhibitor compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human E1A-binding protein p300 (p300) (CBP / p300);L is an optional linker; wherein L is covalently attached at a position of SB-CBP / p300 that is solvent exposed when SB binds to CBP / p300;B-AR is a binder of the androgen receptor (AR), wherein the B-AR comprises option 1), option 2), or option 3):1) a head group that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety is covalently attached to the core moiety; wherein the head group is:Attorney Docket No.: P60303-WO-1the structure of Formula (A):, Formula (A);wherein:each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4;2) a head group that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety is covalently attached to the core moiety; wherein the head group is:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1, and an optional tail moiety is covalently attached to the core moietythe optional tail moiety comprises a ring D that is covalently attached to the core, wherein ring D is a 5-, 6-, 8-, 9- or 10-membered aryl or a 5-, 6-, 8-, 9- or 10-membered heteroaryl that is optionally substituted with w R3; w is 1, 2, 3, or 4;Z is -O- or -NR5-;each X1is independently -CR1- or -N-;X4is -CRd- or -N-;each R1is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Cs-C. cycloalkyl. substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -OR4, OC(=O)R4, -OC(=O)N(R5)2, - OC(=O)OR5, -OC(=O)NR5, -SH, -SR4, -S(=O)R4, -S(=O)2R5, -S(=O)2OR4, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, -NR5C(=O)OR5, -NR5S(=O)2R5, -C(=O)R5, - C(=O)OR5, or -C(=O)N(R5)2;Rlais hydrogen, halogen, -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -NO2, -C(=O)R5, -C(=O)OR5, - C(=O)N(R5)2, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;Rldis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4;each R2is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Attorney Docket No.: P60303-WO-1C6heteroalkyl, -CN, -NO2, -OH, -OR4, OC(=O)R4, -S(=O)R4, -S(=O)2R5, -S(=O)2N(R5)2;N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; or two R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each R3is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, -CN, -OH, -OR4, or -N(R5)2.each R4is independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two R5on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; andwherein L is covalently attached to the core moiety at position (*) if the optional tail moiety is absent, or L is covalently attached to the tail moiety if present.

[0292] Alternate Embodiment 1. A heterobifunctional conditional inhibitor compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:SB-CBP / p300 B-ARwherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human E1A-binding protein p300 (p300) (CBP / p300);L is an optional linker; wherein L is covalently attached at a position of SB-CBP / p300 that is solvent exposed when SB binds to CBP / p300;B-AR is a binder of the androgen receptor (AR), wherein the B-AR comprises option 1), option 2), or option 3):option 1) a head group A3that occupies the ligand-binding domain (LBD) of AR, and an optional tail moiety (ring D) is covalently attached to the core moiety; wherein the core comprises an optionally substituted cycloalkyl and the core and head group A3have the structure of Formula (A):Attorney Docket No.: P60303-WO-1(R )m, Formula (A);wherein each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4; andR1option 2) a head group A3that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety (ring D) is covalently attached to the coreAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1, and an optional tail moiety (ring D) is covalently attached to the core moiety;the optional tail moiety of option 1), option 2), and option 3) comprises a ring D that is covalently attached to the core, wherein ring D is a 5-, 6-, 8-, 9- or 10-membered aryl or a 5-, 6-, 8-, 9- or 10-membered heteroaryl that is optionally substituted with w R3; w is 1, 2, 3, 4;Z is -O- or -NR5-;each X1is independently -CR1- or -N-;X4is -CRd- or -N-;each R1is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -OR4, OC(=O)R4, -OC(=O)N(R5)2, -OC(=O)OR5, -OC(=O)NR5, -SH, -SR4, - S(=O)R4, -S(=O)2R5, -S(=O)2OR4, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, - NR5C(=O)OR5, -NR5S(=O)2R5, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlais hydrogen, halogen, -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -NO2, -C(=O)R5, -C(=O)OR5, - C(=O)N(R5)2, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;Attorney Docket No.: P60303-WO-1Rldis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4;each R2is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, - OR4, OC(=O)R4, -S(=O)R4, -S(=O)2R5, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, - C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; ortwo R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -OR4, or - N(R5)2;each R4is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two R5on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; andwherein L is covalently attached to the core moiety at position (*) if the optional tail moiety is absent, or L is covalently attached to the tail moiety if present.

[0293] Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and a tail moiety that is covalently attached to the core, wherein the tail moiety comprises a ring D and the core and tail moiety have the structure:

[0294] Embodiment 3. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) andAttorney Docket No.: P60303-WO-1each R2is independently hydrogen, -CH3, -CH₂F, -CHF₂, or -CF3

[0295] Embodiment 4. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) andeach R2is independently hydrogen, -CH3, -CH₂F, -CHF₂, or -CF3

[0296] Embodiment 5. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and

[0297] Embodiment 6. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and

[0298] Embodiment 7. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and

[0299] Embodiment 8. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and Z is -O-, -NH-. or -N(CH3)-.

[0300] Embodiment 9. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and Z is -O- or -N(CH3)-.

[0301] Embodiment 10. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and Z is -O-.Attorney Docket No.: P60303-WO-1

[0302] Embodiment 11. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and the head group is:

[0303] Embodiment 12. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and the head group is:

[0304] Embodiment 13. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and the head group is:

[0305] Embodiment 14. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH₂CH₃, -CH₂F, -CHF₂, -CFs, - CH2CH2F, -CH₂CHF₂, - CH2CF3, -OH, -OCF₃, -OCH₃, -OCD₃, -OCH₂CH₃, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CD3).

[0306] Embodiment 15. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and the head group is:Attorney Docket No.: P60303-WO-1

[0307] Embodiment 16. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and the head group is:

[0308] Embodiment 17. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1

[0309] Embodiment 18. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:

[0310] Embodiment 19. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH₂CH₃, -CH₂F, -CHF₂, -CFs, -OH, -OCF₃, -OCH₃, -OCD₃, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CD3).

[0311] Embodiment 20. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1

[0312] Embodiment 21. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:

[0313] Embodiment 22. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1

[0314] Embodiment 23. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:

[0315] Embodiment 24. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH₂CH₃, -CH₂F, -CHF₂, -CF₃, -OH, -OCF₃, -OCH₃, -OCD₃, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CD3).

[0316] Embodiment 25. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1

[0317] Embodiment 26. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-1

[0318] Embodiment 27. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core comprises:Attorney Docket No.: P60303-WO-1

[0319] Embodiment 28. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core comprises:

[0320] Embodiment 29. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1o

[0321] Embodiment 30. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

[0322] Embodiment 31. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

[0323] Embodiment 32. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

[0324] Embodiment 33. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1

[0325] Embodiment 34. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

[0326] Embodiment 35. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

[0327] Embodiment 36. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1

[0328] Embodiment 37. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

[0329] Embodiment 38. The compound of any one of embodiments 26-37, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and head group is selected from:eachX1is independently -CR1- or -N-; Rlais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;each R1is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4; each R4is independently Ci-C4alkyl, or Ci-C4fluoroalkyl;each R5is independently hydrogen, Ci-C4alkyl, or Ci-C4fluoroalkyl.

[0330] Embodiment 39. The compound of any one of embodiments 1-11 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises a head group and an optional core, wherein the head group is:Attorney Docket No.: P60303-WO-1Rlais -CN, -NO2, -C(=O)NH2, or -C(=O)NH(CH3);Rlbis hydrogen, F, Cl, Br, I, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or -CN; each Rlcis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, or -CF3;each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or - OCH3.

[0331] Embodiment 40. The compound of any one of embodiments 26-37, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises a head group and an optional core, wherein the head group is selected from:

[0332] Embodiment 41. The compound of any one of embodiments 26-37, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises a head group and an optional core, wherein the head group is:

[0333] Embodiment 42. The compound of embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1

[0334] Embodiment 42. The compound of embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0335] Embodiment 43. The compound of embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, wherein:CNRib is

[0336] Embodiment 44. The compound of any embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises a head group and an optional core, wherein the head group is selected from:Attorney Docket No.: P60303-WO-1Cl

[0337] Embodiment 45. The compound of any one of embodiments 26-37, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises a head group and an optional core, wherein the head group is selected from:CN, or CN.

[0338] Embodiment 46. The compound of any one of embodiments 26-37, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises a head group and an optional core, wherein the head group is selected from:Attorney Docket No.: P60303-WO-1

[0339] Embodiment 47. The compound of embodiment 46, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0341] Embodiment 49. The compound of any one of embodiments 26-37, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises a head group and an optional core, wherein the head group is selected from:

[0342] Embodiment 50. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1

[0343] Embodiment 51. The compound of any one of embodiments 1-50, or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl, wherein each ring D is optionally substituted with w R3.

[0344] Embodiment 52. The compound of any one of embodiments 1-50, or a pharmaceuticallyCR3- or -N-.

[0345] Embodiment 53. The compound of any one of embodiments 1-50, or a pharmaceutically

[0346] Embodiment 54. The compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OH, -OCF3, -OCH3, -OCH2CH3, CN, -C(=O)NH2, or -C(=O)NH(CH3).Attorney Docket No.: P60303-WO-1

[0347] Embodiment 55. The compound of any one of embodiments 29-33, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0348] Embodiment 56. The compound of embodiment 1-11 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0349] Embodiment 57. The compound of any one of embodiments 1-56, or a pharmaceutically acceptable salt or solvate thereof, wherein SB-CBP / p300 binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300, optionally wherein SB-CBP / p300 comprises an acetyl-lysine mimetic moiety that binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300, wherein L is covalently attached at a position of SB-CBP / p300 that is solvent exposed when SB-CBP / p300 binds the KAc binding site of the bromodomain of CBP / p300.

[0350] Embodiment 58. The compound of any one of embodiments 1-56, or a pharmaceutically acceptable salt or solvate thereof, wherein SB-CBP / p300 further comprises:1) a moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300;or2) a moiety that occupies the BC Loop region of the bromodomain of CBP / p300; or3) both 1) and 2);wherein L is covalently attached to SB-CBP / p300 on:• the acetyl-lysine mimetic moiety; or• the moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300, if present; or• the moiety that occupies the BC Loop region of the bromodomain of CBP / p300, if present;wherein L is covalently attached to SB-p300 / CBP at a position that does not interfere with the binding of the acetyl-lysine mimetic moiety in the acetylated lysine (KAc) binding site of CBP / p300.

[0351] Embodiment 59. The compound of embodiment 57-58, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises a moiety selected from pyrrolidonyl, phenyl, pyridinyl, pyridinonyl, triazolyl, pyrrolyl, isoxazolyl, pyrazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolonyl, quinazolinyl, dihydroquinazolinonyl, imidazo[4,5-c]quinolinyl fused to a dimethylisoxazolyl, triazolophthalazinyl, indolizinyl, benzoimidazolyl, isoxazole-indolizinyl, thienodiazepine-indolizinyl, benzodiazepine -indolizinyl, 5-isoxazolylbenzimidazolyl, 6-isoxazolylbenzimidazolyl, 7-isoxazolo-quinolinyl, diazobenzyl, triazolophthalazinyl, isoxazoloquinolinyl, 2-thiazolidinonyl, triazolopyrimidinyl, thienodiazepinyl, benzodiazepinyl, benzotriazepinyl, triazolobenzodiazepinyl,Attorney Docket No.: P60303-WO-1triazolothienodiazepinyl, triazolothienodiazepinyl, and isoxazole-azepinyl.

[0352] Embodiment 60. The compound of any one of embodiments 57-59, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises a moiety selected from:each R32is independently an optional moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300;Attorney Docket No.: P60303-WO-1or each R32is independently an optional moiety that occupies the BC Loop region of the bromodomain of CBP / p300;-I is the point of attachment to L that covalently connects SB-CBP / p300 to B-AR;or R32comprises -I and L that covalently connects SB-CBP / p300 to B-AR is attached to R32; each R28is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;each R34is independently hydrogen or substituted or unsubstituted Ci-Cealkyl;each R35is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -OH, -ORa, or -N(Rb)2;m is 0, 1, 2, 3, or 4;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, - NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;Y is -C(R30)2- or C(=O);each X3is independently CR27or N;each R30is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted G-Gfluoroalkyl, substituted or unsubstituted G-Gheteroalkyl, -CN, -NO2, - OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, - C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;q is 0, 1, 2, 3, or 4;each R31is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted G-Gfluoroalkyl, substituted or unsubstituted G- heteroalkyl, substituted or unsubstituted G-Cefluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, - NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or - C(=O)N(Rb)2;each R36is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;Attorney Docket No.: P60303-WO-1Ring B is a fused substituted or unsubstituted 5 or 6 membered heterocycloalkyl;each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0353] Embodiment 61. The compound of embodiment 58-60, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300 is R32, wherein:R32is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2- Cealkenyl, substituted or unsubstituted C2-Cealkynyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Cs-Cncycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;y is 1 or 2;Z1is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted Ci-Cealkyl;R26is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each X2is independently -CR30- or -N-;each X3is independently -CR27- or -N-;Attorney Docket No.: P60303-WO-1each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, - NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen or substituted or unsubstituted Ci-Cealkyl;R29is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;Y is -C(R30)2- or -N(R28)-;each R30is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, - OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, - C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;q is 0, 1, 2, 3, or 4;or R32is -L-C;L is substituted or unsubstituted Ci-Cealkyl or substituted or unsubstituted Ci-Ceheteroalkyl; C is substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rais independently substituted or unsubstituted -Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G- Gcycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted G-Gfluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0354] Embodiment 62. The compound of any one of embodiments 58-61, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety that occupies the BC Loop region of the bromodomain of CBP / p300 is R32, wherein:Attorney Docket No.: P60303-WO-1each of which is substituted or unsubstituted.

[0355] Embodiment 63. The compound of any one of embodiments 58-59, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises

[0356] Embodiment 64. The compound of embodiment 63, or a pharmaceutically acceptable salt or solvate thereof, wherein:R27is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Attorney Docket No.: P60303-WO-1Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, - OH, or -ORa; andeach R27is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, -CN, -OH, or - ORa; andeach Rais independently substituted or unsubstituted C1-C6alkyl.

[0357] Embodiment 65. The compound of embodiment 64, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R27is independently hydrogen, -CH3, -CH₂CH₃, -F, -CHF2, -CF₃, -CN, -OH, -OCH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrazolyl, 1- methyl pyrazolyl, pyridinyl, or pyrimidinyl.

[0358] Embodiment 66. The compound of any one of embodiments 57-65, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprisesR32

[0359] Embodiment 67. The compound of any one of embodiments 57-65, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprisesR32

[0360] Embodiment 68. The compound of any one of embodiments 63-67, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1N.'~~N cPPcx~ N^CC '~~NP fPAttorney Docket No.: P60303-WO-1

[0361] Embodiment 69. The compound of any one of embodiments 57-62, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises

[0362] Embodiment 70. The compound of embodiment 69, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises

[0363] Embodiment 71. The compound of embodiment 69, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic compriseswherein:each R28is independently hydrogen or substituted or unsubstituted Ci-Cealkyl;R29each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, - OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -Attorney Docket No.: P60303-WO-1C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2

[0364] Embodiment 72. The compound of any one of embodiments 69-71, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0365] Embodiment 73. The compound of any one of embodiments 57-62, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises

[0366] Embodiment 74. The compound of embodiment 73, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises

[0367] Embodiment 75. The compound of any one of embodiments 73-74, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0368] Embodiment 76. The compound of embodiment 61, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises:Attorney Docket No.: P60303-WO-1

[0369] Embodiment 77. The compound of embodiment 74 or 76, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0370] Embodiment 78. The compound of any one of embodiments 73, 74, 76, or 77, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0371] Embodiment 79. The compound of any one of embodiments 57-62, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises

[0372] Embodiment 80. The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic compriseswherein:each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;R33is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, or substituted or unsubstituted Ci-Ceheteroalkyl;Attorney Docket No.: P60303-WO-1R34is hydrogen or substituted or unsubstituted Ci-Cealkyl;each R37is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;each R38is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, - S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted -Cefluoroalkyl, substituted or unsubstituted -Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle;r is 0, 1, 2, 3, or 4.

[0373] Embodiment 81. The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0374] Embodiment 82. The compound of embodiment 79, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprisesAttorney Docket No.: P60303-WO-1

[0375] Embodiment 83. The compound of any one of embodiments 79-82, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0376] Embodiment 84. The compound of any one of embodiments 79-82, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0377] Embodiment 85. The compound of any one of embodiments 1-56, or a pharmaceutically acceptable salt or solvate thereof, wherein the binder of CBP / p300 comprises an acetyl-lysine mimetic moiety that binds in the acetyl-lysine (KAc) binding site of the bromodomain of human CREB-binding protein (CBP) or human ElA-binding protein p300 (p300) (CBP / p300) and has the structure:R28is -C(=O)CH3, -C(=O)CH2CH3, -C(=O)NH2, -C(=O)NH(CH3); or -C(=O)NH(CH2CH3); R32is a moiety that occupies the BC Loop region of the bromodomain of CBP / p300;R32ais a moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300; each R35is independently hydrogen, Ci-C4alkyl, or Ci-C4fluoroalkyl;m is 0, 1, 2, 3, or 4;L is an optional linker;wherein L is covalently attached to the R32group, or at the position occupied by R32, or the R32agroup.Attorney Docket No.: P60303-WO-1

[0378] Embodiment 86. The compound of embodiment 85, or a pharmaceutically acceptable salt or solvate thereof, wherein:R32is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3- Cncycloalkyl, or substituted or unsubstituted 3- to 12-membered heterocycloalkyl;at least one X2is -CR30- and at most two X2are -N-;Z1is -NRC- or -O-;Rcis hydrogen or C1-C6alkyl;R26is hydrogen, substituted or unsubstituted C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;X3is -CR27- or -N-;R27is hydrogen, halogen, substituted or unsubstituted C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CN, - OH, -ORa, -N(Rb)2, -NRbC(=O)Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p>26 R26 p26 p26p is 0, 1, 2, or 3;R29is hydrogen, substituted or unsubstituted Ci-C4alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;Y is -C(R30)2- or -N(R28)-;Attorney Docket No.: P60303-WO-1each R30is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, -CN, -OH, or -ORa;q is 0, 1, 2, 3, or 4;each Rais independently Ci-C4alkyl, Ci-Cefluoroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0379] Embodiment 87. The compound of embodiment 86, or a pharmaceutically acceptable salt or solvate thereof, wherein:R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic 5- or 6-membered heteroaryl, - CN, -OH, -ORa, -N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, - C(=O)ORb, or -C(=O)N(Rb)2;

[0380] Embodiment 88. The compound of any one of embodiments 85-87, or a pharmaceutically acceptable salt or solvate thereof, wherein:unsubstituted or substituted with F, Cl, Br, -CH3, -CD3, -CH₂CH₃, -CH2F, -CHF2, -CF₃, - CH2CH2F, -CH2CHF2, -CH2CF3, -CN, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2F, - C(=O)CHF2, -C(=O)CF3, -C(=O)CH2CH2F, -C(=O)CH2CHF2, -C(=O)CH2CF3, -C(=O)CD3, or - SO2CH3, -SO2CH2CH3, -SO2CD3, or -SO2CH2CD3;Attorney Docket No.: P60303-WO-1at least one X2is -CR30- and at most two X2are -N-;each R27is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OH, or -ORa; andeach Rais independently substituted or unsubstituted C1-C6alkyl.

[0381] Embodiment 89. The compound of any one of embodiments 85-87, or a pharmaceutically acceptable salt or solvate thereof, wherein:R27is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH3)2, -(CH3)3, -F, -CHF2, -CF3, -CN, -OH, -OCH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted pyrimidinyl; orsubstituted with F, Cl, Br, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, CN, -C(=O)CH3, - C(=O)CH2F, -C(=O)CHF2, -C(=O)CF3, -C(=O)CD3.

[0382] Embodiment 90. The compound of embodiment 86-89, or a pharmaceutically acceptable salt or solvate thereof, wherein:R32is, wherein the optional linker is covalently attached to the nitrogen of R32group;Attorney Docket No.: P60303-WO-1or R32is absent and L is covalently attached to the acetyl-lysine mimetic moiety at the position occupied by R32; andhk N NF~F N N N N NR32a isJ / oa ccfNoar oo^ co^Attorney Docket No.: P60303-WO-1

[0383] Embodiment 91. The compound of any one of embodiments 85-89, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1

[0384] Embodiment 92. The compound of any one of embodiments 1-56, or a pharmaceutically acceptable salt or solvate thereof, wherein:(R3?)m R28-NSB-CBP / p300 has the structure: R32aR28is -C(=O)CH3or -C(=O)NH(CH3); each R35is independently hydrogen, -CH3, -CH₂F, -CHF₂, -CF3; m is 0, 1, or 2;substituted with F, -CH₃, -CH₂F, -CHF₂, or -CF3;at least one X2is -CR30- and at most two X2are -N-;R26is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted Cs-C. cycloalkyl. or substituted or unsubstituted 3- to 6-membered heterocycloalkyl;R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic 5- or 6-membered heteroaryl, - CN, -OH, -ORa, or -N(Rb)2;each R30is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -ORa;Attorney Docket No.: P60303-WO-1Rais Ci-C4alkyl;each Rbis independently hydrogen or Ci-Cealkyl;wherein L is covalently attached to the R32group, or at the position occupied by R26, or at the position occupied by R27;X.CNX'XB-AR has the structure: R^.each X is independently -CR3- or -N-;X1is -CR1- or -N-;Rlbis hydrogen, F, Cl, -CH3, -CH₂F, -CHF₂, -CF₃, or -OCF3;R1is hydrogen, F, Cl, -CH3, -CH₂F, -CHF₂, or -CF3;each R3is independently hydrogen, F, Cl, Br, -CH₃, -CH₂F, -CHF₂, -CF₃, -OH, -OCF3, -OCH3, or -CN.

[0385] Embodiment 93. The compound of embodiment 92, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0386] Embodiment 94. The compound of any one of embodiments 92-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:, wherein the optional linker is covalently attached to the nitrogen of R32group;or R32is absent and the optional linker is covalently attached to the acetyl-lysine mimetic moietyAttorney Docket No.: P60303-WO-1at the position occupied by R32;at least one X2is -CR30- and at most two X2are -N-;X3is -CR27- or -N-;Z1is -NH- or -O-;R26is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted Cs-C. cycloalkyl. or substituted or unsubstituted 3- to 6-membered heterocycloalkyl;R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic 5- or 6-membered heteroaryl, - CN, -OH, -ORa, or -N(Rb)2;each R30is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -ORa.

[0387] Embodiment 95. The compound of any one of embodiments 92-94, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1

[0388] Embodiment 96. The compound of any one of embodiments 1-56, or a pharmaceutically acceptable salt or solvate thereof, wherein SB-CBP / p300 has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1or a pharmaceutically acceptable salt or solvate thereof.

[0390] Embodiment 98. The compound of any one of embodiments 1-56, or a pharmaceutically acceptable salt or solvate thereof, wherein SB-CBP / p300 has one of the following structures:

[0391] Embodiment 99. The compound of any one of embodiments 1-56, or a pharmaceutically acceptable salt or solvate thereof, wherein SB-CBP / p300 has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0392] Embodiment 100. The compound of any one of embodiments 1-99, or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent.

[0393] Embodiment 101. The compound of any one of embodiments 1-99, or a pharmaceutically acceptable salt or solvate thereof, wherein L comprises substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Cs-Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or combinations thereof.

[0394] Embodiment 102. The compound of any one of embodiments 1-99, or a pharmaceutically I— C* )— (L1)n -acceptable salt or solvate thereof, wherein L is absent or * (A) - |, wherein: each A is independently absent, substituted or unsubstituted monocyclic Cs-Ciocycloalkyl, substituted or unsubstituted bridged bicyclic Cs-Ciocycloalkyl, substituted or unsubstituted fused bicyclic Cs-Ciocycloalkyl, substituted or unsubstituted spiro bicyclic Cs-Ciocycloalkyl, substituted or unsubstituted monocyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted bridged bicyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted fused bicyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted spiro bicyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstitutedAttorney Docket No.: P60303-WO-1heteroaryl, wherein each A is independently unsubstituted or substituted with x R2b;each L1is independently absent,n is 1, 2, 3, 4, 5, or 6;each x is independently 1, 2, 3, 4, 5, 6, 7, or 8;each R2ais independently hydrogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci-C4fluoroalkyl, or substituted or unsubstituted Cs-Cecycloalkyl; andeach R2bis independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, - NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-Attorney Docket No.: P60303-WO-1membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

[0395] Embodiment 103. The compound of embodiment 102, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1

[0396] Embodiment 104. The compound of any one of embodiments 1-99, or a pharmaceuticallyacceptable salt or solvate thereof, wherein L is absent orwherein:each A is independently absent,Ran is 1, 2, or 3; each x is independently 1, 2, 3, 4, 5, or 6;each Rais independently hydrogen or substituted or unsubstituted C1-C6alkyl; andeach Rbis independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl.

[0397] Embodiment 105. The compound of any one of embodiments 102-104, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1

[0398] Embodiment 106. The compound of any one of embodiments 1-99, or a pharmaceutically acceptable salt or solvate thereof, wherein L has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1NHAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1or a pharmaceutically acceptable salt or solvate thereof.

[0399] Embodiment 107. The compound of any one of embodiments 1-99, or a pharmaceutically acceptable salt or solvate thereof, wherein L has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1or a pharmaceutically acceptable salt or solvate thereof.

[0400] Embodiment 108. A compound selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0401] Embodiment 109. A compound selected from Table 1A, or a pharmaceutically acceptable salt or solvate thereof.

[0402] Embodiment 110. A stable ternary complex comprising:a. CBP / p300;b. Androgen Receptor (AR); andc. heterobifunctional conditional inhibitor compound of any one of embodiments 1-109.

[0403] Embodiment 111. A stable ternary complex comprising:1. CBP / p300;2. Androgen receptor (AR); and3. heterobifunctional conditional inhibitor compound of any one of embodiments 1-109; wherein CBP / p300 and DP are present in a prostate cancer cell.Attorney Docket No.: P60303-WO-1

[0404] Embodiment 112. A method of selectively inhibiting the activity of CREB-binding protein (CBP) / p300 in a cell expressing the androgen receptor of a mammal comprising administering a heterobifunctional compound of any one of embodiments 1-109, or a pharmaceutically acceptable salt or solvate thereof.

[0405] Embodiment 113. The method of embodiment 112, wherein the heterobifunctional compound of any one of embodiments 1-109, or a pharmaceutically acceptable salt or solvate thereof, inhibits the activity of CBP / p300 in the cell but does not inhibit the activity of the CBP / p300 in cells not expressing the AR.

[0406] Embodiment 114. The method of embodiment 112, wherein the AR is overexpressed, overactive or both overexpressed and overactive in the COI.

[0407] Embodiment 115. A method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any one of embodiments 1-109, or a pharmaceutically acceptable salt or solvate thereof.

[0408] Embodiment 116. The method of embodiment 115, wherein the cancer is an androgen dependent cancer.

[0409] Embodiment 117. The method of embodiment 115, wherein the cancer is prostate cancer.

[0410] Embodiment 118. A method of treating an androgen receptor dependent or androgen receptor mediated disease or condition in mammal comprising administering to the mammal a therapeutically effective amount of a compound according to any one of embodiments 1-109, or a pharmaceutically acceptable salt or solvate thereof.

[0411] Embodiment 119. The method of embodiment 118, wherein androgen receptor dependent or androgen receptor mediated disease or condition is selected from benign prostate hyperplasia, hirsutism, adenomas and neoplasms of the prostate, benign or malignant tumor cells containing the androgen receptor, prostate cancer, breast cancer, endometrial cancer, and uterine cancer.

[0412] Embodiment 120. A pharmaceutical composition comprising a compound of any one of embodiments 1-109, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.Further Forms of Compounds

[0413] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.Attorney Docket No.: P60303-WO-1

[0414] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0415] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S. M. Berge, U. D. Bighley, D. C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0416] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with an acid. In some embodiments, the compound disclosed herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1 -hydroxyl-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (U); aspartic acid (U); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane- 1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DU); lactobionic acid; lauric acid; maleic acid; malic acid (- U); malonic acid; mandelic acid (DU); methanesulfonic acid; naphthalene-l,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- U); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ U); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.Attorney Docket No.: P60303-WO-1

[0417] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with a base. In some embodiments, the compound disclosed herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound disclosed herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0418] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0419] The methods and formulations described herein include the use of A-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure disclosed herein, as well as active metabolites of these compounds having the same type of activity.

[0420] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds disclosed herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[0421] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0422] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into theAttorney Docket No.: P60303-WO-1present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,180,170,35S,18F,36C1,1231,1241,125I,1311,32P and33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0423] In some embodiments, the compounds disclosed herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound disclosed herein exists in the R configuration. In some embodiments, the compound disclosed herein exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0424] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, compounds disclosed herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0425] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then isAttorney Docket No.: P60303-WO-1metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0426] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.Certain Terminology

[0427] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0428] As used herein, Ci-Cxincludes C1-C2, C1-C3... Ci-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, Ao-propyl, w-butyl, Ao-butyl, sec-butyl, and / -butyl.

[0429] The term “acyl,” as used herein refers to the group -C(=O)-R, where R is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon. An “acetyl” group refers to a -C(=O)CH3 group.Attorney Docket No.: P60303-WO-1

[0430] The term “alkenyl,” as used herein refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, alkenyl includes 2 to 6 carbon atoms. The term “alkenylene” refers to a divalent alkenyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (z.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0431] The term “alkoxy” refers to a (alkyl)-O- group, where alkyl is as defined herein. In some embodiments, the alkoxy group is a Ci-Cealkoxy, which refers to a (Ci-Cealkyl)-O- group. Examples of alkyl groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0432] An “alkyl” group refers to an aliphatic hydrocarbon group. In some embodiments, the alkyl is a straight-chain or branched-chain aliphatic hydrocarbon group containing from 1 to 20 carbon atoms. In certain embodiments, alkyl includes 1 to 10 carbon atoms. In further embodiments, the alkyl includes 1 to 8 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, and the like. In some embodiments, an alkyl is a Ci-Cealkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. The term “alkylene” refers to a divalent alkyl, such as methylene (-CH2-). In some embodiments, an alkylene is a Ci-Cealkylene. In other embodiments, an alkylene is a Ci-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0433] The term “amino,” as used herein refers to -NRR, wherein R and R are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R’ may combine to form heterocycloalkyl, either of which may be optionally substituted. In one aspect, “amino” as used herein refers to an -NH2group.

[0434] The term “alkynyl,” as used herein refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. In one embodiment, an alkenyl group has the formula -C=C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C=CH, -C=CCH3-C=CCH2CH3, -CH2C=CH. The term “alkynylene” refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C=C-). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyn-2-yl, pentyn-l-yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups.Attorney Docket No.: P60303-WO-1

[0435] The term “aromatic” refers to a planar ring having a delocalized K -electron system containing 4n+2 electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0436] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

[0437] The term “aryl” as used herein means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahyodronaphthyl. In some embodiments, an aryl is a Ce-Cioaryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0438] The terms “benzo” and “benz,” as used herein refer to fused bicyclic or polyclic ring system that is formed with benzene as one of the rings. Examples include benzofuran, benzothiophene, and benzimidazole.

[0439] The term “cycloalkyl,” as used herein refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms. In certain embodiments, said cycloalkyl will comprise from 5 to 7 carbon atoms. In certain embodiments, said cycloalkyl will comprise from 3 to 6 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH-indenyl, adamantly, and the like. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by,bicyclofl, l,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane. In some embodiments, a cycloalkyl is a Cs-Cecycloalkyl. In some embodiments, a cycloalkyl is a Cs-C^ycloalkyl.

[0440] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 toAttorney Docket No.: P60303-WO-110 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3 -azabicyclo [4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin- 1 -onyl, isoindoline- 1,3 -dionyl, 3,4-dihydroisoquinolin- 1 (2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline- 1, 3 -dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or A'-attachcd where such is possible. For instance, a group derived from pyrrole includes both pyrrol- 1-yl (A'-attachcd) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) moi eties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0441] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the term "heteroaryl," as used herein refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from N, O, and S. In certain embodiments, said heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heteroaryl will comprise from 5 to 7 atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, orAttorney Docket No.: P60303-WO-1wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1 O atom in the ring. In some embodiments, a heteroaryl contains 1 S atom in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclic heteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C₆-C₉heteroaryl.

[0442] A “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the term “heterocycloalkyl” as used herein each refer to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said hetercycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited. In one aspect, a heterocycloalkyl is a C2-Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-Cioheterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkylAttorney Docket No.: P60303-WO-1is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring. In some embodiments, a heterocycloalkyl contains 1-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 1-20 atoms. In some embodiments, a heterocycloalkyl contains 1 S atom. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0443] The term “carbamate,” as used herein refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.

[0444] The term “carboxyl” or “carboxy,” as used herein, refers to -C(=O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.

[0445] The term “cyano,” as used herein refers to -CN.

[0446] The term “ester,” as used herein refers to a carboxy group bridging two moieties linked at carbon atoms.

[0447] The term “ether,” as used herein refers to an oxy group bridging two moieties linked at carbon atoms.

[0448] The term “halo,” or “halogen,” as used herein refers to fluorine, chlorine, bromine, or iodine. In some embodiments, halo is fluoro, chloro, or bromo.

[0449] The term “haloalkyl,” as used herein refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2 -), chloromethylene (-CHC1-), and the like. In one aspect, a haloalkyl is a Ci-Cehaloalkyl. In another aspect, a haloalkyl is a Ci-C4haloalkyl.

[0450] The term “haloalkoxy,” as used herein refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. In one aspect, the haloalkoxy is a Ci-Cehaloalkoxy, which refers to a (Ci-Cehaloalkyl)-O- group. In another aspect, the haloalkoxy is a Ci-C4haloalkoxy, which refers to a (Ci-C4haloalkyl)-O- group.

[0451] The term “heteroalkyl” refers to an alkyl wherein 1 or more carbon atoms are replaced with a heteroatom. In some embodiments, “heteroalkyl” refers to an alkyl wherein 1 or more carbon atoms are replaced with one or more heteroatoms that are independently selected from NH, -N(alkyl), O, S,Attorney Docket No.: P60303-WO-1S(=O) and S(=O)₂. The attachment of the heteroatom(s) to the remainder of the compound is at a carbon atoms of the heteroalkyl. In some embodiments, up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. In some embodiments, “heteroalkyl” is an “alkoxyalkyl”, “alkylthioalkyl”, or “alkylaminoalkyl”. “Alkoxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by an alkoxy group, as defined herein. In some embodiments, an alkoxyalkyl is a (Ci-C6alkoxy)-Ci-Cealkyl. Typical alkoxyalkyl groups include, but are not limited to, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH3, -CH2O-CH₂CH₃, -CH2CH2O-CH₂CH₃, -CH2CH2CH2O-CH₂CH₃, -CH2CH2CH2CH2O-CH₂CH₃, and the like. “Alkylthioalkyl” refers to an alkyl in which one hydrogen atom is replaced by an alkylthio group, as defined herein. In some embodiments, an alkoxyalkyl is a (Ci-Ce alkylthio)-Ci-C6alkyl. Typical alkoxyalkyl groups include, but are not limited to, -CH2SCH3, -CH2CH2SCH3, -CH2CH2CH2SCH3, -CH2CH2CH2CH2SCH3, -CH2S-CH₂CH₃, -CH2CH2S-CH₂CH₃, -CH2CH2CH2S-CH₂CH₃, -CH2CH2CH2CH2S-CH₂CH₃, and the like. “Alkylaminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by an alkylamino group, as defined herein. In some embodiments, an alkoxyalkyl is a (Ci-C6alkylamino)-Ci-C6alkyl. Typical alkoxyalkyl groups include, but are not limited to, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2CH2NHCH3, -CH2NH-CH₂CH₃, -CH2CH2NH-CH₂CH₃, -CH2CH2CH2NH-CH₂CH₃, -CH2CH2CH2CH2NH-CH₂CH₃, and the like.

[0452] The term “hydroxy,” or “hydroxyl,” as used herein refers to -OH.

[0453] The term “hydroxyalkyl,” as used herein refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. In some embodiments, a hydroxyalkyl is a Ci-C4hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0454] The phrase “linear chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

[0455] The term “nitro,” as used herein refers to -NO2.

[0456] The term “oxo,” as used herein refers to =0.

[0457] The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein refer the -SO3H group and its anion as the sulfonic acid is used in salt formation.

[0458] The term “sulfanyl,” as used herein refers to -S-.

[0459] The term “sulfinyl,” as used herein refers to -S(=O)-.

[0460] The term “sulfonyl,” as used herein refers to a -S(=O)2-, -S(=O)2R, or -S(=O)2R- group, with R as defined herein.

[0461] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group atached to the parent molecule through an amido group, and the term alkoxyalkyl wouldAttorney Docket No.: P60303-WO-1represent an alkoxy group attached to the parent molecule through an alkyl group.

[0462] When a group is defined to be “null,” what is meant is that said group is absent.

[0463] In some embodiments, the term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), -C(=O)NH2, -C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4hctcroalkyl. Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF₂, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[0464] The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[0465] The term “disease” or “disorder” as used herein refers to any condition that impairs the normal functioning of the body, such as a functional abnormality or disturbance that impairs normal functioning.

[0466] The term “combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure.

[0467] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.

[0468] The term “therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0469] As used herein, “treating,” “treatment,” and the like means ameliorating a disease, so as to reduce, ameliorate, or eliminate its cause, its progression, its severity, or one or more of its symptoms, or otherwise beneficially alter the disease in a subject. In certain embodiments, reference to “treating” or “treatment” of a subject at risk for developing a disease, or at risk of disease progression to a worseAttorney Docket No.: P60303-WO-1state, is intended to include prophylaxis. Prevention of a disease may involve complete protection from disease or may involve prevention of disease progression. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease.

[0470] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, non-human primates such as chimpanzees, and other apes and monkey species; livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.Pharmaceutical Compositions and Formulations

[0471] Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.

[0472] Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tableting lubricants and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound provided herein in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.

[0473] A compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically-acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et. al.).

[0474] The compounds provided herein, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.Attorney Docket No.: P60303-WO-1

[0475] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, com starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, com starch or gelatins; with disintegrators such as com starch, potato starch or sodium carboxymethyl -cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.

[0476] Compounds provided herein or a salt, solvate, or hydrate thereof can be used as active ingredients in pharmaceutical compositions. The term “active ingredient”, defined in the context of a “pharmaceutical composition”, refers to a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an “inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.

[0477] The dose when using the compounds provided herein can vary within wide limits and as is customary and is known to the physician or other clinician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated, or prophylaxis conducted, or on whether further active compounds are administered in addition to the compounds provided herein. Representative doses include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3, or 4 doses. Depending on the individual and as deemed appropriate from the healthcare provider it may be necessary to deviate upward or downward from the doses described herein.

[0478] The amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerationsAttorney Docket No.: P60303-WO-1such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated, or prophylaxis conducted, or on whether further active compounds are administered in addition to the compounds provided herein and as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and / or compositions provided herein is selected in accordance with a variety of factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods provided herein.

[0479] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.

[0480] Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.

[0481] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0482] For topical administration to the epidermis the compounds provided herein may be formulated as ointments, creams, or lotions, or as a transdermal patch.

[0483] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

[0484] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.Attorney Docket No.: P60303-WO-1Methods of Dosing and Treatment Regimens

[0485] In one embodiment, the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound disclosed herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[0486] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0487] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0488] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0489] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.Attorney Docket No.: P60303-WO-1

[0490] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0491] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0492] In one embodiment, the daily dosages appropriate for the compound disclosed herein, or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0493] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[0494] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non-systemically or locally to the mammal.

[0495] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammalAttorney Docket No.: P60303-WO-1multiple times over the span of one day.

[0496] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0497] In certain instances, it is appropriate to administer at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0498] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:ACN or MeCN acetonitrileAc acetylAc₂O acetic anhydrideAcOH acetic acidAIBN azobisisobutyronitrileBINAP 2,2'-bis(diphenylphosphino)- 1, 1 '-binaphthaleneBn benzylBOC or Boc tert-butyl carbamateBoc₂O di-tert-butyl decarbonate or Boc anhydrideBPO benzoyl peroxideBrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1, 1 '-biphenyl)-2-(2'-amino- 1,1' -biphenyl)]palladium(II) methane sulfonate methane sulfonatet-Bu tert-butylC Phos Pd G3 [(2-Dicyclohexylphosphino-2',6'-bis(N, N-dimethylamino) -1,1'- biphenyl)-2-(2'-amino- 1, 1 '-biphenyl)] palladium(II) methanesulfonateCy cyclohexylDBA or dba dibenzylideneacetoneDBU 1, 8 -diazabicyclo [5.4.0]undec-7-eneAttorney Docket No.: P60303-WO-1DCE dichloroethane (CICH2CH2CI)DCM dichloromethane (CH2CI2)DIPEA or DIEA diisopropylethylamineDMAP 4-(N,N-dimethylamino)pyridineDMF dimethylformamideDMA N,N-dimethylacetamideDMSO dimethylsulfoxideDppf 1, 1 '-bis(diphenylphosphino)ferroceneEEDQ 2-Ethoxy- 1 -ethoxycarbonyl- 1,2-dihydroquinolineeq equivalent(s)Et ethylEt2O diethyl etherEtOH ethanolEtOAc ethyl acetateFA formic acidHATU 1 -[bis(dimethylamino)methylene] - 1H- 1,2,3-triazolo[4,5- b] pyridinium 3-oxid hexafluorophosphateHPLC high performance liquid chromatographyH2O waterK2CO3potassium carbonateLAH lithium aluminum anhydrideLCMS liquid chromatography mass spectrometryMe methylMeOH methanolMS mass spectrometryMsCl mesyl chlorideNa2CO3sodium carbonateNaBH(OAc)3sodium triacetoxyborohydrideNaH sodium hydrideNa2SO4sodium sulfateNBS N-bromo succinamideNMP N-methyl-pyrrolidin-2-oneNMR nuclear magnetic resonancePd(dppf)Cl2(1,1 '-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride Ph phenylPin pinacolatoAttorney Docket No.: P60303-WO-1Prep-HPLC preparative high performance liquid chromatographyi-Pr iso-propylRP-HPLC reverse phase-high pressure liquid chromatographyRuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonateTBS tert-butyldimethylsilylTFA trifluoroacetic acidTEA triethylamineTHF tetrahydrofuranTsCl tosyl chlorideTLC thin layer chromatographyEXAMPLES

[0499] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0500] Compound A was prepared according to the procedure described in WO 2022 / 42707 Al.Attorney Docket No.: P60303-WO-1

[0501] Compound C was prepared according to the following procedure:AC2O, Et3N DCM0-25 °C, 12 h 91%Compound C

[0502] 1 was prepared according to the procedure described in WO 2022 / 42707 Al.

[0503] To a solution of benzyl 4-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-l-yl]piperidine-l-carboxylate (0.250 g, 349 pmol, 1.0 eq, TFA) in DCM (0.5 mL) was added TEA (106 mg, 1.05 mmol, 146 μL, 3.0 eq) and Ac₂O (53.5 mg, 524 μmol, 49.2 μL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was poured into ice-water (20 mL). The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-TLC (silica, dichloromethane / methyl alcohol= 10 / 1). Compound benzyl 4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]piperidine-l -carboxylate (0.21 g, 316 pmol, 91% yield) was obtained as a light yellow solid. LC-MS: MS (ESI+): tR= 0.980 min, m / z = 644.3 [M + H+]

[0504] Pd / C (0.110 g, 10% Pd on carbon, w / w) was added into a 100 mL single-necked round bottom flask under N₂, and then EtOAc (10 mL) was added at 25 °C under N₂. After addition, benzyl 4-[5-acetyl-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate (0.210 g, 326 μmol, 1.0 eq) was added under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (15 psi) at 25 °C for 1.5 h. The reaction mixture was filtered and washed with MeOH (20 mL × 3). The collected filtrate was concentrated to give a residue. The residue was used for the next step without further purification. Compound 1-[3-[7-(difluoromethyl)-6-(1-Attorney Docket No.: P60303-WO-1methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(4-piperidyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (0.15 g, 294 μmol, 90% yield) was obtained as a white solid. LC-MS: MS (ESI+): tR= 0.429 min, m / z = 510.3 [M + H+]

[0505] Compound E was prepared according to the procedure described in WO 2017 / 205538 Al.

[0506] Compound G was prepared according to the following procedure:Compound G

[0507] To a solution of methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (0.15 g, 570.13 pmol, 1 eq) and Na2CO3(120.86 mg, 1.14 mmol, 2 eq) and Pd(dppf)Cl2(41.72 mg, 57.01 μmol, 0.1 eq) in dioxane (5 mL) and H2O (0.5 mL) was added [8-(5-acetyl-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl] trifluoromethanesulfonate (299 mg, 570 μmol, 1.0 eq). The mixture was stirred at 80 °C for 12 h. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organics were washed with brine (200 mL × 2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1, DCM / MeOH = 50 / 1 to 20 / 1). Compound methyl 5-[8-(5-acetyl-l-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl]pyridine-2-carboxylate (0.20 g, 390.95 pmol, 68% yield) was obtained as a yellow solid. LC-MS: MS (ESI+): tR= 0.468 min, m / z = 512.2 [M + H+]Attorney Docket No.: P60303-WO-1

[0508] To a solution of methyl 5-[8-(5-acetyl-l-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl]pyridine-2-carboxylate (0.20 g, 391 pmol, 1.0 eq) in MeCN (3 mL) and H2O (1 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[l,2-a]pyrimidine (109 mg, 782 pmol, 2.0 eq). The mixture was stirred at 25 °C for 12 h. The mixture was added 1 M HC1 (0.10 mL) and extracted with DCM (100 mL x 2). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(HCl)-ACN] gradient: 13%-43% B over 10 min). Compound 5-[8-(5-acetyl-l-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl]pyridine-2-carboxylic acid (0.12 g, 241 pmol, 62% yield) was obtained as a yellow solid. LC-MS: MS (ESI+): tR= 0.477 min, m / z = 498.3 [M + Na+]

[0509] Compound H was prepared according to the following procedure:Cs2CO3, MeI TFA DMF, 25 °C, 12 h DCM, 25 °C, 0.5 h 27 %Ac2O, Et3NDCM, 25 °C, 12 h88 % from 2ACompound HAttorney Docket No.: P60303-WO-1

[0510] Synthesis of 5A was reported in WO2021 / 231174, 2021, Al.

[0511] A mixture of tert-butyl 3-iodo-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (15.0 g, 42.96 mmol, 1 eq), Cs2CO3(41.9 g, 128.88 mmol, 3.0 eq) in DMF (150 mL) was degassed and purged with N₂ for 3 times, and then added Mel (9.15 g, 64.44 mmol, 4.01 mL, 1.5 eq), the mixture was stirred at 25 °C for 1 2h under N2. The reaction mixture was quenched by addition water 1000 mL, and then extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=10 / l to 2 / 1). Compound tert-butyl 3-iodo-l-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (4.3 g, 11.84 mmol, 27 % yield) was obtained as a white solid.

[0512] 1H NMR (400 MHz, DMSO-d6): δ = 4.09 (s, 2H), 3.69 (s, 3H), 3.59 (t, J = 5.6 Hz, 2H), 2.64 (t, J = 5.6 Hz, 2H), 1.41 (s, 9H)

[0513] LC-MS: MS (ESI+): tR= 0.521 min, m / z = 364.1 [M + H+]

[0514] To a solution of tert-butyl 3-iodo-l-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (4.30 g, 11.84 mmol, 1.0 eq) in DCM (20 mL) was added TFA (15.35 g, 134.62 mmol, 10 mL, 11.3 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give the crude product. Compound 3-iodo-l-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (4.46 g) was obtained as a white solid and directly used in the next step without further purification.

[0515] LC-MS: MS (ESI+): tR= 0.218 min, m / z = 263.1 [M + H+].

[0516] To a solution of 3-iodo-l-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (4.46 g, 11.83 mmol, 1.0 eq) in DCM (40 mL) was added Et3N (3.59 g, 35.48 mmol, 4.94 mL, 3.0 eq), Ac2O (1.81 g, 17.74 mmol, 1.67 mL, 1.5 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=10 / l to 0 / 1). Compound l-(3-iodo-l-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (3.20 g, 10.49 mmol, 88 % yield over two steps) was obtained as a white solid.

[0517] LC-MS: MS (ESI+): tR= 0.378 min, m / z = 306.1 [M + H+]

[0518] A mixture of l-(3-iodo-l-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)ethanone (3.00 g, 9.83 mmol, 1.0 eq), triisopropyl-[[8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolyl]oxy]silane (7.00 g, 11.46 mmol, 1.1 eq), Pd(dppf)Cl2(359 mg, 491.62 μmol, 0.05 eq), K3PO4(7.30 g, 34.41 mmol, 3.5 eq) and water (50 mL) in dioxane (80 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90 °C for 4 h under N2. The reaction mixture was quenched by addition water 500 mL, and then extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2,Attorney Docket No.: P60303-WO-1dichloromethane: methanol= 100 / 1 to 20 / 1). Compound l-[l-methyl-3-(3-triisopropylsilyloxy-8-isoquinolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (2.43 g, 5.08 mmol, 51 % yield) was obtained as a white solid.

[0519] LC-MS: MS (ESI+): tR= 0.893 min, m / z = 479.3 [M + H+]

[0520] To a solution of l-[l-methyl-3-(3-triisopropylsilyloxy-8-isoquinolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (2.43 g, 5.08 mmol, 1.0 eq) in MeOH (20 mL) was added NH4F (1.88 g, 50.76 mmol, 10.0 eq). The mixture was stirred at 45 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane: methanol=50 / 1 to 10 / 1). Compound l-[3-(3-hydroxy-8-isoquinolyl)-l-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.6 g, 4.96 mmol, 97 % yield) was obtained as a yellow solid.

[0521] 1H NMR (400 MHz, DMSO-d6): δ = 10.97 (br s, 1H), 9.44 - 9.21 (m, 1H), 7.70 - 7.63 (m, 1H), 7.63 - 7.55 (m, 1H), 7.28 - 7.17 (m, 1H), 6.90 (s, 1H), 4.48 (s, 2H), 3.89 - 3.72 (m, 5H), 2.92 - 2.71 (m, 2H), 2.14 - 1.94 (m, 3H)

[0522] LC-MS: MS (ESI+): tR= 0.368 min, m / z = 323.2 [M + H+]

[0523] To a solution of l-[3-(3-hydroxy-8-isoquinolyl)-l-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.60 g, 4.96 mmol, 1.0 eq) in DCM (20 mL) was added Et3N (1.51 g, 14.89 mmol, 2.07 mL, 3.0 eq), and added Tf2O (2.10 g, 7.45 mmol, 1.23 mL, 1.5 eq). The mixture was stirred at -10 °C for 1 h. The reaction mixture was quenched by addition water 200 mL, and then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane: methanol=50 / 1 to 10 / 1).Compound [8-(5-acetyl-l-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl)-3-isoquinolyl] trifluoromethanesulfonate (1.3 g, 2.86 mmol, 57 % yield) was obtained as a yellow solid.

[0524] 1H NMR (400 MHz, DMSO-d6): δ = 9.82 - 9.76 (m, 1H), 8.21 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.04 - 7.96 (m, 1H), 7.82 - 7.71 (m, 1H), 4.56 (s, 2H), 3.89 - 3.76 (m, 5H), 2.93 - 2.74 (m, 2H), 2.16 - 1.98 (m, 3H)

[0525] LC-MS: MS (ESI+): tR= 0.521 min, m / z = 455.2 [M + H+]Example 1: Synthesis of 6-[4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl]methyl] - 1 -piperidyl]-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (Compound 21)Attorney Docket No.: P60303-WO-14 Compound 21NaBH(OAc)2, TEA, DCM TFA, DCM 25 “C, 1 h 25 °C, 1 h88 % CBP / p300 intermediate B

[0526] To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (437 mg, 2.03 mmol,1.0 eq) in THF (3.5 mb) was added NaH (97 mg, 2.44 mmol, 60% purity, 1.2 eq) at 0 °C underN2, The mixture was stirred at 0 °C for 1 h under N2. Then 5 -fluoroquinoline -8 -carbonitrile (350 mg, 2.03 mmol, 1.0 eq) was added into it. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with NH4CI solution (50 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2; Petroleum ether:Ethyl acetate=l / l). Compound tert-butyl N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]carbamate (520 mg, 1.42 mmol, 69% yield) was obtained as a white solid.

[0527] LC-MS: MS (ESI+): tR= 0.855 min, m / z = 368.2 [M + H+]

[0528] To a solution of tert-butyl N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]carbamate (520 mg, 1.42 mmol, 1.0 eq) in HCl / dioxane (2 M, 4.64 mL, 6.5 eq). The mixture was stirred at 25 °C for 1 h.The reaction mixture was concentrated under reduced pressure to give a residue. The crude product 5- (4-aminocyclohexoxy)quinoline-8-carbonitrile ( 429 mg ) was obtained as a white solid and directly used in the next step without further purification.

[0529] LC-MS: MS (ESI+): tR= 0.446 min, m / z = 268.2 [M + H+]

[0530] To a solution of 5-(4-aminocyclohexoxy)quinoline-8-carbonitrile ( 379 mg ) and 6- chloropyridazine -3 -carboxylic acid (791 mg, 4.99 mmol, 4. Oeq) in EtOAc (4 mL) was added T4PAttorney Docket No.: P60303-WO-1(4.49 g, 6.24 mmol, 50 % purity, 5.0 eq) and TEA (1.01 g, 9.98 mmol, 1.39 mL, 8.0 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (10 mL) andthen extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product 6-chloro-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (500 mg, 1.23 mmol, 98 % yield over two steps) was obtained as a white solid and used into the next step without further purification.

[0531] LC-MS: MS (ESI+): tR= 0.798 min, m / z = 408.1 [M + H+]

[0532] To a solution of 1-[3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-(4-piperidyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.00 g) and tert-butyl 4-formylpiperidine-1-carboxylate (512 mg, 2.41 mmol, 1.5 eq) in DCM (10 mL) was added TEA (811 mg, 8.02 mmol, 1.12 mL, 5.0 eq) and NaBH(OAc)3(1.02 g, 4.81 mmol, 3.0 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (10 mL) and then extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous ISfeSCh, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC ( column: Phenomenex luna C18 150*40mm* 15um;mobile phase:|watcr(FA)-ACN |:gradicnt: 18%-48% B over 15 min). Compound tert-butyl 4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]-l-piperidyl]methyl]piperidine-l-carboxylate (1.00 g, 1.41 mmol, 88 % yield) was obtained as a white solid.

[0533] LC-MS: MS (ESI+): tR= 0.498 min, m / z = 707.5 [M + H+]

[0534] Preparation of 4A

[0535] To a solution of tert-butyl 4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl]methyl]piperidine-l -carboxylate (1.00 g, 1.41 mmol, 1.00 eq) in DCM (9 mL) was added TFA (4.61 g, 40.39 mmol, 3 mL, 28.5 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo. The crude product l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-l-[l-(4-piperidylmethyl)-4-piperidyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone ( 800 mg ) was obtained as a white solid and directly used in the next step without further purification.

[0536] LC-MS: MS (ESI+): tR= 0.396 min, m / z = 607.4 [M + H+]

[0537] Preparation of Compound 21

[0538] To a solution of 6-chloro-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (356 mg, 873.51 pmol, 1.0 eq) and in NMP (5 mL) was added K2CO3 (362 mg, 2.62 mmol, 3.0 eq) and l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-Attorney Docket No.: P60303-WO-1l-[l-(4-piperidylmethyl)-4-piperidyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (530 mg). The mixture was stirred at 70 °C for 12 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; gradient: 22%-52% B over 10 min).Compound 6-[4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl]-1-piperidyl]methyl]-1-piperidyl]-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (515.53 mg, 501.54 μmol, 57 % yield over two steps) was obtained as a white solid.

[0539] 1H NMR (400 MHz, CHLOROFORM-d) δ = 9.09 (dd, J = 1.6, 4.3 Hz, 1H), 8.64 (dd, J = 1.6, 8.4 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.01-7.89 (m, 2H), 7.57-7.48 (m, 2H), 7.41 (d, J = 6.6 Hz, 1H), 7.08-6.84 (m, 4H), 6.72-6.34 (m, 1H), 4.67-4.56 (m, 1H), 4.56-4.44 (m, 2H), 4.26 (s, 1H), 4.20-4.07 (m, 2H), 3.99-3.94 (m, 3H), 3.93-3.87 (m, 2H), 3.82-3.60 (m, 3H), 3.13-2.95 (m, 4H), 2.93-2.79 (m, 3H), 2.75 (t, J = 5.4 Hz, 1H), 2.37-2.21 (m, 8H), 2.17 (s, 1H), 2.14-2.04 (m, 5H), 1.99-1.79 (m, 7H), 1.60-1.49 (m, 2H), 1.34-1.17 (m, 3H)

[0540] LC-MS: MS (ESI+): tR= 2.771 min, m / z = 978.7 [M + H+]Example 2: Synthesis of 6-[4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl]methyl] - 1 -piperidyl]-N-[3-[(8-cyano-5-quinolyl)oxy]-2,2,4,4-tetramethyl-cyclobutyl]pyridazine-3-carboxamide (Compound 20)HCl / dioxane Cs2CO3, ACN 25 °C, 1 h HATU, TEA, DCM 100 °C, 12 h 25 °C, 12 h 63% 2 3 31% from 2

[0541] To a solution of 5-fluoroquinoline-8-carbonitrile (300 mg, 1.7 mmol, 1.0 eq) and tert-butyl N-(3-hydroxy-2,2,4,4-tetramethyl-cyclobutyl)carbamate (424 mg, 1.7 mmol, 1.0 eq) in ACN (6 mb) was added Cs2CO3(1.14 g, 3.4 mmol, 2.0 eq). The mixture was stirred at 100 °C for 12 h. Thereaction mixture was diluted with water (20 mb) and the mixture was extracted with EtOAc (20 mL*Attorney Docket No.: P60303-WO-13). The combined organic phase was washed with brine (20 mb), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (SiC>2, Petroleum ether: Ethyl acetate= 3:1). Compound tert-butyl N-[3-[(8-cyano-5-quinolyl)oxy]-2,2,4,4-tetramethyl-cyclobutyl] carbamate (500 mg, 1.10 mmol, 63% yield) was obtained as a white solid.

[0542] LC-MS: MS (ESI+): tR= 0.626 min, m / z = 396.2 [M + H+]

[0543] To a solution of tert-butyl N-[3-[(8-cyano-5-quinolyl)oxy]-2,2,4,4-tetramethyl-cyclobutyl] carbamate (500 mg, 1.1 mmol, 1.0 eq) in dioxane (5 mL) was added HCl / dioxane (10 mL). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated in vacuo.Compound 5-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)quinoline-8-carbonitrile (364 mg) was obtained as a yellow solid.

[0544] LC-MS: MS (ESC): tR= 0.414 min, m / z = 296.2 [M + H+]

[0545] To a solution of 5-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)quinoline-8-carbonitrile (197 mg) and 6-chloropyridazine-3-carboxylic acid (113 mg, 711 pmol, 1.2 eq) in DCM (2 mL) was added TEA (180 mg, 1.78 mmol, 247 pL, 3.0 eq) and HATU (338 mg, 889 pmol, 1.5 eq). The mixture was stirred at 25 °C for 12 h. The reaction was filtered and concentrated to give the crude. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um; mobile phase: [water (FA)-ACN]; gradient: 53%-83% B over 10 min). Compound 6-chloro-N-[3-[(8-cyano-5-quinolyl)oxy]-2,2,4,4-tetramethyl-cyclobutyl]pyridazine-3-carboxamide (80 mg, 183 pmol, 31% yield over two steps) was obtained as a yellow solid.

[0546] LC-MS: MS (ESI⁺): tR= 0.585 min, m / z = 436.6 [M + H+]

[0547] To a solution of l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] - 1 -[ 1 -(4-piperidylmethyl)-4-piperidyl] -6,7-dihydro-4H-pyrazolo [4,3-c]pyridin-5 -yl]ethanone (65 mg) in NMP (1 mL) was added DIEA (6 mg, 505 pmol, 88 pL, 5.0 eq) and K2CO3 (42 mg, 303 pmol, 3.0 eq) and 6-chloro-N-[3-[(8-cyano-5-quinolyl)oxy]-2,2,4,4-tetramethyl-cyclobutyl]pyridazine-3-carboxamide (44 mg, 101 pmol, 1.0 eq). The mixture was stirred at 50 °C for 12 h. The mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; gradient: 29%-59% B over 10 min). Compound 6-[4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo[4,3 -c]pyridin- 1 -yl] - 1 -piperidyl] methyl] -l-piperidyl]-N-[3-[(8-cyano-5-quinolyl)oxy]-2,2,4,4-tetramethyl-cyclobutyl]pyridazine-3-carboxamide (18 mg, 17.43 pmol, 17.25% yield) was obtained as a white solid.

[0548] 'H NMR (400 MHz, CHLOROFORM-d) 5 = 9.25-9.11 (m, 1H), 8.78-8.70 (m, 1H), 8.28-8.20 (m, 1H), 8.09-7.96 (m, 1H), 7.63-7.52 (m, 2H), 7.46-7.36 (m, 1H), 7.10-6.97 (m, 2H), 6.88-6.85 (m, 1H), 6.75-6.70 (m, 1H), 6.69- 6.37 (m, 1H), 4.62-4.51 (m, 2H), 4.35-4.24 (m, 3H), 4.22-4.11 (m, 1H), 4.01- 3.88 (m, 5H), 3.76-3.68 (m, 3H), 3.15-3.00 (m, 4H), 2.96-2.80 (m, 3H), 2.80-2.75 (m, 1H), 2.36-2.23 (m, 4H), 2.21-2.05 (m, 7H), 2.02-1.88 (m, 5H), 1.34 (s, 6H), 1.29 (s, 6H), 1.31-1.21 (m,Attorney Docket No.: P60303-WO-12H)

[0549] LC-MS: MS (ESI+): tR= 1.909 min, m / z = 1006.8 [M + H+]Example 3: Synthesis of 6-[4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl]methyl] -3,3-dimethyl-l-piperidyl]-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (Compound 19)K2CO3, DMF,70°C,12 h 40%T4P, TEA, DCM 25°C,0.5 h 75%

[0550] To a solution of l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-l-(4-piperidyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.00 g, 1.96 mmol, 1 eq) in DCE (15 mL) was added NMM (5.52 g, 54.57 mmol, 6.00 mL, 27.81 eq) and added tert-butyl 4-formyl-3,3-dimethyl-piperidine-l-carboxylate (947 mg, 3.92 mmol, 2 eq) and NaBH(OAc)3 (831 mg, 3.92 mmol, 2 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition water 200 mL, and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, DCM: MeOH =1 / 0 to 10 / 1). Compound tert-butyl 4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]-l-piperidyl]methyl]-3,3-dimethyl-piperidine-l-carboxylate (700 mg,Attorney Docket No.: P60303-WO-1952.49 pmol, 48% yield) was obtained as a white solid.

[0551] LC-MS: MS (ESI+): tR= 0.492 min, m / z = 735.5 [M + H+]

[0552] To a solution of tert-butyl 4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl]methyl] -3,3 -dimethyl -piperidine- 1 -carboxylate (700 mg, 952.49 pmol, 1 eq) in DCM (10 mL) was added TFA (15.35 g, 134.62 mmol, 10 mL, 141.34 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 150*40mm* 15um;mobile phase: [H₂O(0.225% FA)-ACN];gradient:5%-35% B over 15.0 min). Compound l-[3-[7-(difhioromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-l-[l-[(3,3-dimethyl-4-piperidyl)methyl]-4-piperidyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (600 mg, 945.17 pmol, 99% yield) was obtained as a yellow solid.

[0553] LC-MS: MS (ESI+): tR= 0.403 min, m / z = 635.4 [M + H+]

[0554] Preparation of 3A

[0555] To a solution of 5-(4-aminocyclohexoxy)quinoline-8-carbonitrile (2.49 g, 6.53 mmol, 1 eq),6-chloropyridazine-3-carboxylic acid (2.07 g, 13.06 mmol, 2 eq) and TEA (6.61 g, 65.29 mmol, 9.09 mL, 10 eq) in DCM (30 mL) was added dropwise T4P (7.06 g, 9.79 mmol, 50% purity, 1.5 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition water 100 mL, and then extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3). dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with Ethyl acetate (50mL) at 25 °C for 30 min. Compound 6-chloro-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (2.00 g, 4.90 mmol, 75% yield) was obtained as a white solid.

[0556] 'H NMR (400 MHz, CHLOROFORM- ): 5 = 9.10 (d, J = 4.0 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.11 - 7.94 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 3.6, 8.8 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.70 - 4.53 (m, 1H), 4.26 - 4.08 (m, 1H), 2.44 - 2.21 (m, 4H), 1.94 -1.78 (m, 2H), 1.64 - 1.55 (m, 2H)

[0557] LC-MS: MS (ESC): tR= 0.530 min, m / z = 408.0 [M + H+]

[0558] Preparation of Compound 19

[0559] To a solution of l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] - 1 -[ 1 -[(3,3 -dim ethyl -4-piperidyl)methyl]-4-piperidyl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin-5-yl]ethanone (300 mg, 472.59 pmol, 1 eq) in DMF (10 mL) was added K2CO3 (200 mg, 1.45 mmol, 3.06 eq) and 6-chloro-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (220 mg, 539.41 pmol, 1.14 eq). The mixture was stirred at 70 °C for 12 h. The reaction mixture was quenched by addition water 100 mL, and then extracted with Ethyl acetate (30 mL x 3).Attorney Docket No.: P60303-WO-1The combined organic layers were washed with brine (30 mL x 3). dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Unisil 3-100 C18 Ultra 150*50mm*3 um;mobile phase: [H₂O(0.225% FA)-ACN];gradient:20%-50% B over 15.0 min). Compound 6-[4-[[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3-c]pyridin- 1 -yl] -1-piperidyl]methyl]-3,3-dimethyl-l-piperidyl]-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (195.99 mg, 193.36 prnol, 40% yield) was obtained as an off-white solid.

[0560] 'H NMR (400 MHz, CHLOROFORM- ): 5 = 9.08 (dd, J = 2.0, 4.4 Hz, 1H), 8.64 (dd, J = 1.6, 8.4 Hz, 1H), 8.35 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 8.4, 14.8 Hz, 2H), 7.59 - 7.46 (m, 2H), 7.41 (d, J = 6.8 Hz, 1H), 7.08 - 6.86 (m, 4H), 6.73 - 6.34 (m, 1H), 4.66 - 4.54 (m, 1H), 4.48 (br d, J = 12.0 Hz, 1H), 4.30 - 4.07 (m, 4H), 3.91 (brt, J = 6.0 Hz, 1H), 3.81 - 3.64 (m, 3H), 3.26 - 3.12 (m, 1H), 3.10 - 2.93 (m, 2H), 2.93 - 2.78 (m, 4H), 2.75 (brt, J = 5.6 Hz, 1H), 2.48 (brd, J= 12.8 Hz, 1H), 2.37 -2.20 (m, 8H), 2.17 (s, 2H), 2.14 - 1.98 (m, 10H), 1.93 - 1.77 (m, 3H), 1.66 - 1.42 (m, 4H), 1.07 (s, 3H), 0.84 (s, 3H)

[0561] LC-MS: MS (ESI+): tR= 2.872 min, m / z = 1006.7 [M + H+]Example 4: Synthesis of 6-[4-[7-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] -2-azaspiro [3,5]nonan-2-yl] -l-piperidyl]-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (Compound 18)

[0562] Synthesis of 1 was reported in WO2022 / 32026, 2022, Al

[0563] Synthesis of 1A was reported in Journal of Medicinal Chemistry, 2024, vol. 67, # 7, p.Attorney Docket No.: P60303-WO-15275 - 5304.

[0564] Synthesis of 4A was reported in Cell Chemical Biology, 2021, vol. 28, # 4, p. 503 - 512, 514.

[0565] To a solution of l-(3-iodo-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (2.73 g, 9.39 mmol, 1.0 eq), tertbutyl 7-methylsulfonyloxy-2-azaspiro[3.5]nonane-2-carboxylate (3.00 g, 9.39 mmol, 1.0 eq) in DMF (30 mL) was added Cs2CO3(9.18 g, 28.2 mmol, 3.0 eq). The mixture was stirred at 100 °C for 12 h. The mixture was diluted with water (100 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). Compound tert-butyl 7-(5-acetyl-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl)-2-azaspiro[3.5]nonane-2 -carboxylate (2.40 g, 4.67 mmol, 50% yield) was obtained as a yellow oil.

[0566] LC-MS: MS (ESI⁺): tR= 0.513 min, m / z = 515.1 [M + H+]

[0567] To a solution of tert-butyl 7-(5-acetyl-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl)-2-azaspiro[3.5]nonane-2- carboxylate (2.10 g, 4.08 mmol, 1.0 eq) in DCM (5 mL) was added TFA (7.68 g, 67.3 mmol, 5.0 mL, 16.5 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue. Compound l-[l-(2-azaspiro[3.5]nonan-7-yl)-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (2.16 g) was obtained as a yellow oil and directly used in the next step without further purification.

[0568] LC-MS: MS (ESI+): tR= 0.360 min, m / z = 415.1 [M + H+]

[0569] To a solution of l-[l-(2-azaspiro[3.5]nonan-7-yl)-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (2.16 g) in DCM (20 mL) was added EtsN (1.24 g, 12.3 mmol, 1.71 mL, 3.0 eq), then tert-butyl 4- oxopiperidine- 1 -carboxylate (1.22 g, 6.13 mmol, 1.5 eq) and NaBH(OAc)3 (1.30 g, 6.13 mmol, 1.5 eq) was added. The mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (100 mL), and then extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Welch Ultimate XB-SiOH 250 x 70 x 10 um; mobile phase: [Hexane EtOH 0.1% NH3 • H2O ]; gradient: 5%-45% B over 15 min). Compound tert-butyl 4-[7-(5-acetyl-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl)-2-azaspiro[3.5]nonan-2-yl]piperidine-l- carboxylate (600 mg, 1.0 mmol, 25% yield over two steps) was obtained as a white solid.

[0570] LC-MS: MS (ESI⁺): tR= 0.436 min, m / z = 598.2 [M + H+]

[0571] A mixture of tert-butyl 4-[7-(5-acetyl-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl)-2-azaspiro[3.5]nonan-2-yl]piperidine-l-carboxylate (550 mg, 920.5 pmol, 1.0 eq), 7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-l,2,3,4-tetrahydroquinoline (315 mg, 1.2 mmol, 1.3 eq), tBuXPhos Pd G3 (146 mg, 184.1 pmol, 0.2 eq) and t-BuOK (1 M, 1.84 mL, 2.0 eq) in 2-methylbutan-2-ol (11 mL) wasAttorney Docket No.: P60303-WO-1degassed and purged with N₂ for 3 times, and then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). Compound tert-butyl 4-[7-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] -2-azaspiro [3,5]nonan-2-yl]piperidine-l -carboxylate (480 mg, 654.9 pmol, 71% yield) was obtained as a yellow solid.

[0572] 'H NMR (400 MHz, CDCh) 5 = 7.52 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 6.4 Hz, 1H), 7.01 (d, J = 21.6 Hz, 1H), 6.87 (d, J = 6.8 Hz, 1H), 6.70 - 6.35 (m, 1H), 4.25 (s, 1H), 3.99 - 3.79 (m, 7H), 3.76 - 3.64 (m, 3H), 3.17 - 2.99 (m, 4H), 2.96 - 2.65 (m, 7H), 2.27 - 2.16 (m, 2H), 2.13 - 2.03 (m, 8H), 1.98 - 1.83 (m, 4H), 1.67 - 1.52 (m, 4H), 1.44 (s, 9H)

[0573] LC-MS: MS (ESI+): tR= 0.841 min, m / z = 733.4 [M + H+]

[0574] To a solution of tert-butyl 4-[7-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] -2-azaspiro [3,5]nonan-2-yl]piperidine-l -carboxylate (480 mg, 576.3 pmol, 1.0 eq) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-l-[2-(4-piperidyl)-2-azaspiro[3.5]nonan-7-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (430 mg) was obtained as a yellow oil and directly used in the next step without further purification.

[0575] LC-MS: MS (ESI+): tR= 0.758 min, m / z = 633.4 [M + H+]

[0576] To a solution of l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] - 1 -[2-(4-piperidyl)-2 -azaspiro [3,5]nonan-7 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin-5-yl]ethanone (430 mg) in DMF (5 mL) was added K2CO3 (470 mg, 3.4 mmol, 5.0 eq) and 6-chloro-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (333 mg, 815.4 pmol, 1.2 eq). The mixture was stirred at 70 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 um; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 25%-55% B over 10.0 min). Compound 6-[4-[7-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] -2-azaspiro [3.5]nonan-2-yl] - 1 -piperidyl] -N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (333.77 mg, 323.17 pmol, 48% yield over two steps) was obtained as a yellow solid.

[0577] 'H NMR (400 MHz, CDCI3) 5 = 9.06 - 9.04 (m, 1H), 8.64 - 8.61 (m, 1H), 8.04 - 7.98 (m, 2H), 7.89 (d, J = 8.2 Hz, 1H), 7.56 - 7.46 (m, 2H), 7.39 (d, J = 5.6 Hz, 1H), 7.06 - 6.83 (m, 4H), 6.71 -6.33 (m, 1H), 4.66 -4.41 (m, 3H), 4.24 (s, 1H), 4.16 - 4.06 (m, 2H), 3.97 - 3.82 (m, 5H), 3.79 - 3.48 (m, 7H), 3.09 (t, J= 11.8 Hz, 2H), 2.98 -2.66 (m, 5H), 2.34 -2.12 (m, 7H), 2.11 - 1.75 (m, 12H), 1.72 - 1.47 (m, 6H)Attorney Docket No.: P60303-WO-1

[0578] LC-MS: MS (ESI+): tR= 2.836 min, m / z = 1004.9 [M + H+]Example 5: Synthesis of 6-[7-[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl] -2-azaspiro[3.5]nonan-2-yl]-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamideCompound 178 4

[0579] Preparation of 4

[0580] A mixture of 8-bromo-5-fluoro-quinoline (5.00 g, 22.12 mmol, 1.0 eq), Zn(CN)₂ (5.19 g, 44.24 mmol, 2.81 mL, 2.0 eq), Ruphos Pd G2 (859 mg, 1.11 mmol, 0.05 eq) in DMF (50 mb) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100 °C for 3 h under N2 atmosphere. The reaction mixture was filtered and quenched by addition water (500 mb), and then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 100 / 1 to 3 / 1).Compound 5 -fluoroquinoline -8 -carbonitrile (2.61 g, 15.01 mmol, 67% yield) was obtained as a whiteAttorney Docket No.: P60303-WO-1solid.

[0581] LC-MS: MS (ESI+): tR= 0.461 min, m / z = 172.9 [M + H+]

[0582] 'H NMR (400 MHz, CHLOROFORM -d) 5 = 9.17 (m, 1H), 8.52 (m, 1H), 8.14 (m, 1H), 7.64 (m, 1H), 7.32 (t, J = 8.4 Hz, 1H).

[0583] To a solution of 5-fluoroquinoline-8-carbonitrile (1.5 g, 8.71 mmol, 1.0 eq) in ACN (40 mL) was added Cs2CO3(8.52 g, 26.14 mmol, 3.0 eq) and tert-butyl N-(4-hydroxycyclohexyl)carbamate (2.25 g, 10.46 mmol, 1.2 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by addition water (100 mL) at 25 °C, and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (60 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, DCM / MeOH = 1 / 0 to 50 / 1). Compound tert-butyl N-[4-[(8-cyano-5-quinolyl) oxy] cyclohexyl] carbamate (3.2 g, 7.93 mmol, 90% yield) was obtained as a yellow solid.

[0584] LC-MS: MS (ESI⁺): tR= 0.543 min, m / z = 368.1 [M + H+]

[0585] To a solution of tert-butyl N-[4-[(8-cyano-5-quinolyl) oxy] cyclohexyl] carbamate (3.20 g, 8.71 mmol, 1.0 eq) in DCM (4 mL) was added HCl / dioxane (2 M, 30 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue.Compound 5-(4-aminocyclohexoxy) quinoline-8-carbonitrile (2.65 g) was obtained as a white solid and directly used in the next step without further purification.

[0586] LC-MS: MS (ESI⁺): tR= 0.469 min, m / z = 268.1 [M + H+]

[0587] To a solution of 5-(4-aminocyclohexoxy)quinoline-8-carbonitrile (2.55 g) in DCM (40 mL) was added Et₃N (2.55 g, 25.18 mmol, 3.51 mL, 3.0 eq) at 0 °C for 0.5 h under N2 then 6-chloropyridazine -3 -carbonyl chloride (1.78 g, 10.07 mmol, 1.2 eq) was added. The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched by addition water (60 mL) at 25 °C, and then extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (10 mL) at 25 °C for 0.5 h. Compound 6-chloro-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (1.86 g, 3.92 mmol, 46%yield over two steps) was obtained as a brown solid.LC-MS: MS (ESC): fe = 0.528 min, m / z = 408.2 [M + H+]

[0588] Preparation of Compound 17

[0589] To a solution of l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-l-(4-piperidyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (250 mg, 490 pmol, 1.0 eq) and tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (235 mg, 981 pmol, 2.0 eq) in DCM (5 mL) was added EtsN (0.2 mL, 3.0 eq) and NaBH(OAc)3 (520 mg, 2.45 mmol, 5.0 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition water (40 mL) at 25 °C, and then extracted with DCM (20 mL x 3). The combined organic layers were washed withAttorney Docket No.: P60303-WO-1brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO₂, DCM / MeOH = 10 / 1). Compound tert-butyl 7-[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]-l-piperidyl]-2-azaspiro[3.5]nonane-2 -carboxylate (280 mg, 382 pmol, 77% yield) was obtained as a white solid.

[0590] LC-MS: MS (ESI+): tR= 0.480 min, m / z = 733.5 [M + H+]

[0591] To a solution of tert-butyl 7-[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl] -2-azaspiro[3.5]nonane-2 -carboxylate (280 mg, 382 pmol, 1.0 eq) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove solvent. Compound l-[l-[l-(2-azaspiro[3.5]nonan-7-yl)-4-piperidyl]-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (242 mg) was obtained as a yellow solid and directly used in the next step without further purification.

[0592] LC-MS: MS (ESI⁺): tR= 0.500 min, m / z = 633.3 [M + H+]

[0593] To a solution of l-[l-[l-(2-azaspiro[3.5]nonan-7-yl)-4-piperidyl]-3-[7-(difluoromethyl)-6-( 1 -methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin-5 -yl]ethanone (242 mg, 382 pmol, 1.0 eq) in DMSO (2 mL) was added DIPEA (148 mg, 1.15 mmol, 0.2 mL, 3.0 eq) and 6-chloro-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (234 mg, 573 pmol, 1.5 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by addition water (40 mL) at 25 °C, and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 28%-58% B over 11.0 min). Compound 6-[7-[4-[5-acetyl-3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl] -2-azaspiro[3.5]nonan-2-yl]-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (21.94 mg, 21.21 pmol, 5% yield over two steps) was obtained as a white solid.

[0594] 'H NMR (400 MHz, DMSO-6) 5 = 9.08 (m, 1H), 8.65 (m, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.76 (s, 1H), 7.70 (m, 1H), 7.50 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 6.98 - 6.63 (m, 3H), 4.74 (m, 1H), 4.20 - 4.03 (m, 3H), 3.99 - 3.90 (m, 1H), 3.87 (s, 5H), 3.81 - 3.67 (m, 4H), 3.63 - 3.56 (m, 2H), 3.17 - 3.04 (m, 2H), 2.85 (d, J = 4.4 Hz, 3H), 2.78 - 2.70 (m, 1H), 2.54 (s, 2H), 2.28 - 2.21 (m, 2H), 2.08 (s, 3H), 2.06 - 1.99 (m, 4H), 1.97 (s, 7H), 1.82 - 1.65 (m, 6H), 1.60 - 1.50 (m, 2H), 1.46 - 1.32 (m, 2H).

[0595] LC-MS: MS (ESI⁺): tR= 2.697 min, m / z = 1004.7 [M + H+]Attorney Docket No.: P60303-WO-1Example 6: Synthesis of -[4-[[4-[5-acetyl-3-(6-cyano-7-methyl-3,4-dihydro-2H-quinolin-l-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]-l-piperidyl]methyl]-3,3-dimethyl-l-piperidyl]-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (Compound 15)TzR Et3N, DCM 25 °C, 16 h, 40 %

[0596] Synthesis of 1 was reported in US2021 / 87171 Al.

[0597] Preparation of 2

[0598] To a solution of 5-(4-aminocyclohexoxy)quinoline-8-carbonitrile (700 mg) and 6-chloropyridazine -3 -carboxylic acid (291 mg, 1.84 mmol, 1.0 eq) in dichloromethane (10 mL) was added triethylamine (929 mg, 9.18 mmol, 1.28 mL, 5.0 eq) and T4P (1.98 g, 2.75 mmol, 50% purity, 1.5 eq). The mixture was stirred at 25 °C for 16 h. The mixture was poured into water (50 mL). The aqueous phase was extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with brine (50 mL x 3). dried with anhydrous sodium sulfate, fdtered and concentrated in vacuum. The crude product was triturated with ethyl acetate at 25 °C for 30 min. Compound 6-chloro-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (300 mg, 735.56 pmol, 40 % yield) was obtianed as an off-white solid.

[0599] 'H NMR (400 MHz, CHLOROFORM-d) 5 = 9.09 (br d, J= 2.8 Hz, 1H), 8.64 (br d, J = 7.6 Hz, 1H), 8.30 (d, J= 8.8 Hz, 1H), 8.14 - 7.93 (m, 2H), 7.72 (d, J= 8.8 Hz, 1H), 7.52 (dd, J= 4.4,Attorney Docket No.: P60303-WO-18.4 Hz, 1H), 6.94 (d, J= 8.4Hz, 1H), 4.73 - 4.51 (m, 1H), 4.29 - 4.05 (m, 1H), 2.44 - 2.23 (m, 4H), 1.89 - 1.81 (m, 2H), 1.69 - 1.57 (m, 2H)

[0600] LC-MS: MS (ESI+): tR= 0.533 min, m / z = 408.0 [M + H+]

[0601] Preparation of Compound 15

[0602] To a solution of tert-butyl 4-[[4-[5-acetyl-3-(6-cyano-7-methyl-3,4-dihydro-2H-quinolin-l-yl)-6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl]methyl] -3,3 -dimethyl -piperidine- 1 -carboxylate (90 mg, 139.78 pmol, 1.0 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (4.61 g, 40.39 mmol, 3 mL, 288.93 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was used into next step directly. Compound l-[5-acetyl-l-[l-[(3,3-dimethyl-4-piperidyl)methyl]-4-piperidyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-7-methyl-3,4-dihydro-2H-quinoline-6-carbonitrile (90 mg) was obtained as a yellow oil and directly used in the next step without further purification.

[0603] LC-MS: MS (ESI+): tR= 0.405 min, m / z = 544.4 [M + H+]

[0604] To a solution of l-[5-acetyl-l-[l-[(3,3-dimethyl-4-piperidyl)methyl]-4-piperidyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-7-methyl-3,4-dihydro-2H-quinoline-6-carbonitrile (90 mg) and 6-chloro-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (61 mg, 150.51 pmol, 1.1 eq) in N, N-dimethylformamide (5 mL) was added potassium carbonate (100 mg, 723.56 pmol, 5.29 eq). The mixture was stirred at 70 °C for 16 h. The mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL x 3). dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna Cl 8150*25mm* 10um;mobile phase: [H₂O (0.225% FA)-ACN] gradient: 18%-48% B over 15.0 min). Compound 6-[4-[[4-[5-acetyl-3-(6-cyano-7-methyl-3,4-dihydro-2H-quinolin-l-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]-l-piperidyl]methyl]-3,3-dimethyl-l-piperidyl]-N-[4-[(8-cyano-5-quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (32.38 mg, 34.55 pmol, 25 % yield over two steps) was obtained as a white solid.

[0605] 1H NMR (400 MHz, CHLOROFORM-d) 5 = 9.09 (dd, J= 1.6, 4.4 Hz, 1H), 8.64 (dd, J = 1.6, 8.4 Hz, 1H), 8.05 (d, J= 8.4Hz, 1H), 7.96 (br d, J= 9.2 Hz, 1H), 7.90 (br d, J= 8.0 Hz, 1H), 7.52 (dd, J= 4.4, 8.5 Hz, 1H), 7.22 (br d, J= 10.4 Hz, 1H), 6.96 (dd, J= 9.2, 12.4 Hz, 2H), 6.28 (d, J = 2.4 Hz, 1H), 4.63 -4.56 (m, 1H), 4.51 - 4.42 (m, 1H), 4.28 (s, 1H), 4.16 - 4.09 (m, 2H), 3.92 ( t, J = 6.0 Hz, 1H), 3.77 ( t, J = 5.2 Hz, 1H), 3.69 - 3.63 (m, 2H), 3.22 - 2.92 (m, 3H), 2.91 - 2.68 (m, 6H), 2.33 ( d, J = 7.2 Hz, 4H), 2.29 ( s, 2H), 2.25 ( s, 2H), 2.19 (s, 2H), 2.10 - 1.99 (m, 5H), 1.90 - 1.78 (m, 3H), 1.65 - 1.46 (m, 9H), 1.36 - 1.15 (m, 1H), 1.08 (s, 3H), 0.85 (s, 3H)

[0606] LC-MS: MS (ESI+): tR= 2.812 min, m / z = 915.8 [M + H+]Attorney Docket No.: P60303-WO-1Example 7: Synthesis of 6-[4-[[4-[5-acetyl-3-(6-cyano-7-methyl-3,4-dihydro-2H-quinolin-l-yl)-6,7-dihydro-4H-pyrazolo [4,3 -c] pyridin- 1 -yl] - 1 -piperidyl] methyl] -3,5 -dimethyl- 1 -piperidyl] -N-[4-[(8-cyano-5 -quinolyl) oxy] cyclohexyl] pyridazine-3 -carboxamide (Compound 14)

[0607] To a solution of l-[5-acetyl-l-[l-[(3,5-dimethyl-4-piperidyl) methyl] -4-piperidyl] -6,7-dihydro-4H-pyrazolo [4,3 -c] pyridin-3-yl] -7 -methyl-3,4-dihydro-2H-quinoline-6-carbonitrile (100 mg, 183 pmol, 1.0 eq) and 6-chloro-N-[4-[(8-cyano-5-quinolyl) oxy] cyclohexyl] pyridazine-3-carboxamide (75 mg, 183 pmol, 1.0 eq) in NMP (2 mL) was added K2CO3 (127 mg, 919 pmol,5.0 eq). The mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*25mm*5um; mobile phase:[H₂O (10mM NH₄HCO₃)-ACN]; gradient: 48%-78% B over 15.0 min). Compound 6-[4-[[4-[5-acetyl-3 -(6-cyano-7-methyl-3,4-dihydro-2H-quinolin- 1 -yl)-6,7-dihydro-4H-pyrazolo [4,3-c] pyridin- 1 -yl] - 1 -piperidyl] methyl]-3,5-dimethyl-l-piperidyl]-N-[4-[(8-cyano-5-quinolyl) oxy] cyclohexyl] pyridazine-3-carboxamide (45.69 mg, 27% yield) was obtained as a white solid.

[0608] 'H NMR (400 MHz, DMSO-6) 5 = 9.12 - 9.03 (m, 1H), 8.67 - 8.56 (m, 2H), 8.31 - 8.24 (m, 1H), 7.82 - 7.74 (m, 1H), 7.72 - 7.64 (m, 1H), 7.37 - 7.31 (m, 3H), 6.36 - 6.29 (m, 1H), 4.80 - 4.65 (m, 1H), 4.17 - 4.08 (m, 2H), 4.03 (s, 1H), 3.96 - 3.89 (m, 1H), 3.82 - 3.70 (m, 4H), 3.62 - 3.54 (m, 2H), 3.04 - 3.01 (m, 2H), 2.85 (s, 2H), 2.79 - 2.72 (m, 4H), 2.32 (s, 2H), 2.23 (s, 6H), 2.08 (s, 2H),1.99 - 1.86 (m, 13H), 1.69 (s, 4H), 0.97 (s, 3H), 0.96 (s, 3H).

[0609] LC-MS: MS (ESI+): tR= 2.818 min, m / z = 915.8 [M + H+]Attorney Docket No.: P60303-WO-1Example 8: Synthesis of 6-[4-[[4-[5-acetyl-3-[6-cyano-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1 -yl] -6,7-dihydro-4Hpyrazolo [4,3 -c]pyridin- 1 -yl] - 1 -piperidyl]methyl] -3,3 -dimethyl- 1 -piperidyl] -N-[4-[(8-cyano-5- quinolyl)oxy]cyclohexyl]pyridazine-3-carboxamide (Compound 13)

[0610] Synthesis of 1 was reported in US2019 / 308978 Al

[0611] Synthesis of 4A was report in US2022 / 289752 Al

[0612] To a solution of 6-bromo-7-(difhioromethyl)-l, 2, 3, 4-tetrahydroquinoline (1.40 g, 5.34 mmol, 1 eq) in NMP (14 mL) was added CuCN (4.78 g, 53.42 mmol, 11.67 m, 10 eq). The mixture was stirred at 140 °C for 12 h under N2 atmosphere. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2Petroleum ether: Ethyl acetate =1: 0 to 3: 1). Compound 7-(difluoromethyl)-l, 2, 3, 4-tetrahydroquinoline-6-carbonitrile (650 mg, 3.12 mmol, 58% yield) was obtained as a yellow solid.Attorney Docket No.: P60303-WO-1

[0613] 'H NMR (400 MHz, CHLOROFORM-d) 5 = 7.34 (s, 1H), 7.10 - 6.81 (m, 2H), 6.70 (s, 1H), 3.25 (t, J = 6.4 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H), 1.81 - 1.71 (m, 2H).

[0614] LC-MS: MS (ESI+): tR= 0.547 min, m / z = 209.1 [M + H+]

[0615] To a solution of 7-(difluoromethyl)-l,2,3,4-tetrahydroquinoline-6-carbonitrile (300 mg, 1.44 mmol, 1 eq) in 2- methylbutan-2-ol (7 mL) was added CPHOS PD Gs (116 mg, 144.09 pmol, 0.1 eq), tert-butyl 4-(5-acetyl-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (683 mg, 1.44 mmol, 1 eq) and Cs2CO3(469 mg, 1.44 mmol, 1 eq) under N2 atmosphere. The mixture was stirred at 90°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um;mobile phase: [H₂O(0.225% FA)-ACN] gradient: 42%-72% B over 15.0 min). Compound tertbutyl 4-[5-acetyl-3-[6-cyano-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4Hpyrazolo[4,3-c]pyridin-l-yl]piperidine-l-carboxylate (320 mg, 576.96 pmol, 40% yield) was obtained as a white solid.

[0616] 'H NMR (400 MHz, CHLOROFORM-d) 5 = 7.35 (d, J = 12.0 Hz, 1H), 6.98 - 6.55 (m, 2H), 4.29 (s, 3H), 4.16 - 4.01 (m, 2H), 3.93 (s, 1H), 3.84 - 3.65 (m, 3H), 3.04 - 2.80 (m, 5H), 2.78 (t, J = 6.0 Hz, 1H), 2.20 (s, 2H), 2.14 - 2.02 (m, 5H), 1.91 (d, J = 11.3 Hz, 2H), 1.48 (s, 9H).

[0617] LC-MS: MS (ESI+): tR= 0.614 min, m / z = 555.3 [M + H+]

[0618] To a solution of tert-butyl 4-[5-acetyl-3-[6-cyano-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4Hpyrazolo[4,3-c]pyridin-l-yl]piperidine-l-carboxylate (300 mg, 540.90 pmol, 1 eq) in DCM (3 mL) was added TFA (4.61 g, 40.39 mmol, 3 mL, 74.67 eq) and stirred at 25°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with saturated NaHCO₃ solution (10 mL) and extracted with DCM: MeOH = 10: 1 (10 mL * 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound l-[5-acetyl-l-(4-piperidyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4-dihydro2H-quinoline-6-carbonitrile (229 mg) was obtained as a yellow solid and directly used in the next step without further purification.

[0619] LC-MS: MS (ESI+): tR= 0.396 min, m / z = 455.2 [M + H+]

[0620] To a solution of l-[5-acetyl-l-(4-piperidyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-7-(difluoromethyl)-3,4- dihydro-2H-quinoline-6-carbonitrile (200 mg, 440.03 pmol, 1 eq) in DCM (3 mL) was added NMM (2.23 g, 22.00 mmol, 2.42 mL, 50 eq) and tert-butyl 4-formyl-3,3-dimethyl-piperidine-1 -carboxylate (425 mg, 1.76 mmol, 4 eq) and stirred at 25°C for 0.5 h. Then to the mixture was added NaBH(OAc)3(466 mg, 2.20 mmol, 5 eq) and stirred at 25°C for 11.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150x50mm><3 pm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 20%-50% B over 15.0 min). Compound tert-butyl 4-[[4-[5-acetyl-3-[6-cyano-7-(difluoromethyl)-3,4-dihydro-2H-quinolin- 1 -yl]...

Claims

1. Attorney Docket No.: P60303-WO-1CLAIMS WHAT IS CLAIMED IS:

1. A heterobifunctional conditional inhibitor compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human E1A-binding protein p300 (p300) (CBP / p300);L is an optional linker; wherein L is covalently attached at a position of SB-CBP / p300 that is solvent exposed when SB binds to CBP / p300;B-AR is a binder of the androgen receptor (AR), wherein the B-AR comprises option 1), option 2), or option 3):option 1) a head group A3that occupies the ligand-binding domain (LBD) of AR, and an optional tail moiety (ring D) is covalently attached to the core moiety; wherein the core comprises an optionally substituted cycloalkyl and the core and head group A3have the structure of Formula (A):Formula (A);wherein each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4; andAttorney Docket No.: P60303-WO-1option 2) a head group A3that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety, and an optional tail moiety (ring D) is covalently attached to the core moiety; wherein the core and head group A3have one of the following structures:Attorney Docket No.: P60303-WO-1moiety;the optional tail moiety of option 1), option 2), and option 3) comprises a ring D that is covalently attached to the core, wherein ring D is a 5-, 6-, 8-, 9- or 10-membered aryl or a 5-, 6-, 8-, 9- or 10-Attorney Docket No.: P60303-WO-1membered heteroaryl that is optionally substituted with w R3; w is 1, 2, 3, 4;Z is -0- or -NR5-;each X1is independently -CR1- or -N-;X4is -CRd- or -N-;each R1is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -OR4, OC(=O)R4, -OC(=O)N(R5)2, -OC(=O)OR5, -OC(=O)NR5, -SH, -SR4, - S(=O)R4, -S(=O)2R5, -S(=O)2OR4, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, -NR5C(=O)R4, - NR5C(=O)OR5, -NR5S(=O)2R5, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlais hydrogen, halogen, -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -NO2, -C(=O)R5, -C(=O)OR5, - C(=O)N(R5)2, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;Rldis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4;each R2is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, - OH, -OR4, OC(=O)R4, -S(=O)R4, -S(=O)2R5, -S(=O)2N(R5)2, -N(R5)2, -NR5C(=O)NR5, - NR5C(=O)R4, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; ortwo R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-C8cycloalkyl or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, - OR4, or -N(R5)2;each R4is independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two R5on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; andAttorney Docket No.: P60303-WO-1wherein L is covalently attached to the core moiety at position (*) if the optional tail moiety is absent, or L is covalently attached to the tail moiety if present.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein SB- CBP / p300 binds in the acetyl -lysine (KAc) binding site of the bromodomain of CBP / p300, optionally wherein SB-CBP / p300 comprises an acetyl-lysine mimetic moiety that binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300,wherein L is covalently attached at a position of SB-CBP / p300 that is solvent exposed when SB-CBP / p300 binds the KAc binding site of the bromodomain of CBP / p300.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein SB-CBP / p300 further comprises:1) a moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300;or2) a moiety that occupies the BC Loop region of the bromodomain of CBP / p300; or3) both 1) and 2);wherein L is covalently attached to SB-CBP / p300 on:• the acetyl-lysine mimetic moiety; or• the moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300, if present; or• the moiety that occupies the BC Loop region of the bromodomain of CBP / p300, if present;wherein L is covalently attached to SB-p300 / CBP at a position that does not interfere with the binding of the acetyl-lysine mimetic moiety in the acetylated lysine (KAc) binding site of CBP / p300.

4. The compound of claim 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises a moiety selected from pyrrolidonyl, phenyl, pyridinyl, pyridinonyl, triazolyl, pyrrolyl, isoxazolyl, pyrazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolonyl, quinazolinyl, dihydroquinazolinonyl, imidazo[4,5-c]quinolinyl fused to a dimethylisoxazolyl, triazolophthalazinyl, indolizinyl, benzoimidazolyl, isoxazole-indolizinyl, thienodiazepine- indolizinyl, benzodiazepine-indolizinyl, 5-isoxazolylbenzimidazolyl, 6-isoxazolylbenzimidazolyl, 7-isoxazolo-quinolinyl, diazobenzyl, triazolophthalazinyl, isoxazoloquinolinyl, 2-thiazolidinonyl, triazolopyrimidinyl, thienodiazepinyl, benzodiazepinyl, benzotriazepinyl, triazolobenzodiazepinyl, triazolothienodiazepinyl, triazolothienodiazepinyl, and isoxazole- azepinyl.Attorney Docket No.: P60303-WO-15. The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises a moiety selected from:each R32is independently an optional moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300;or each R32is independently an optional moiety that occupies the BC Loop region of the bromodomain of CBP / p300;-I is the point of attachment to L that covalently connects SB-CBP / p300 to B-AR;Attorney Docket No.: P60303-WO-1or R32comprises ⁻| and L that covalently connects SB-CBP / p300 to B-AR is attached to R32; each R28is independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;each R34is independently hydrogen or substituted or unsubstituted Ci-Cealkyl;each R35is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted G-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -OH, -ORa, or -N(Rb)2;m is 0, 1, 2, 3, or 4;each R27is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted G-Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, - NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;Y is -C(R30)2- or C(=O);each X3is independently CR27or N;each R30is independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted G-Cefluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2; q is 0, 1, 2, 3, or 4; each R31is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C1-C6fluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, - NRbC(=O)NRb, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or - C(=O)N(Rb)2;each R36is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;Ring B is a fused substituted or unsubstituted 5 or 6 membered heterocycloalkyl;each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-Attorney Docket No.: P60303-WO-1Gcycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

6. The compound of claim 3-5, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300 is R32, wherein:R32is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C2- Cealkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C12cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;y is 1 or 2;Z1is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted Ci-Cealkyl;R26is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;each X2is independently -CR30- or -N-;each X3is independently -CR27- or -N-;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl,Attorney Docket No.: P60303-WO-1substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -OC(=O)N(Rb)2, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, - NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;p is 0, 1, 2, or 3;R28is hydrogen or substituted or unsubstituted Ci-Cealkyl;R29is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;Y is -C(R30)2- or -N(R28)-;each R30is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, - OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, - C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;q is 0, 1, 2, 3, or 4;or R32is -L-C;L is substituted or unsubstituted Ci-Cealkyl or substituted or unsubstituted Ci-Ceheteroalkyl; C is substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rais independently substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.Attorney Docket No.: P60303-WO-17. The compound of any one of claims 3-5, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety that occupies the BC Loop region of the bromodomain of CBP / p300 is R32, wherein:is substituted or unsubstituted.

8. The compound of any one of claims 5-6, or a pharmaceutically acceptable salt or solvate thereof,R32Attorney Docket No.: P60303-WO-19. The compound of claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein:R27is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, - OH, or -ORa; andeach R27is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, or - ORa; andeach Rais independently substituted or unsubstituted C1-C6alkyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R27is independently hydrogen, -CH3, -CH₂CH₃, -F, -CHF2, -CF₃, -CN, -OH, -OCH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrazolyl, 1- methyl pyrazolyl, pyridinyl, or pyrimidinyl.

11. The compound of any one of claims 5-10, or a pharmaceutically acceptable salt or solvate thereof,wherein the moiety comprising an acetyl-lysine mimetic comprises12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein themoiety comprising an acetyl-lysine mimetic comprisesAttorney Docket No.: P60303-WO-113. The compound of any one of claims 8-12, or a pharmaceutically acceptable salt or solvate thereof, wherein:N,CP~CCPC Cp cPco*' 0 wwlww3 oco" oorAttorney Docket No.: P60303-WO-114. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein themoiety comprising an acetyl-lysine mimetic compriseswherein:each R28is independently hydrogen or substituted or unsubstituted Ci-Cealkyl;each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, - OH, -ORa, OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, - C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2.Attorney Docket No.: P60303-WO-115. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein themoiety comprising an acetyl-lysine mimetic compriseseach R34is independently selected from hydrogen, -CH3, -CD3, -CH₂F, -CHF₂, and -CFs;16. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein themoiety comprising an acetyl-lysine mimetic compriseswherein:each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl,Attorney Docket No.: P60303-WO-1-CN, -OH, -ORa, or -N(Rb)2;R33is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, or substituted or unsubstituted Ci-Ceheteroalkyl;R34is hydrogen or substituted or unsubstituted Ci-Cealkyl;each R37is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;each R38is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)N(Rb)2, -OC(=O)ORa, - S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, -NRbC(=O)N(Rb)2, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted -Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle;r is 0, 1, 2, 3, or 4.

17. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein the binder of CBP / p300 comprises an acetyl-lysine mimetic moiety that binds in the acetyl -lysine (KAc) binding site of the bromodomain of human CREB-binding protein (CBP) or human ElA-binding protein p300 (p300) (CBP / p300) and has the structure:R28-R28is -C(=O)CH3, -C(=O)CH2CH3, -C(=O)NH2, -C(=O)NH(CH3); or -C(=O)NH(CH2CH3); R32is a moiety that occupies the BC Loop region of the bromodomain of CBP / p300;Attorney Docket No.: P60303-WO-1R32ais a moiety that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300; each R35is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl;m is 0, 1, 2, 3, or 4;L is an optional linker;wherein L is covalently attached to the R32group; orL is covalently attached at the position occupied by R32; orL is covalently attached at the position occupied by the R32agroup.

18. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein:R32is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C12cycloalkyl, or substituted or unsubstituted 3- to 12-membered heterocycloalkyl;at least one X2is -CR30- and at most two X2are -N-;Z1is -NRC- or -O-;Rcis hydrogen or C1-C6alkyl;R26is hydrogen, substituted or unsubstituted C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;X3is -CR27- or -N-;R27is hydrogen, halogen, substituted or unsubstituted C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CN, - OH, -ORa, -N(Rb)2, -NRbC(=O)Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;Attorney Docket No.: P60303-WO-1p is 0, 1, 2, or 3;R29is hydrogen, substituted or unsubstituted Ci-C4alkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;Y is -C(R30)2- or -N(R28)-;each R30is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, -CN, -OH, or -ORa;q is 0, 1, 2, 3, or 4;each Rais independently Ci-C4alkyl, Ci-Cefluoroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; each Rbis independently hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

19. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein:R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic 5- or 6-membered heteroaryl, - CN, -OH, -ORa, -N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, - C(=O)ORb, or -C(=O)N(Rb)2;20. The compound of any one of claims 18-19, or a pharmaceutically acceptable salt or solvate thereof, wherein:unsubstituted or substituted with F, Cl, Br, -CH3, -CD3, -OCH3, -CH2F, -CHF2, -CF₃, - CH2CH2F, -CH2CHF2, -CH2CF3, -CN, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2F, -Attorney Docket No.: P60303-WO-1C(=O)CHF2, -C(=O)CF3, -C(=O)CH2CH2F, -C(=O)CH2CHF2, -C(=O)CH2CF3, -C(=O)CD3, or - SO2CH3, -SO2CH2CH3, -SO2CD3, or -SO2CH2CD3;at least one X2is -CR30- and at most two X2are -N-;each R27is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -OH, or -ORa; andeach Rais independently substituted or unsubstituted C1-C6alkyl.

21. The compound of any one of claims 18-19, or a pharmaceutically acceptable salt or solvate thereof, wherein:R27is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH3)2, -(CH3)3, -F, -CHF2, -CF3, -CN, -OH, -OCH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted pyrimidinyl; orR27issubstituted with F, Cl, Br, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, CN, -C(=O)CH3, - C(=O)CH2F, -C(=O)CHF2, -C(=O)CF3, -C(=O)CD3.

22. The compound of claim 17-20, or a pharmaceutically acceptable salt or solvate thereof, wherein:, wherein the optional linker is covalently attached to the nitrogen ofAttorney Docket No.: P60303-WO-1R32group;or R32is absent and L is covalently attached to the acetyl-lysine mimetic moiety at the position occupied by R32; andN, N NF-F N N N NR32a isJ / Attorney Docket No.: P60303-WO-123. The compound of any one of claims 17-20, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-124. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein:(R3\)m r\\ R32R28'\ AN' SB-CBP / p300 has the structure: R32aR28is -C(=O)CH3or -C(=O)NH(CH3); each R35is independently hydrogen, -CH3, -CH2F, -CHF2, -CF3; m is 0, 1, or 2;substituted with F, -CH3, -CH2F, -CHF2, or -CF3;at least one X2is -CR30- and at most two X2are -N-;R26is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3-Cecycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl;R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic 5- or 6-membered heteroaryl, - CN, -OH, -ORa, or -N(Rb)2;each R30is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -ORa; Rais Ci-C4alkyl;Attorney Docket No.: P60303-WO-1each Rbis independently hydrogen or C1-C6alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein:R32is, wherein the optional linker is covalently attached to the nitrogen of R32group;or R32is absent and the optional linker is covalently attached to the acetyl-lysine mimetic moiety at the position occupied by R32;at least one X2is -CR30- and at most two X2are -N-;X3is -CR27- or -N-;Z1is -NH- or -O-;R26is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted Cs-C. cycloalkyl. or substituted or unsubstituted 3- to 6-membered heterocycloalkyl;R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic 5- or 6-membered heteroaryl, - CN, -OH, -ORa, or -N(Rb)2;each R30is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -ORa.

26. The compound of any one of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1Z1is -NH- or -O-;is the point of attachment to the optional linker.

27. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein SB-Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1or a pharmaceutically acceptable salt or solvate thereof.

29. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein SB- CBP / p300 has one of the following structures:, or30. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein SB- CBP / p300 has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-131. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and a tail moiety that is covalently attached to the core, wherein the tail moiety comprises a ring D and the core and tail moiety have the structure:

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) andeach R2is independently hydrogen, -CH₃, -CH₂F, -CHF₂, or -CF3Attorney Docket No.: P60303-WO-133. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof,wherein B-AR comprises option 1) and34. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof,,2-35. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof,wherein B-AR comprises option 1) and36. The compound of any one of claims 31-35, or a pharmaceutically acceptable salt or solvate thereof, wherein B -AR comprises option 1) and Z is -O-, -NH-. or -N(CH3)-.

37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -O- or -N(CH3)-.

38. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -O-.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof,wherein B-AR comprises option 1) and A3is:

40. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof,wherein B-AR comprises option 1) and A3isAttorney Docket No.: P60303-WO-141. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof,wherein B-AR comprises option 1) and A3is:

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R1is independently hydrogen, F, Cl, Br, I, -CH₃, -CD3, -CH₂CH₃, -CH₂F, -CHF₂, -CFs, - CH2CH2F, -CH₂CHF₂, - CH2CF3, -OH, -OCF₃, -OCH₃, -OCD₃, -OCH₂CH₃, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CD3).

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and A3is:

44. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof,wherein B-AR comprises option 1) and A3is:Attorney Docket No.: P60303-WO-145. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein B- AR comprises option 1) and has the structure:R1' R1', R’R1R1'.R1, R1£, R’^0RK1' O. O \ R?1 orAttorney Docket No.: P60303-WO-146. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein B- AR comprises option 1) and has the structure:

47. The compound of claim 45 or 46, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R1is independently hydrogen, F, Cl, Br, I, -CH₃, -CD3, -CH₂CH₃, -CH₂F, -CHF₂, -CFs, -OH, -OCF₃, -OCH₃, -OCD₃, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CD3).Attorney Docket No.: P60303-WO-149. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:

50. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein B- AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-151. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-152. The compound of claim 51 or 52, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R1is independently hydrogen, F, Cl, Br, I, -CH₃, -CD3, -CH₂CH₃, -CH₂F, -CHF₂, -CFs, -OH, -OCF₃, -OCH₃, -OCD₃, -CN, -C(=O)NH2, -C(=O)NH(CH3)or -C(=O)NH(CD3).

53. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein B- AR comprises option 1) and has the structure:Attorney Docket No.: P60303-WO-154. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein B- AR comprises option 1) and has the structure:

55. The compound of any one of claims 31-54, or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl, wherein each ring D is optionally substituted with w R3.

56. The compound of any one of claims 31-54, or a pharmaceutically acceptable salt or solvate; and each X is independently -CR3- or -N-.Attorney Docket No.: P60303-WO-157. The compound of any one of claims 31-54, or a pharmaceutically acceptable salt or solvate R3thereof, wherein ring D is R-58. The compound of any one of claims 31-57, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently hydrogen, F, Cl, Br, I, -CH₃, -CH₂CH₃, -CH₂F, -CHF₂, - CF3, -CH₂CH₂F, -CH₂CHF₂, -CH₂CF₃, -OH, -OCF3, -OCH3, -OCH₂CH₃, -CN, -C(=O)NH2, or - C(=O)NH(CH3).

59. The compound of any one of claims 31-57, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently hydrogen, F, Cl, -CH3, -CH₂F, -CHF₂, -CF₃, -OH, - OCF3, -OCH3, or -CN.

60. The compound of any one of claims 31-54, or a pharmaceutically acceptable salt or solvate61. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1N NN NN NAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-162. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:

63. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core comprises:Attorney Docket No.: P60303-WO-164. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

065. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

66. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-167. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

68. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:NH69. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:

70. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-171. The compound of any one of claims 63-70, or a pharmaceutically acceptable salt or solvate thereof, wherein B -AR comprises option 2) and A3is selected from:each X1is independently -CR1- or -N-;Rlais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, or -CN;each R1is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, or -OR4; each R4is independently Ci-C4alkyl, or Ci-C4fluoroalkyl;each R5is independently hydrogen, Ci-C4alkyl, or Ci-C4fluoroalkyl.

72. The compound of claim 71, or a pharmaceutically acceptable salt or solvate thereof, wherein:Rlais -CN, -NO2, -C(=O)NH2, or -C(=O)NH(CH3);Rlbis hydrogen, F, Cl, Br, I, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or -CN;Attorney Docket No.: P60303-WO-1each Rlcis hydrogen, F, Cl, Br, -CH3, -CH₂F, -CHF₂, or -CF3;each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CH₂F, -CHF₂, -CF₃, -OH, -OCF3, or - OCH3.

73. The compound of any one of claims 63-72, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and A3is:R174. The compound of claim 73, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and A3is:

75. The compound of claim 74, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-176. The compound of claim 73, or a pharmaceutically acceptable salt or solvate thereof, wherein:

77. The compound of claim 73, or a pharmaceutically acceptable salt or solvate thereof, wherein B- AR comprises a head group and an optional core, wherein the head group is selected from:Attorney Docket No.: P60303-WO-178. The compound of any one of claims 63-73, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises a head group A3and an optional core, wherein A3is selected from:R1Attorney Docket No.: P60303-WO-179. The compound of claim 78, or a pharmaceutically acceptable salt or solvate thereof, wherein A380. The compound of claim 78, or a pharmaceutically acceptable salt or solvate thereof, wherein A3is:

81. The compound of any one of claims 26-37, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises a head group and an optional core, wherein A3is selected from:

82. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR comprises option 2) and the core and tail moiety comprises:Attorney Docket No.: P60303-WO-1CN83. The compound of any one of claims 63-82, or a pharmaceutically acceptable salt or solvate thereof, wherein ring D is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl, wherein each ring D is optionally substituted with w R3.

84. The compound of any one of claims 63-82, or a pharmaceutically acceptable salt or solvate85. The compound of any one of claims 63-82, or a pharmaceutically acceptable salt or solvatethereof, wherein ring D is86. The compound of any one of claims 83-85, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently hydrogen, F, Cl, Br, I, -CH₃, -CH₂CH₃, -CH₂F, -CHF₂, - CF3, -CH₂CH₂F, -CH₂CHF₂, -CH₂CF₃, -OH, -OCF3, -OCH3, -OCH₂CH₃, -CN, -C(=O)NH2, or - C(=O)NH(CH3).

87. The compound of any one of claims 83-85, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently hydrogen, F, Cl, -CH3, -CH₂F, -CHF₂, -CF₃, -OH, - OCF3, -OCH3, or -CN.Attorney Docket No.: P60303-WO-188. The compound of any one of claims 63-82, or a pharmaceutically acceptable salt or solvatethereof, wherein ring D is89. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:

90. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:Attorney Docket No.: P60303-WO-191. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:Attorney Docket No.: P60303-WO-192. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:

93. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-194. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof,wherein B-AR has one of the following structures:

95. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof,wherein B-AR has one of the following structures:

96. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1N-N97. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:Attorney Docket No.: P60303-WO-198. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:Attorney Docket No.: P60303-WO-199. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:

100. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:Attorney Docket No.: P60303-WO-1101. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein B-ARhas one of the following structures:Ato^eyDocketNop60303-WO-l102. The compound of any one of claims 1-30, or a pharmaceutical!thereof, wherein B-ARhas one of the following structures:ty acceptable salt or solvate rN< NCl N _: N / / ClN >_ N N~^\ rN< / / y-NH Cl N N N N NH Cl rN< N NCl N N N N NH ClAttorney Docket No.: P60303-WO-1103. The compound of any one of claims 1-102, or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent.

104. The compound of any one of claims 1-99, or a pharmaceutically acceptable salt or solvate thereof, wherein L comprises substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- Ciocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or combinations thereof.

105. The compound of any one of claims 1-102, or a pharmaceutically acceptable salt or solvatethereof, wherein L is absent or*, wherein:each A is independently absent, substituted or unsubstituted monocyclic Cs-Ciocycloalkyl, substituted or unsubstituted bridged bicyclic Cs-Ciocycloalkyl, substituted or unsubstituted fused bicyclic Cs-Ciocycloalkyl, substituted or unsubstituted spiro bicyclic Cs-Ciocycloalkyl, substituted or unsubstituted monocyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted bridged bicyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted fused bicyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted spiro bicyclic 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein each A is independently unsubstituted or substituted with x R2b;Attorney Docket No.: P60303-WO-1with x R2b; n is 1, 2, 3, 4, 5, or 6;each x is independently 1, 2, 3, 4, 5, 6, 7, or 8;each R2ais independently hydrogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci-C4fluoroalkyl, or substituted or unsubstituted Cs-Cecycloalkyl; andeach R2bis independently hydrogen, halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)N(Rb)2, - OC(=O)ORa, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2N(Rb)2, -N(Rb)2, - NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.Attorney Docket No.: P60303-WO-1106. The compound of claim 105, or a pharmaceutically acceptable salt or solvate thereof,wherein:Attorney Docket No.: P60303-WO-1107. The compound of any one of claims 1-102, or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent orwherein:Attorney Docket No.: P60303-WO-1o N-NM N~Ny 'K \ jxxn is 1, 2, or 3; each x is independently 1, 2, 3, 4, 5, or 6;each Rais independently hydrogen or substituted or unsubstituted C1-C6alkyl; andeach Rbis independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl.

108. The compound of any one of claims 103-107, or a pharmaceutically acceptable salt or solvate thereof, wherein:(L’)nis absent,Attorney Docket No.: P60303-WO-1109. The compound of any one of claims 1-102, or a pharmaceutically acceptable salt or solvate thereof, wherein L has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1NHAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1or a pharmaceutically acceptable salt or solvate thereof.

110. The compound of any one of claims 1-102, or a pharmaceutically acceptable salt or solvate thereof, wherein L has one of the following structures:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1111. A compound that is a heterobifunctional conditional inhibitor of CBP / p300 having the structure of Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), or Formula (X), or a pharmaceutically acceptable salt or solvate thereof:Formula (IV),Attorney Docket No.: P60303-WO-1Formula (VII),Formula (X), wherein,Attorney Docket No.: P60303-WO-1R1each s is independently 1, 2, or 3; m is 0, 1, 2, 3, or 4;Z is -O- or -NR5-;each X1is independently -CR1- or -N-;X4is -CRld- or -N-;each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4;Rlais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2;Rlbis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4;Rlcis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, or -CN;Rldis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4;Attorney Docket No.: P60303-WO-1or Rlband Rldare taken together with the intervening carbon atoms between Rlband Rldto form a phenyl, pyridinyl, pyridazinyl, or pyrimidinyl optionally substituted with 1 or 2 R1; each X is independently -CR3- or -N-;each R2is independently hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl; or two R2on the same carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;each R3is independently hydrogen, halogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci- C4fluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, -CN, -OH, -OR4, or -N(R5)2. each R4is independently Ci-C4alkyl, Ci-C4deuteroalkyl, or Ci-C4fluoroalkyl;each R5is independently hydrogen, Ci-C4alkyl, Ci-C4deuteroalkyl, or Ci-C4fluoroalkyl; R28is -C(=O)CH3, -C(=O)CD3, -C(=O)CF3, -C(=O)CH2F, -C(=O)CHF2, -C(=O)CH2CH3, - C(=O)CD2CH3, -C(=O)CH2CD3, -C(=O)CD2CD3, -C(=O)CH2CF3, -C(=O)CF2CF3, - C(=O)CH2CH2F, -C(=O)CH2CHF2, -C(=O)NH2, -C(=O)NH(CH3), -C(=O)NH(CD3), - C(=O)NH(CF3), -C(=O)NH(CH2F), -C(=O)NH(CHF2), -C(=O)NH(CH3), - C(=O)NH(CH2CH3), -C(=O)NH(CD2CD3), -C(=O)NH(CH2CF3), -C(=O)NH(CF2CF3), - C(=O)NH(CH2CH2F), or -C(=O)NH(CH2CHF2);each X2is independently -CR30- or -N- provided that at most two X2are -N-;Z1is -NRC- or -O-; Rcis hydrogen or C1-C6alkyl;R26is hydrogen, substituted or unsubstituted Ci-C4alkyl, Ci-C4deuteroalkyl, Ci- C4fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;X3is -CR27- or -N-;R27is hydrogen, halogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci-C4fluoroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -CN, -OH, -ORa, -N(Rb)2, -NRbC(=O)Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2;R26R26r R27isAttorney Docket No.: P60303-WO-1each R30is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, substituted or unsubstituted Ci-Ceheteroalkyl, -CN, -OH, or -ORa;each R35is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl;m is 0, 1, or 2; p is 0, 1, 2, or 3;each of A1and A2is independently absent, substituted or unsubstituted monocyclic Cs- Ciocycloalkyl, substituted or unsubstituted spiro bicyclic Cs-Cncycloalkyl, substituted or unsubstituted monocyclic 3- to 6-membered heterocycloalkyl, or substituted or unsubstituted spiro bicyclic 5- to 12-membered heterocycloalkyl, wherein each A is independently unsubstituted or substituted with x R2b;Attorney Docket No.: P60303-WO-1each R2ais independently hydrogen, Ci-C4alkyl, Ci-C4deuteroalkyl, Ci-C4fluoroalkyl, or substituted or unsubstituted C3-C6cycloalkyl:each R2bis independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, C1-C6heteroalkyl, -CN, -OH, -ORa, or -N(Rb)2;each Rais independently Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cefluoroalkyl, Ci-Ceheteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl;each Rbis independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted monocyclic heteroaryl;or two Rbon the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.

112. The compound of claim 111, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the following structure:R28 (R35)mFormula (IVa),Formula (Va),Formula (Vb),Attorney Docket No.: P60303-WO-1Formula (Vc), Formula (VIb),Attorney Docket No.: P60303-WO-1Formula (Xb).

113. The compound claim 111 or 112, or a pharmaceutically acceptable salt or solvate thereof, wherein:

114. The compound of claim 82 or 83, or a pharmaceutically acceptable salt or solvate thereof, wherein:each X1is -CR1- or -N-, provided that at most 2 X1are -N-;Rlais -CN;Rlbis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; each Rlcis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, or -CF3;Rldis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; or Rlband Rldare taken together with the intervening carbon atoms between Rlband Rldto form a phenyl or pyridinyl optionally substituted with 1 or 2 R1;each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, -CH2CF3, -OH, -OCF3, -OCH3, or -OCH2CH3.

115. The compound of any one of claims 82-84, or a pharmaceutically acceptable salt or solvateAttorney Docket No.: P60303-WO-1, N_, CN N^ / CN N.. CN. N^ ^CN XX xx / x xxxx xx xX xX x x:N^ / CN N^CN N^. CN N^CN X xx xx xx F, F Cl Cl ClCl, Cl, or Cl; or / CN / CNAttorney Docket No.: P60303-WO-1each R3is independently hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, - CH2CF3, -OH, -OCF₃, -OCH₃, -OCH2CH3, -OCD₃, -OCH2CD3, -CN, -NH2, -NH(CH3), -NH(CH3)2, -NH(CD3) or -N(CD3)2.

116. The compound claim 111 or 112, or a pharmaceutically acceptable salt or solvatethereof, wherein A4isAttorney Docket No.: P60303-WO-1117. The compound claim 111 or 112, or a pharmaceutically acceptable salt or solvate thereof,each R3is independently hydrogen, F, Cl, -CH3, -CD3, -CH₂F, -CHF₂, -CF3, -OH, -OCF3, - OCH3, -OCD₃, or -CN.

118. The compound claim 111 or 112, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:R28 (R35)mFormula (IVa),Attorney Docket No.: P60303-WO-1119. The compound claim 111 or 112, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:Formula (Va),Attorney Docket No.: P60303-WO-1120. The compound claim 111 or 112, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof:Formula (Vila),Attorney Docket No.: P60303-WO-1121. The compound claim 111 or 112, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.: P60303-WO-1122. The compound claim 111 or 112, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof:Formula (Via),Attorney Docket No.: P60303-WO-1123. The compound claim 111 or 112, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1124. The compound of any one of claims 111-123, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R30is independently hydrogen, F, Cl, Br, I, -CH3, -CD3, -CF3, -CH₂F, -CHF₂, -CH₂CH₃, - CD2CH3, -CH₂CD₃, -CD₂CD₃, -CH₂CF₃, --CF₂CF₃, -CH₂CH₂F, -CH₂CHF₂, -OCH₃, -OCD₃ OCFs, -OCH₂F, -OCHF₂, -OCH₂CH₃, -OCD₂CH₃, --OCH₂CD₃, -OCD₂CD₃, -OCH₂CF₃ O-CF₂CF₃, -OCH₂CH₂F, -OCH₂CHF₂, or -CN.

125. The compound of claim 124, or a pharmaceutically acceptable salt or solvate thereof,wherein:Attorney Docket No.: P60303-WO-1126. The compound of any one of claims 111-123, or a pharmaceutically acceptable salt or solvate thereof, wherein:R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, -ORa, -N(Rb)2, - NRbC(=O)Ra, -NRbC(=O)ORa, -NRbS(=O)2Ra, -C(=O)Rb, -C(=O)ORb, or -C(=O)N(Rb)2; orR27isAttorney Docket No.: P60303-WO-1127. The compound of any one of claims 111-125, or a pharmaceutically acceptable salt or solvate thereof, wherein:R27is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, -CN, -OH, -ORa, -N(Rb)2, -C(=O)Rb, or -C(=O)N(Rb)2;R26is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -(CH3)3, -CD3, -CD2CH3, - CH2CD3, -CD₂CD₃, -CF3, -CH2F, -CHF2, -CH2CF3, -CF2CF3, -CH2CH2F, -CH2CHF2;unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, unsubstituted or substituted cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

128. The compound of any one of claims 111-128, or a pharmaceutically acceptable salt or solvate thereof, wherein:R27is hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, - CH2CF3, -OH, -OCF3, -OCH3, -OCH2CH3, -OCD3, -OCH2CD3, -CN, -NH2, - NH(CH3), -NH(CH3)2, -NH(CD3) or -N(CD3)2, -C(=O)CH3, -C(=O)CD3, -C(=O)CF3, - C(=O)CH2F, -C(=O)CHF2, -C(=O)CH2CH3, -C(=O)CD2CD3, -C(=O)CH2CF3, - C(=O)CF2CF3, -C(=O)CH2CH2F, -C(=O)CH2CHF2, -C(=O)NH2, -C(=O)NH(CH3), - C(=O)NH(CD3), -C(=O)NH(CF3), -C(=O)NH(CH2F), -C(=O)NH(CHF2), -C(=O)NH(CH3), -Attorney Docket No.: P60303-WO-1C(=O)NH(CH2CH3), -C(=O)NH(CD2CD3), -C(=O)NH(CH2CF3), -C(=O)NH(CF2CF3), - C(=O)NH(CH2CH2F), or -C(=O)NH(CH2CHF2); orR26is hydrogen, -CH3, -CH2CH3, -CH2(CH3)2, -(CH3)3, -CD3, -CF3, -CH2F, -CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

129. The compound of any one of claims 111-128, or a pharmaceutically acceptable salt or solvate thereof, wherein:R30is hydrogen, -CH3, -CD3, -CF3, -CH2F, -CHF2, or -CN.

130. The compound of any one of claims 111-123, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1131. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvateAttorney Docket No.: P60303-WO-1CDs, -CH₂CH₃, -CH(CHS)2, or cyclopropyl;, each of which is optionally substituted with one or more D, F, Cl, -CH₃, -CD3, -CF3, -CH2F, -CHF2, -OH, -OCH3, -OCD3, -OCF3, -OCH₂F, or -OCHF2;L2is absent,Attorney Docket No.: P60303-WO-1R2ais hydrogen, -CH₃, -CD3, -CH₂CH₃, -CH(CHs)2, or cyclopropyl.

132. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1133. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1134. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:

135. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1136. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvateAttorney Docket No.: P60303-WO-1137. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1°> Hey & 'Xta N^ P60303-Wo-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1138. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1139. The compound of any one of claims 111-130, or a pharmacally acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1each Rdis independently hydrogen, or -CH₃;each R2ais independently hydrogen, -CH₃, -CH₂CH₃, -CH(CH3)2, -CF₃, -CH₂F, -CHF₂, or cyclopropyl;andeach R2bis independently hydrogen, F, Cl, -CH3, -CF₃, -CH₂F, -CHF₂, -OH, -OCH3, -OCD3, - OCF3, -OCH₂F, -OCHF₂, -CN or cyclopropyl.

140. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1each Rdis independently hydrogen, or -CH3;each R2ais independently hydrogen, -CH3, -CH₂CH₃, -CH(CH3)2, -CF₃, -CH₂F, -CHF₂, or cyclopropyl;andeach R2bis independently hydrogen, F, Cl, -CH3, -CF₃, -CH₂F, -CHF₂, -OH, -OCH3, -OCD3, - OCF3, -OCH₂F, -OCHF₂, -CN or cyclopropyl.

141. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1R2b R2bRdxVRdRR2bx / R2bR VRdF p2b R \j R v2b R XN-V \ j 2| ] / (Rr J""7R2b / X / 5 \ I p"7R^ / x. N^y \ _ ) R2bR2b R2bR2b ^Ny yOR2b^ 75 5 5Attorney Docket No.: P60303-WO-1142. The compound of any one of claims 111-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1NNNAttorney Docket No.: P60303-WO-1NNNNAttorney Docket No.: P60303-WO-1NNNAttorney Docket No.: P60303-WO-1NAttorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1or a pharmaceutically acceptable salt or solvate thereof.

144. A compound selected from:Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1Attorney Docket No.: P60303-WO-1or a pharmaceutically acceptable salt or solvate thereof.

145. A stable ternary complex comprising:a. CBP / p300;b. Androgen Receptor (AR); andc. heterobifunctional conditional inhibitor compound of any one of claims 1-144.

146. A stable ternary complex comprising:a. CBP / p300;b. Androgen receptor (AR); andc. heterobifunctional conditional inhibitor compound of any one of claims 1-144; wherein CBP / p300 and DP are present in a prostate cancer cell.

147. A method of selectively inhibiting the activity of CREB-binding protein (CBP) / p300 in a cell expressing the androgen receptor of a mammal comprising administering a heterobifunctional compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof.

148. The method of claim 147, wherein the heterobifunctional compound of any one of claims 1- 144, or a pharmaceutically acceptable salt or solvate thereof, inhibits the activity of CBP / p300 in the cell but does not inhibit the activity of the CBP / p300 in cells not expressing the AR.

149. The method of claim 148, wherein the AR is overexpressed, overactive or both overexpressed and overactive in the COI.

150. A method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof.Attorney Docket No.: P60303-WO-1151. The method of claim 150, wherein the cancer is an androgen dependent cancer.

152. The method of claim 150, wherein the cancer is prostate cancer.

153. A method of treating an androgen receptor dependent or androgen receptor mediated disease or condition in mammal comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof.

154. The method of claim 153, wherein androgen receptor dependent or androgen receptor mediated disease or condition is selected from benign prostate hyperplasia, hirsutism, adenomas and neoplasms of the prostate, benign or malignant tumor cells containing the androgen receptor, prostate cancer, breast cancer, endometrial cancer, and uterine cancer.

155. A pharmaceutical composition comprising a compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

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