CBP / p300 heterobifunctional conditional inhibitors

Abstract

Described herein are heterobifunctional small molecules that conditionally inhibit CBP / p300, methods of making, pharmaceutical compositions and medicaments comprising such heterobifunctional small molecules, and methods of using such conditional inhibitors are described herein, in the treatment of diseases and conditions, such as cancer. The inhibition of CBP / p300 is conditioned on the simultaneous binding of CBP / p300 and AR by the heterobifunctional small molecules.

Description

CBP / p300 HETEROBIFUNCTIONAL CONDITIONAL INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 636,293, filed April 19, 2024, and U.S. Provisional Patent Application No. 63 / 730,177, filed December 10, 2024, which are incorporated herein by reference in their entireties.FIELD OF THE INVENTION

[0002] Described herein are heterobifimctional small molecules, methods of making, pharmaceutical compositions and medicaments comprising such heterobifunctional small molecules, and methods of using such heterobifimctional 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 monofimctional 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 monofimctional molecules have provided a conceptual pathway toward many FDA -approved drugs as a means for treating the disease state.

[0004] However, many monofimctional molecules lack specificity for the disease proteins in question leading to undesired toxicities or lack of efficacy, or the disease proteins adapts to the monofimctional 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 heterobifimctional 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 heterobifimctional small molecules described herein comprise at least one silent binder to CBP / p300 and at least one binder to AR. Such heterobifimctional small molecules offer a new means for treatment of diseases or conditions, such as AR positive prostate cancers, with a wider therapeutic index.SUMMARY OF THE INVENTION

[0006] In one aspect, disclosed herein is a heterobifimctional conditional inhibitor compound ofCBP / p300 that has the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human ElA-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:1) a head group A3that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety; and2) an optional tail moiety covalently attached to the core moiety; wherein the core comprises an optionally substituted spiro bicyclic heterocycloalkyl having the structure of Formula (C):, Formula (C); wherein: the head group A3is covalently attached at position (A); the optional tail moiety comprises a ring D that is covalently attached to the nitrogen (*), 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 s R3; s is 1, 2, or 3; w is 2 or 3; k is 0 or 1; m is 0, 1, 2, or 3; each R2is independently hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -CN, OH, -OR4, or -N(R5)2; 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 C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Cs-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 Cs-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.

[0007] In some embodiments, SB-CBP / p300 binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300; 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 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; and w is 2; and s is 1; k is 0; and m is 1; andhydrogen, -CH3, or -CH2CH3; and the head group A3of B-AR forms hydrogen bonds with the side chains of Gin 711 and Arg752 of the LBD of AR.

[0008] In some embodiments, SB-CBP / p300 further comprises a moiety that interacts with Argl 173 in the bromodomain of CBP or Asnl 137 in the bromodomain of p300.

[0009] In some embodiments, 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-CBP / p300 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.

[0010] In some embodiments, SB-CBP / p300 further comprises: the acetyl-lysine mimetic moiety that binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300 comprises: 1 -(1,4, 6, 7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-l-one; or N-methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-5-carboxamide; wherein the acetyl-lysine mimetic moiety optionally further comprises:1) a moiety at the 1-position of the l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl group that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300; or2) a moiety that at the 3-position of the l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl group occupies the BC Loop region of the bromodomain of CBP / p300; or3) both 1) and 2).

[0011] In another aspect, disclosed herein is a heterobifunctional conditional inhibitor compound of CBP / p300 that has the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:SB-CBP / p300 has the structure:R28is -C(=O)CH3, -C(=O)CH2CH3, -C(=O)NH2, -C(=O)NH(CH3), or -C(=O)NH(CH2CH3); each R35is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl; m is 0, 1, 2, 3, or 4;R32is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C12cycloalkyl, or substituted or unsubstituted 3- to 12-membered heterocycloalkyl, wherein L is covalently attached to R32if R26or R27are not L; or R32is L if R26or R27are not L;p is 0, 1, 2, or 3;X2is -CR30- or N, wherein at most two X2are -N-; X3is -CR27- or -N-;Z1is -NRC- or -O-; Rcis hydrogen or C1-C6alkyl;R27is hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-Cscycloalkyl, 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;R26is hydrogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3- Cscycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; or R26is L if R32or R27are not L; or R27is L if R26or R32are not L; each R30is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, or -ORa; q is 0, 1, 2, 3, or 4; each Rais independently C1-C4alkyl, C1-C6fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl. 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- C6cycloalkyl, 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;at position (A), and L is attached at position * ; each X1is independently -CR1- or -N-; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, or -CN; each R1is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; each R2is hydrogen or C1-C4alkyl; each X is independently -CR3- or -N-; each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2; each R4is independently substituted or unsubstituted C1-C4alkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl; and each s is 1, 2, or 3.

[0012] In yet another aspect, disclosed herein is a heterobifunctional conditional inhibitor compound ofCBP / p300 that has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein,R28is -C(=O)CH3, -C(=O)CD3, -C(=O)CF3, -C(=O)CH2F, -C(=O)CHF2, -C(=O)CH2CH3, -C(=O)CD2CH3C(=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 C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3- C8cycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;X3is -CR27- or -N-;R27is hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, 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;each R30is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -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-C1ocycloalkyl, substituted or unsubstituted spiro bicyclic 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, C1-C4alkyl, C1-C4deuteroalkyl, C1-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-C8alkyl, 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.each X1is independently -CR1- or -N-;X4is -CR1d- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, or -CN; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl, pyridinyl, pyridazinyl, or pyrimidinyl optionally substituted with 1 or 2 R1; each X is independently -CR3- or -N-; 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 C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl.

[0013] In some embodiments, disclosed herein is a ternary complex comprising: a. CBP / p300; b. Androgen receptor (AR); andc. heterobifunctional conditional inhibitor compound as described herein; wherein CBP / p300 and AR are present in a cell of interest (COI) and the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI.

[0014] In another aspect, described herein is a method of selectively inhibiting the activity of CBP / p300 in a cell of interest (COI) of a mammal comprising administering a heterobifunctional compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the COI expresses the androgen receptor (AR). In some embodiments, the heterobifunctional compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, inhibits the activity of CBP / p300 in the COI but does not inhibit the activity of CBP / p300 in cells expressing CBP / p300 and not expressing the AR. In some embodiments, the AR is overexpressed, overactive or both overexpressed and overactive in the COI.

[0015] In another aspect, described herein is a method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is a hormone dependent cancer. In some embodiments, the cancer is prostate cancer.

[0016] In another aspect, 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 as 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.

[0017] 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.

[0018] 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.

[0019] In any of the embodiments disclosed herein, the mammal is a human. In some embodiments, compounds disclosed herein are orally administered to a human.

[0020] Other objects, features and advantages of the compounds, methods and compositions describedherein 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.BRIEF DESCRIPTION OF THE FIGURES

[0021] FIG. 1 shows the ternary complex formation assay for Compound 135

[0022] FIG. 2 shows the ternary complex formation for Compound 137

[0023] FIG. 3 shows the ternary complex formation for Compound 160.

[0001] FIG. 4 shows the normalized bioluminescence resonance energy transfer (BRET) response as a function of compound concentration for Compound A and control GNE-781.

[0002] FIG. 5 shows the normalized bioluminescence resonance energy transfer (BRET) response as a function of compound concentration for GNE-781.DETAILED DESCRIPTION OF THE INVENTION

[0003] 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.

[0004] 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.

[0005] 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.

[0006] 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.

[0007] 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 activitybased profding. Such applications have been proposed to replace combination therapies.

[0008] 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 partners into 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).

[0009] 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.

[0010] 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.

[0011] 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 monofiinctional 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., CCS 1477, 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.

[0012] In some embodiments disclosed herein is a heterobifimctional inhibitor. In some embodiments, the heterobifimctional inhibitor is a heterobifimctional conditional inhibitor. In some embodiments disclosed herein is a heterobifimctional inhibitor of CBP / p300. In some embodiments, the heterobifimctional inhibitoris a heterobifunctional conditional inhibitor of CBP / p300.

[0013] In some embodiments, 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.

[0014] In some embodiments, CBP / p300 and AR are both expressed in a cell of interest (COI).

[0015] 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.

[0016] 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 nondiseased 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 non -diseased 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.

[0017] 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 thecompound 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.

[0018] 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)

[0019] 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.

[0020] 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 bone cancer, 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, nonHodgkin lymphoma, Hodgkin-lymphoma, multiple myeloma, myelodysplastic syndromes, thymus cancer, or Waldenstrom macroglobulinemia.

[0021] 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

[0022] 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.

[0023] 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.

[0024] 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, CBP / p300 appears to be crucial for AR transcriptional activity in both the presence and absence of androgens.Compounds

[0025] A heterobifunctional conditional inhibitor compound of CBP / p300 that has the structure ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human ElA-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:1) a head group A3that occupies the ligand -binding domain (LBD) of AR and is covalently attached to a core moiety; and2) an optional tail moiety covalently attached to the core moiety; wherein the core comprises an optionally substituted spiro bicyclic heterocycloalkyl having the structure of Formula (C):wherein: the head group A3is covalently attached at position (A); the optional tail moiety comprises a ring D that is covalently attached to the nitrogen (*), 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 s R3; s is 1, 2, or 3; w is 2 or 3; k is 0 or 1; m is 0, 1, 2, or 3; each R2is independently hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -CN, OH, -OR4, or -N(R5)2; 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 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 asubstituted or unsubstituted N-containing heterocycle; and wherein 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.

[0026] In some embodiments, described herein is a conditional inhibitor compound of CBP / p300 that has the structure of Formula (I):Formula (I) wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human ElA-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:1) a head group that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety; and2) an optional tail moiety covalently attached to the core moiety; wherein the core comprises an optionally substituted spiro bicyclic heterocycloalkyl having the structure of Formula (C):, Formula (C); wherein: the head group is covalently attached at position (A); the optional tail moiety comprises a ring D that is covalently attached to the nitrogen (*), 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 s R3; s is 1, 2, or 3; w is 2 or 3; k is 0 or 1; m is 0, 1, 2, or 3; each R2is independently hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -CN, OH, -OR4, or -N(R5)2; 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 C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Cs-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; and wherein 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.

[0027] In some embodiments, the heterobifunctional conditional inhibitor compound is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:SB-CBP / p300 is a silent binder of the bromodomain of human CREB-binding protein (CBP) or human E1A- binding protein p300 (p300) (CBP / p300), 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, 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, or at the position occupied by R32, or the R32agroup;B-AR is a binder of the androgen receptor (AR), wherein the B-AR comprises: a head group that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core with a tail moiety covalently attached to the core moiety; wherein B-AR has the structure of Formula (D):wherein head groupthe head group is covalently attached at position (A), and L is attached at position * ; each X1is independently -CR1- or -N-; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, or -CN; each R1is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; each R2is hydrogen or C1-C4alkyl; each X is independently -CR3- or -N-; each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2; each R4is independently substituted or unsubstituted C1-C4alkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl; and each s is 1, 2, or 3.

[0028] In some embodiments, A3is 4-cyanophenyl; 3-fluoro-4-cyanophenyl; 3-chloro-4-cyanophenyl; 3- methoxy-4-cyanophenyl; 3 -methyl -4-cyanophenyl; 3-trifluroromethyl-4-cyanophenyl; 3-trifluroromethoxy- 4-cyanophenyl; 5 -fluoro-6-cyanopyridin-3 -yl; 5 -chloro-6-cyanopyridin-3 -yl; 5 -methoxy-6-cyanopyridin-3 - yl; 5-methyl-6-cyanopyridin-3-yl; 5-trifluroromethyl-6-cyanopyridin-3-yl; 5-trifluroromethoxy-6- cyanopyridin-3-yl; [l,2,4]triazolo[4,3-b]pyridazin-6-yl; or 3-(trifluoromethyl)-[l,2,4]triazolo[4,3- b]pyridazin-6-yl.

[0029] In some embodiments,each X1is independently -CR1- or -N-; X4is -CR1d- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1- C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4; R1cis hydrogen, halogen, C1-C4alkyl, C1- C4deuteroalkyl, C1-C4fluoroalkyl, or -CN; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1- C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl, pyridinyl, pyridazinyl, or pyrimidinyl, each of which is optionally substituted with 1 or 2 R1.

[0030] In some embodiments, one X1is -CR1- and the other X1is -CR1- or -N-; R1ais -CN; R1bis hydrogen, F, Cl, Br, I, -CH2, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; each R1cis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, or -CF3; R1dis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, - OH, -OCF3, or -OCH3; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto 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 -OCH2CH3each X1is independently -CR1- or -N-;X4is -CRd- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, or -CN; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl or pyridinyl optionally substituted with 1 or 2 R1; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; and each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl.

[0033] In some embodiments, A3is selected from:each X1is independently -CR1- or -N-;X4is -CRd- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl or pyridinyl optionally substituted with 1 or 2 R1; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; and each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl.

[0034] In some embodiments, A3is selected from:one X1is -CR1- and the other X1is -CR1- or -N-; R1ais -CN, -NO2, -C(=O)NH2or -C(=O)NH(CH3); R1bis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, -OCH2CH3, or -CN; each R1cis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, or -CF3; each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CHs, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OH, -OCFs, -OCHs, or -OCH2CH3embodiments, A3is:In some embodiments,

[0036] In some embodiments, SB- CBP / p300 binds in the acetyl -lysine (Kac) binding site of the bromodomain CBP / p300. In some embodiments, the SB CBP / p300 comprises an acetyl-lysine mimetic moiety that binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300.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.

[0037] In some embodiments, wherein SB-CBP / p300 binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300; wherein SB-CBP / p300 comprises an acetyl-lysine mimetic moiety that binds inthe acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300; wherein 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; and w is 2; and s is 1; k is 0; and m is 1; andhydrogen, -CH,. or -CH2CH3; and the head group A3of B-AR forms hydrogen bonds with the side chains of Gin 711 and Arg752 of the LBD of AR.

[0038] 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. In some embodiments, the head group of B-AR forms hydrogen bonds with the side chains of Gin 711 and Arg752 of the LBD of AR 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; and the head group of B-AR forms hydrogen bonds with the side chains of Gin 711 and Arg752 of the LBD of AR.

[0039] In some embodiments, SB- CBP / p300 further comprises a moiety that interacts with Argl 173 in the bromodomain of CBP or Asnl 137 in the bromodomain of p300.

[0040] In some embodiments, 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).

[0041] 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.

[0042] In some embodiments, 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- CBP / p300 at a position that does not interfere with the binding ofthe acetyl-lysine mimetic moiety in the acetylated lysine (KAc) binding site of CBP / p300.

[0043] In some embodiments, the acetyl-lysine mimetic moiety that binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300 comprises:1 -( 1 ,4,6,7-tetrahydro-5H-pyrazolo [4,3 -c]pyridin-5 -yl)ethan- 1 -one; orN-methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide; wherein the acetyl-lysine mimetic moiety optionally further comprises:1) a moiety at the 1-position of the l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl group that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300; or2) a moiety that at the 3-position of the l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl group occupies the BC Loop region of the bromodomain of CBP / p300; or3) both 1) and 2).

[0044] In some embodiments, w is 2; and s is 1.

[0045] In some embodiments, k is 0. In some embodiments, k is 1.

[0046] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0047] In some embodiments,hydrogen or -CH;.,

[0051] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:each X1is independently -CR1- or -N-; and 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

[0052] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:;each X1is independently -CR1- 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.

[0053] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:each X1is independently -CR1- or -N-;X4is -CRd- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, or -CN; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl or pyridinyl optionally substituted with 1 or 2 R1; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; and each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl.

[0055] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:each X1is independently -CR1- or -N-; X4is -CRd- or -N-; each R1isindependently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, - C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, or -CN; R1dis hydrogen, halogen, C1- C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl or pyridinyl optionally substituted with 1 or 2 R1; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; and each R5is independently hydrogen, C1-C4alkyl, or C1- C4fluoroalkyl.

[0056] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:; each X1is independently -CR1- or -N-; X4is -CRd- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, - C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl or pyridinyl optionally substituted with 1 or 2 R1; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; and each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl.

[0057] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:R1ais -CN, -NO2, -C(=O)NH2or -C(=O)NH(CH3); R1bis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, - CHF2, -CF3, -OH, -OCF3, -OCH3, -OCH2CH3, or -CN; each R1cis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2. or -CF3; and each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, -CH2CF3, -OH, -OCF3, -OCH3, or -OCH2CH3

[0058] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:X1is -CR1- or -N-; R1ais -CN, -NO2, -C(=O)NH2or -C(=O)NH(CH3); R1bis hydrogen, F, Cl, Br, I, -CH3, - CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, -OCH2CH3, or -CN; each R1cis hydrogen, F, Cl, Br, - CH3, -CH2F, -CHF2, or -CF3; and each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OH, -OCFs, -OCHs, or -OCH2CH3

[0059] In some embodiments, B-AR comprises a head group and an optional core, wherein the head

[0060] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:

[0061] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:

[0062] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is:

[0063] In some embodiments, B-Ar comprises a head group and an optional core, wherein the headgroup is:

[0064] In some embodiments, B-AR has the structure of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof:wherein:X1is -CR1- or -N-; m is 0, 1, or 2; each R1is independently hydrogen, F, Cl, Br, I, -CH,. -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, - CH2CF3, -OH, -OCF3, -OCH3, -OCH2CH3, -CN, -C(=O)NH2, or -C(=O)NH(CH3); each R2is C1-C6alkyl; 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 s R3; 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.

[0065] In some embodiments, X1is -CH- or -N-.

[0066] In some embodiments, wherein B-AR has the structure of Formula (Illa), or a pharmaceutically acceptable salt or solvate thereof:Formula (Illa) wherein:X1is -CR1- or -N-;X4is -CRd- or -N-; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl orpyridinyl 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, -OCH2CH3, -CN, -C(=O)NH2, or -C(=O)NH(CH3); each R2is hydrogen or C1-C4alkyl; 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 s R3; each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl; and m is 0, 1, or 2.

[0067] In some embodiments, B-AR has the structure of Formula (Illa), or a pharmaceutically acceptable salt or solvate thereof:Formula (Illa) wherein:X1is -CR1- or -N-; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto 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, -OCH2CH3, -CN, -C(=O)NH2, or -C(=O)NH(CH3); each R2is hydrogen or C1-C4alkyl; 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 s R3; each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl; and m is 0, 1, or 2.

[0068] In some embodiments, R1band R1dare taken together with the intervening carbon atoms betweenR1band R1dto form a phenyl or pyridinyl optionally substituted

[0069] In some embodiments, B-AR has the structure of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof:Formula (lib), wherein:X1is -CR1- or -N-; m is 0, 1, or 2; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; each R1is independently hydrogen, F, Cl, Br, I, -CHs, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, - CH2CF3, -OH, -OCF3, -OCH3, -OCH2CH3, -CN, -C(=O)NH2, or -C(=O)NH(CH3); each R2is C1-C6alkyl; 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 s R3; 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.

[0070] 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 s R3.

[0071] In some embodiments, ringeach X is independently -CR3- or -N-.

[0077] In some embodiments, ring D is

[0078] In some embodiments, B-AR has the structure of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:Formula (Va) wherein:each X is independently -CR3- or -N-; R1ais -CN; R1bis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or -CN; R1dis hydrogen, F, Cl, Br, I, -CH3, -CH2F, -CHF2, or -CF3; each R2is -CH3; 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 C1-C6alkyl, or C1-C6fluoroalkyl; each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, C1-C6fluoroalkyl.

[0079] In some embodiments, B-AR has the structure of Formula (Va-1), or a pharmaceutically acceptable salt or solvate thereof:Formula (Va) wherein: each X is independently -CR3- or -N-; R1ais -CN; R1bis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or -CN; R1dis hydrogen, F, Cl, Br, I, -CH3, -CH2F, -CHF2, or -CF3; each R2is -CH3; 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 C1-C6alkyl, or C1-C6fluoroalkyl; each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, C1-C6fluoroalkyl.

[0080] In some embodiments, R1bis hydrogen, F, Cl, -CH3, -CF3, -OCF3, or -OCH3; R1dis hydrogen, F, Cl, -CH3, or -CF3.

[0081] In some embodiments, B-AR has the structure of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof:Formula (IVa) wherein: each X is independently -CR3- or -N-;n is 2 and one R1is halogen, -CH3, -OCH3, or -CF3, and the other R1is -CN; each R2is hydrogen or C1-C4alkyl; each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl; and m is 0, 1, or 2.

[0082] In some embodiments, one R1is -Cl, -CH3, -OCH3, or -CF3, and the other R1is -CN.

[0083] In some embodiments, one R1is -Cl or -CH3, and the other R1is -CN.

[0084] In some embodiments, B-AR has the structure of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof:wherein: each X is independently -CR3- or -N-; each R1is 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); each R2is hydrogen or C1-C4alkyl; each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl; and m is 0, 1, or 2.

[0085] In some embodiments, each R1is independently hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3.

[0086] In some embodiments, each R1is hydrogen.each R3is independently hydrogen, F, Cl, Br, I, -CH3, -CDs, - CH2CH3, -CH2F, -CHF2, -CFS, -CH2CH2F, -CH2CHF2, - CH2CF3, -OH, -OCFs, -OCHs, -OCH2CH3, -OCDsOCH2CD3, -CN, -NH2, -NH(CHS), -NH(CHS)2, -NH(CDS) or -N(CD3)2

[0088] In some embodiments,

[0090] In some embodiments, each R3is independently hydrogen, F, Cl, Br, I, -CHs, -CH2CH3, -CH2F, - CHF2, -CFS, -CH2CH2F, -CH2CHF2, - CH2CF3, -OH, -OCFs, -OCH3, -OCH2CH3, -CN, -C(=O)NH2, or - C(=O)NH(CHs).

[0093] In some embodiments, ring D is

[0095] In some embodiments, the head group and core

[0096] In some embodiments, B-AR further comprises a tail moiety that is covalently attached to position (*), wherein the tail moiety is a 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 s R3; s is 1, 2, or 3; each R3is independently hydrogen, F, Cl, Br, I, -CHs, -CDs, -CH2CH3, - CH2F, -CHF2, -CFS, -CH2CH2F, -CH2CHF2, - CH2CFS, -OH, -OCFS, -OCHS, -OCH2CHS, -OCDS, - OCH2CDS, -CN, -C(=O)NH2, -C(=O)NH(CHS), or -C(=O)NH(CD3).

[0097] In some embodiments, ring D is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; wherein ring D is optionally substituted with s R3; s is 1, 2, or 3; each R3is independently hydrogen, F, Cl, Br, I, -CHs, -CDs, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, - CH2CF3, -OH, -OCF3, -OCH3, -OCH2CHS, -OCDS, -OCH2CDS, or -CN.

[0098] In some embodiments, B-AR further comprises a tail moiety that is covalently attached to position (*), wherein the tail moiety is a ring D thateach X is independently -CR3- or -N-. In some embodiments, B-AR further comprises a tail moiety that is covalently attached to position (*), wherein the tail moiety is a ring D thateach R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2

[0099] In some embodiments, B-AR has one of the following structures

[0103] In some embodiments, SB-CBP / p300 binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300.

[0104] In some embodiments, SB-CBP / p300 comprises an acetyl-lysine mimetic moiety that binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300.

[0105] In some embodiments, 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.

[0106] 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; and the head group of B-AR forms hydrogen bonds with the side chains of Gin 711 and Arg 752 of the LBD of AR.

[0107] In some embodiments, SB-CBP / p300 further comprises a moiety that interacts with Argl 173 in the bromodomain of CBP or Asnl 137 in the bromodomain of p300.

[0108] In some embodiments, 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).

[0109] In some embodiments, 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-CBP / p300 at a position that does not interfere with the binding of theacetyl -lysine mimetic moiety in the acetylated lysine (KAc) binding site of CBP / p300.

[0110] In some embodiments, 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.

[0111] In some embodiments, 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.

[0112] In some embodiments, 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;is the point of attachment to the optional linker that covalently connects a) to b); or R32comprises and the optional linker that covalently connects a) to b) is attached to R32; each R28is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2; each R34is independently hydrogen or substituted or unsubstituted C1-C6alkyl; each R35is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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 G-Gcycloalkyl. 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 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 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- Cscycloalkyl, 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- Cscycloalkyl, 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.

[0113] 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 C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, 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;Z is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted C1-C6alkyl;R26is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Cs-Cscycloalkyl. 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 G-Gcycloalkyl. 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 C1-C6alkyl;R29is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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 G-Galkyl, substituted or unsubstituted G-Gfhioroalkyl, substituted or unsubstituted G-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 G-Galkyl or substituted or unsubstituted G-C6heteroalkyl;C is substituted or unsubstituted G-Gcycloalkyl. 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 G-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- Cscycloalkyl, 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.

[0114] In some embodiments, the moiety that occupies the BC Loop region of the bromodomain of CBP / p300 is R32, wherein:

[0115] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprisesmoiety comprising an acetyl-lysine mimetic comprisesembodiments, the moiety comprising an acetyl-lysine mimetic comprisesembodiments, the moiety comprising an acetyl-lysine mimetic comprises

[0116] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprisessome embodiments, the moiety comprising an

[0117] In some embodiments, the moiety comprising an acetyl-lysine mimetic compriseshalogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -0C(=0)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.

[0118] In some embodiments, the moiety comprising an acetyl-lysine mimetic compriseswherein: each R28is independently hydrogen or substituted or unsubstituted C1-C6alkyl;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.

[0119] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprises

[0120] In some embodiments, the moiety comprising an acetyl-lysine mimetic comprises:embodiments, the moiety comprising an acetyl-lysine mimetic comprises the moiety comprising an acetyl- lysine mimetic comprises

[0122] 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 C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl;R34is hydrogen or substituted or unsubstituted C1-C6alkyl;each R38is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3Gcycloalkyl. 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; r is 0, 1, 2, 3, or 4;

[0123] In some embodiments,; 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; and each Rais independently substituted or unsubstituted C1-C6alkyl.

[0125] 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.

[0132] In some embodiments, B-AR is a non-steroidal AR ligand or a steroidal AR ligand.

[0133] In some embodiments, 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; orH, each of which is 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, wherein L is covalently attached to R32if R26or R27are not L; or R32is L if R26or R27are not L; R27is 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; each Raishydrogen, 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; and each Rais independently substituted or unsubstituted C1-C6alkyl.

[0135] In some embodiments, R27is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH3)2, -(013)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 pyrimidinyeach of which is unsubstituted or substituted 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

[0137] In some embodiments,, wherein the optional linker is covalently attached to the nitrogen of R32group; or R32is absent and L is covalently attached to the acetyl -lysine mimetic moiety at the position occupiedattachment to the optional linker.CH3, -CH2F, -CHF2, or -CF3, wherein L is covalently attached to the nitrogen of the R32group if R26or R27are not L; or R32is L if R26or R27are not L;at least one X2is -CR30- and at most two X2are -N-;X3is -CR27- or -N-;R27is hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl. 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;or R27is L if R26or R32are not L;R26is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl. or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R26is L if R32or R27are not L; each R30is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -ORa; Rais C1- C4alkyl;wherein L is attached to B-AR at position *;X1is -CR1- or -N-; R1bis hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, or -OCF3;R1is hydrogen, F, Cl, -CH3, -CH2F, -CHF2, or -CF3;each R2is hydrogen or -CH3; each R3is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or -CN.

[0142] In some embodiments,at least one X2is -CR30- and at most two X2are -N-;R26is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-C„cycloalkyl. or substituted or unsubstituted 3- to 6-membered heterocycloalkyl;R27is hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl, 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 C1-C4alkyl; each Rbis independently hydrogen or C1-C6alkyl; wherein L is covalently attached to the R32group, or at the position occupied by R26, or at the position occupied by R27;B-AR has the structure:each X is independently -CR3- or -N-;X1is -CR1- or -N-; R1bis hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, or -OCF3;R1is hydrogen, F, Cl, -CH3, -CH2F, -CHF2, or -CF3;each R2is hydrogen or -CH3; each R3is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or -CN.

[0144] In some embodiments,, wherein L is covalently attached to the nitrogen of the R32group if R26or R27are not L; or R32is L if R26or R27are not L; 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-;R27is hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl, 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;or R27is L if R26or R32are not L;R26is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl. or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R26is L if R32or R27are not L; and each R30is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -ORa.

[0145] In some embodiments,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 C3-C6cycloalkyl. or substituted or unsubstituted 3- to 6-membered heterocycloalkyl;R27is hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl. 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.

[0146] In some embodiments,to the optional linker.

[0147] In some embodiments, B-AR comprises a head group and an optional core, wherein the head group is selected from:each X1is independently -CR1- 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. 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.

[0148] In some embodiments, the head group is selected from:

[0149] In some embodiments, the head group is selected from:

[0150] In some embodiments, the head group of B-AR comprises 4-cyanophenyl; 3-fluoro-4- cyanophenyl; 3-chloro-4-cyanophenyl; 3-methoxy-4-cyanophenyl; 3-methyl-4-cyanophenyl; 3- trifluroromethyl-4-cyanophenyl; 3-trifluroromethoxy-4-cyanophenyl; 5-fluoro-6-cyanopyridin-3-yl; 5- chloro-6-cyanopyridin-3-yl; 5-methoxy-6-cyanopyridin-3-yl; 5-methyl-6-cyanopyridin-3-yl; 5- trifluroromethyl-6-cyanopyridin-3-yl; 5-trifluroromethoxy-6-cyanopyridin-3-yl; [l,2,4]triazolo[4,3- b]pyridazin-6-yl; or 3-(trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazin-6-yl.

[0151] In some embodiments, the optional core comprises a group selected from:each R2is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted orunsubstituted 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; 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 G-Gcycloalkyl or a substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl; m is 0, 1, 2, 3, or 4; 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.

[0152] In some embodiments, the optional core further comprises a ring D that 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 s R3; 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.

[0153] In some embodiments, the optional core comprises a group selected from:each X is independently -CR3- or -N-.

[0156] In some embodiments, B-AR has one of the following structures:

[0157] In some embodiments, B-AR has one of the following structures:pharmaceutically acceptable salt or solvate thereof.

[0158] In some embodiments, B-AR has one of the following structures:pharmaceutically acceptable salt or solvate thereof.

[0159] In some embodiments, B-AR has one of the following structures:

[0160] In some embodiments, the linker is absent.

[0161] In some embodiments, the linker has a prescribed length thereby linking the SB- CBP / p300 and the B-AR while allowing an appropriate distance therebetween.

[0162] In some embodiments, the linker is flexible. In some embodiments, the linker is rigid.

[0163] 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.

[0164] In some embodiments, the use of trivalent linkers allow for the preparation of heterotrifunctional compounds comprising one silent binder to CBP / p300 and two binders to AR, or two silent binders to CBP / p300 and one binder to AR, thereby simultaneously binding AR and CBP / p300 and forming a productive ternary complex. In some embodiments, such heterotrifunctional compounds would result in more sustained and more potent anticancer activity.

[0165] In some embodiments, the linker comprises one or more linear structures, one or more non-linear structures, one or more branched structures, one or more cyclic structures, one or more flexible moieties, one or more rigid moieties, or combinations thereof.

[0166] 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.

[0167] 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.

[0168] In some embodiments, the linker comprises flexible and / or rigid regions.I ( A ) - (L1) — < A J - 1

[0169] In some embodiments, the linker is L, wherein L is absent or ' 'n• . In some embodiments, L is absent. In some embodiments, L is

[0170] In some embodiments, L comprises substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C1ocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or combinations thereof.

[0171] In some embodiments, L is absent orwherein: each A is independently absent, substituted or unsubstituted monocyclic C3-C1ocycloalkyl, substituted or unsubstituted bridged bicyclic C3-C1ocycloalkyl, substituted or unsubstituted fused bicyclic C3- C1ocycloalkyl, substituted or unsubstituted spiro bicyclic C3-C1ocycloalkyl, 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;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, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, or substituted or unsubstituted C3-C6cycloalkyl; and each R2bis independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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);each 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- 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.n 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; and each Rbis independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl.

[0174] In some embodiments, each A is independently absent,n 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; and each Rbis independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl.

[0176] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0177] 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.

[0178] 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.

[0179] In some embodiments, Rbis hydrogen. In some embodiments, each Rbis independently substituted or unsubstituted C1-C6alkyl. 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.

[0184] In some embodiments, L has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

[0185] In some embodiments, L has one of the following structures:pharmaceutically acceptable salt or solvate thereof.

[0186] In some embodiments, L has one of the following structures:

[0187] In some embodiments, L has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

[0188] In some embodiments, L has one of the following structures:pharmaceutically acceptable salt or solvate thereof.

[0191] In some embodiments, L has one of the following structures:pharmaceutically acceptable salt or solvate thereof.

[0192] In some embodiments, L has one of the following structures:acceptable salt or solvate thereof.

[0193] In some embodiments, L has one of the following structures:

[0194] In some embodiments, SB-CBP / p300 has the structure of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof:Formula (Illb) 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 C1-C6fluoroalkyl, substituted or unsubstituted C1-C6cycloalkyl, 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 C1-C6alkyl, substituted or unsubstituted C1-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.

[0195] In some embodiments, SB-CBP / p300 has the structure of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, 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 G-Gcycloalkyl. 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 C1-C6alkyl, substituted or unsubstituted C1-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.

[0196] 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 G-Gcycloalkyl. 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 C1-C6fluoroalkyl, -CN, -NO2, -OH, -ORa, OC(=O)Ra, -0C(=0)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 C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, - C(=O)Rb, or -C(=O)N(Rb)2;Z is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted C1-C6alkyl; 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.

[0197] 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 C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; each R27is independently hydrogen, halogen, substituted or unsubstituted G-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted G-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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 C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, - C(=O)Ra, or -C(=O)N(Rb)2;Z is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted C1-C6alkyl; 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.

[0198] 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 C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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;R29is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted Cs-Cscycloalkyl. 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)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 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)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(R30)2- or C(=O); 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.

[0199] 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 C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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 G-Gcycloalkyl. 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 C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C-Gcycloalkyl. 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 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;Y is -C(R30)2- or C(=O); each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G- 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.

[0200] In some embodiments, SB-CBP / p300 has the structure of Formula (Hie), or a pharmaceutically acceptable salt or solvate thereof:Formula (Iie) 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 C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, - C(=O)Rb, or -C(=O)N(Rb)2;R12is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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 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.

[0201] In some embodiments, SB-CBP / p300 has the structure of Formula (Hie), or a pharmaceutically acceptable salt or solvate thereof, wherein:Formula (Hie)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, substituted or unsubstituted G-Gcycloalkyl. 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 C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, - C(=O)Rb, or -C(=O)N(Rb)2;R32is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;Ring A is absent or substituted or unsubstitutedsubstituted 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 substituted or unsubstituted G-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 unsubstitutedsubstituted or unsubstituted C1- substituted or unsubstitutedsubstituted or unsubstituted G- substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted orunsubstituted 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.

[0202] In some embodiments, SB-CBP / p300 has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

[0203] In some embodiments, SB-CBP / p300 has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

[0204] In some embodiments, SB-CBP / p300 has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

[0205] In some embodiments, SB-CBP / p300 has one of the following structures:pharmaceutically acceptable salt or solvate thereof.

[0206] In some embodiments, SB-CBP / p300 has one of the following structures:pharmaceutically acceptable salt or solvate thereof.

[0207] In some embodiments, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:SB-CBP / p300 has the structure:R28is -C(=O)CH3, -C(=O)CH2CH3, -C(=O)NH2, -C(=O)NH(CH3), or -C(=O)NH(CH2CH3); each R35is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl; m is 0, 1, 2, 3, or 4;R32is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C12cycloalkyl, or substituted or unsubstituted 3- to 12-membered heterocycloalkyl, wherein L is covalently attached to R32if R26or R27are not L; or R32is L if R26or R27are not L;p is 0, 1, 2, or 3;X2is -CR30- or N, wherein at most two X2are -N-; X3is -CR27- or -N-;Z1is -NRC- or -O-; Rcis hydrogen or C1-C6alkyl;R27is hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-Cscycloalkyl, 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;R26is hydrogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3- Cscycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; or R26is L if R32or R27are not L; or R27is L if R26or R32are not L; each R30is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C1- C6heteroalkyl, -CN, -OH, or -ORa; q is 0, 1, 2, 3, or 4; each Rais independently C1-C4alkyl, C1-C6fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl. 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- C6cycloalkyl, 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;at position (A), and L is attached at position * ; each X1is independently -CR1- or -N-; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, or -CN; each R1is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4;each R2is hydrogen or C1-C4alkyl; each X is independently -CR3- or -N-; each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2; each R4is independently substituted or unsubstituted C1-C4alkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl; and each s is 1, 2, or 3.

[0208] In some embodiments, described herein is a compound that is a heterobifunctional conditional inhibitor of CBP / p300 that has the structure of Formula (VI):pharmaceutically acceptable salt or solvate thereof, wherein,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 C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl,substituted or unsubstituted C3-Cscycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;X3is -CR27- or -N-;R27is hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, 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;each R30is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -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- C1ocycloalkyl, 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, C1-C4alkyl, C1-C4deuteroalkyl, C1-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-Cedeuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. or substituted or unsubstituted monocyclic 3- to 8- membered heterocycloalkyl; each Rbis independently hydrogen, C1-C6alkyl, G-Cedeuteroalkyl, G-C6fluoroalkyl, 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.each X1is independently -CR1- or -N-;X4is -CR1d- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or - SR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, or -CN;R1dis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl, pyridinyl, pyridazinyl, or pyrimidinyl optionally substituted with 1 or 2 R1; each X is independently -CR3- or -N-; 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 C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl.

[0209] As described herein, substructures of, including, and L2align with the orientation of the formulas from which they depend(left-to-right orientation).

[0211] In some embodiments, one X1is -CR1- and the other X1is -CR1- or -N-; R1ais -CN; R1bis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; each R1cis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, or -CF3; R1dis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto 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.

[0212] In some embodiments,and each R3is independently hydrogen, F, Cl, -CHs, -CDs, -CH2F, -CHF2, -CFs, -OH, -OCFs, -OCHs, - OCDs, or -CN.

[0217] In some embodiments, R27is hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -ORa, -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.

[0218] 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), -, -CH2(CH3)2, -(CH3)3, -CD3, -CF3, -CH2F, -CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0219] In some embodiments, R30is hydrogen, -CH3, -CD3, -CF3, -CH2F, -CHF2, or -CN.

[0232] 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( 013)2, or cyclopropyl; and each R2bis independently hydrogen, F, -CH3, -OH, or -OCH3.

[0250] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof:Table 1

[0251] In some embodiments, described herein is a compound having the structure:or a pharmaceutically acceptable salt or solvate thereof.

[0252] In some embodiments, described herein is a compound having the structure:wherein Xais Br, I, -OH, or -OTf; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, Xais Br or I. In some embodiments, Xais -OH or -OTf.

[0253] In some embodiments, described herein is a compound having the structure:or a pharmaceutically acceptable salt or solvate thereof.

[0254] In some embodiments, described herein is a compound having the structure:

[0255] In some embodiments, described herein is a compound having the structure:Further Forms of Compounds

[0256] 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.

[0257] “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.

[0258] 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, Wcinhcim / Ziirich:Wilcy-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 neutralform, passage through biological membranes can be adjusted.

[0259] 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 -hydroxy-2 -naphthoic acid; 2,2-dichloroacetic acid; 2- hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzene sulfonic 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 (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); 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 (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0260] 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.

[0261] 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.

[0262] The methods and formulations described herein include the use of A'-oxidcs (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.

[0263] 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.

[0264] 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.

[0265] 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 the present 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,36C1,1231,1241,1251,1311,32P 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.

[0266] 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.

[0267] 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.

[0268] 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 is metabolically 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.

[0269] 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

[0270] 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.

[0271] As used herein, C1-Cxincludes C1-C2, C1-C3 . . . C1-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-C4alkyl” 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, scc-butyl. and / -butyl.

[0272] 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)CH3group.

[0273] 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 (i.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.

[0274] The term “alkoxy” refers to a (alkyl)-O- group, where alkyl is as defined herein. In some embodiments, the alkoxy group is a C1-C6alkoxy, which refers to a (C1-C6alkyl)-O- group. Examples of alkyl groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tertbutoxy, and the like.

[0275] 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, secbutyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, and the like. In some embodiments, an alkyl is a C1- C6alkyl. 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 C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0276] 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 -NH2 group.

[0277] 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 -limitingexamples of an alkynyl group include -C=CH, -C=CCHs -C=CCH2CHs, -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.

[0278] The term “aromatic” refers to a planar ring having a delocalized K -electron system containing 4n+2 it 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 (z.e., rings which share adjacent pairs of carbon atoms) groups.

[0279] 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.

[0280] 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-C1oaryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0281] 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.

[0282] 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- IH-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, bicyclof l, l,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl. In some embodiments, a cycloalkyl is a C3-C4cycloalkyl.

[0283] 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 eachheteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 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-l-onyl, isoindoline- 1, 3-dionyl, 3,4-dihydroisoquinolin-l(2H)-onyl, 3,4- dihydroquinolin-2(lH)-onyl, isoindoline-l,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-l-yl (A'-attachcd) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both A'-attachcd) 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) moieties, 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.

[0284] 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, or wherein 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 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C i -Cgheteroaryl . In some embodiments, monocyclic heteroaryl is a C1- Cshctcroaryl. In some embodiments, monocyclic heteroaryl is a 5 -membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a Ce-Cgheteroaryl.

[0285] 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- C1oheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C1oheterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is 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 1-2 0 atoms. In some embodiments, a heterocycloalkylcontains 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.

[0286] 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.

[0287] 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.

[0288] The term “cyano,” as used herein refers to -CN.

[0289] The term “ester,” as used herein refers to a carboxy group bridging two moieties linked at carbon atoms.

[0290] The term “ether,” as used herein refers to an oxy group bridging two moieties linked at carbon atoms.

[0291] The term “halo,” or “halogen,” as used herein refers to fluorine, chlorine, bromine, or iodine. In some embodiments, halo is fluoro, chloro, or bromo.

[0292] 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 C1-C6haloalkyl. In another aspect, a haloalkyl is a C1- C4haloalkyl.

[0293] 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 C1-C6haloalkoxy, which refers to a (C1- C6haloalkyl)-O- group. In another aspect, the haloalkoxy is a C1-C4haloalkoxy, which refers to a (C1- C4haloalkyl)-O- group.

[0294] 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, S(=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 (C1-C6alkoxy^C1-C6alkyl. Typical alkoxyalkyl groupsinclude, but are not limited to, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH3, - CH2OCH2CH3, -CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2CH2OCH2CH3, 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 (C1-Ce alkylthio)-C1-C6alkyl. Typical alkoxyalkyl groups include, but are not limited to, -CH2SCH3, -CH2CH2SCH3, -CH2CH2CH2SCH3, -CH2CH2CH2CH2SCH3, - CH2SCH2CH3, -CH2CH2SCH2CH3, -CH2CH2CH2SCH2CH3, -CH2CH2CH2CH2SCH2CH3, 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 (C1-C6alkylamino^C1-C6alkyl. Typical alkoxyalkyl groups include, but are not limited to, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, - CH2CH2CH2CH2NHCH3, -CH2NHCH2CH3, -CH2CH2NHCH2CH3, -CH2CH2CH2NHCH2CH3, - CH2CH2CH2CH2NHCH2CH3, and the like.

[0295] The term “hydroxy,” or “hydroxyl,” as used herein refers to -OH.

[0296] 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 C1-C4hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH2CH2CH2OH, and the like.

[0297] The phrase “linear chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

[0298] The term “nitro,” as used herein refers to -NO2.

[0299] The term “oxo,” as used herein refers to =0.

[0300] 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.

[0301] The term “sulfanyl,” as used herein refers to -S-.

[0302] The term “sulfinyl,” as used herein refers to -S(=O)-.

[0303] 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.

[0304] 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 attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[0305] When a group is defined to be “null,” what is meant is that said group is absent.

[0306] 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)3, -OH, - CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, - S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1- C4hctcroalkyl. C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-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).

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] 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.

[0312] 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 worse state, 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.

[0313] 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

[0314] Formulations may be prepared by any suitable method, typically by uniformly mixing the activecompound(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.

[0315] 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.

[0316] 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 ).

[0317] 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.

[0318] 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.

[0319] 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 asproviding no pharmaceutical benefit.

[0320] 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.

[0321] 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 considerations such 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.

[0322] 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.

[0323] Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the activecomponent in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.

[0324] 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.

[0325] For topical administration to the epidermis the compounds provided herein may be formulated as ointments, creams, or lotions, or as a transdermal patch.

[0326] 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.

[0327] 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.Methods of Dosing and Treatment Regimens

[0328] In some embodiments, described herein is a a method of selectively inhibiting the activity of CBP / p300 in a cell of interest (COI) of a mammal comprising administering a heterobifunctional compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the COI expresses the androgen receptor (AR). In some embodiments, the heterobifunctional compound described herein, or a pharmaceutically acceptable salt or solvate thereof, inhibits the activity of CBP / p300 in the COI but does not inhibit the activity of CBP / p300 in cells expressing CBP / p300 and not expressing the AR. In some embodiments, the AR is overexpressed, overactive, or both overexpressed and overactive in the COI.

[0329] In some embodiments, described herein is a method of treating cancer in a mammal comprising administering to the mammal a heterobifunctional compound described herein. In some embodiments, described herein is a a method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is a hormone dependent cancer. In some embodiments, the cancer is prostate cancer.

[0330] 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

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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 circumstancessurrounding 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.

[0337] 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.

[0338] 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.

[0339] 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.

[0340] 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.

[0341] 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 mammal multiple times over the span of one day.

[0342] 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) thecompound 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.

[0343] 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.

[0344] 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 acetonitrile acetyl acetic anhydride acetic acid azobisisobutyronitrile ,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthalene benzyl tert-butyl carbamate di-tert-butyl decarbonate or Boc anhydride benzoyl peroxide[(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1,1'- biphenyl)-2-(2'-amino- 1,1' -biphenyl)]palladium(II) methanesulfonate methanesulfonate tert-butyl[(2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino) -l,l'-biphenyl)- 2-(2'-amino- 1,1 '-biphenyl)] palladium(II) methane sulfonate cyclohexyl dibenzylideneacetone1 , 8 -diazabicyclo [5.4.0] undec-7 -ene dichloroethane (CICH2CH2CI) dichloromethane (CH2CI2) diisopropylethylamine4-(A' A'-dimcthylarmno)pyridinc dimethylformamideN, JV-dimethylacetamide dimethylsulfoxide1 , 1 '-bis(diphenylphosphino)ferrocene2-Ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinolineequivalent(s) ethyl diethyl ether ethanol ethyl acetate formic acid1 - [bis(dimethylamino)methylene] - 1 H- 1 ,2, 3 -triazolo [4,5 -b] pyridinium 3 - oxid hexafluorophosphate high performance liquid chromatography water potassium carbonate lithium aluminum anhydride liquid chromatography mass spectrometry methyl methanol mass spectrometry mesyl chloride sodium carbonate sodium triacetoxyborohydride sodium hydride sodium sulfateN-bromo succinamideA-methyl-pyrrolidin-2-one nuclear magnetic resonance(1,1 '-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride phenyl pinacolato preparative high performance liquid chromatography iso-propyl reverse phase-high pressure liquid chromatography 3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino-1 , 1 '-biphenyl)]palladium(II) methane sulfonate tert-butyldimethylsilyl trifluoroacetic acid triethylamine tetrahydrofuran tosyl chlorideTLC thin layer chromatographyEXAMPLES

[0345] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0346] Intermediate A was prepared according to the procedure described in WO 2022 / 42707 Al .

[0347] Compound C was prepared according to the following procedure:Compound C

[0348] 1 was prepared according to the procedure described in WO 2022 / 42707 Al.

[0349] 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 mb) was added TEA (106 mg, 1.05 mmol, 146 pb, 3.0 eq) and AC2O (53.5 mg, 524 pmol, 49.2 pL, 1.5 eq) at 0 °C .The mixture was stirred at 25 °C for 12 h. The mixture was poured into ice-water (20 mb). The aqueous phase was extracted with dichloromethane (15 mb x 3). The combined organic phase was washed with brine (10 mb x 2), dried over anhydrous sodium sulfate, filtered andconcentrated 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+): fe = 0.980 min, m / z = 644.3 [M + H+]

[0350] 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-(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 (0.210 g, 326 pmol, 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 x 3). The collected filtrate was concentrated to give a residue. The residue was used for the next step without further purification. Compound 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 (0.15 g, 294 pmol, 90% yield) was obtained as a white solid. LC-MS: MS (ESI+): fe = 0.429 min, m / z = 510.3 [M + H+]

[0351] Compound E was prepared according to the procedure described in WO 2017 / 205538 Al.

[0352] Compound G was prepared according to the following procedure:Compound G

[0353] 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 Na2COs (120.86 mg, 1.14 mmol, 2 eq) and Pd(dppf)C12 (41.72 mg, 57.01 pmol, 0.1 eq) in dioxane (5 mL) and H2O (0.5 mL) was added [8-(5-acetyl-l-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin-3-yl)-3 -isoquinolyl] trifluoromethanesulfonate (299 mg, 570 pmol, 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 x 2). The combined organics were washed with brine (200 mL x 2), dried with anhydrous Na2SC>4, 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- 1 -tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin-3 -y 1) -3 - isoquinolyl]pyridine-2 -carboxylate (0.20 g, 390.95 pmol, 68% yield) was obtained as a yellow solid. LC- MS: MS (ESC): fe = 0.468 min, m / z = 512.2 [M + H+]

[0354] 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 C 18 150*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 (ESC): fe = 0.477 min, m / z = 498.3 [M + Na+]

[0355] Compound H was prepared according to the following procedure:

[0356] Synthesis of 5A was reported in WO2021 / 231174, 2021, Al.

[0357] 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 Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=10 / l to 2 / 1). Compound tert-butyl 3 -iodo- 1- 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.

[0358] 1H NMR (400 MHz, DMSO-J6): 5 = 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)

[0359] LC-MS: MS (ESH): & = 0.521 min, m / z = 364.1 [M + H+]

[0360] 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.

[0361] LC-MS: MS (ESI+): & = 0.218 min, m / z = 263.1 [M + H+]

[0362] 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 EtsN (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 (SiCE, 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.

[0363] LC-MS: MS (ESC): & = 0.378 min, m / z = 306.1 [M + H+]

[0364] 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-l,3,2-dioxaborolan-2-yl)-3-isoquinolyl]oxy]silane (7.00 g, 11.46 mmol, 1.1 eq), Pd(dppf)C12 (359 mg, 491.62 pmol, 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 N2 for 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 x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, dichloromethane: methanol= 100 / 1 to 20 / 1). Compound 1 -[1 - 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.

[0365] LC-MS: MS (ESC): & = 0.893 min, m / z = 479.3 [M + H+]

[0366] 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 NELL (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 (SiC>2, dichloromethane : methanol=50 / l 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.

[0367] 1H NMR (400 MHz, DMSO-6): 5 = 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)

[0368] LC-MS: MS (ESC): & = 0.368 min, m / z = 323.2 [M + H+]

[0369] 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 EtsN (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. Thereaction mixture was quenched by addition water 200 mb, and then extracted with DCM (50 mb x 3). The combined organic layers were washed with brine (50 mb x 3). dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, dichloromethane : methanol=50 / l 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.

[0370] 1H NMR (400 MHz, DMSO-J6): 5 = 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)

[0371] LC-MS: MS (ESI+): & = 0.521 min, m / z = 455.2 [M + H+]Example 1: Synthesis of 4-[8-[4-[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]phenyl]-l-methyl-2,8-diazaspiro[4.5]decan-2-yl]-2 -chloro-benzonitrile (Compound 1)Compound 1

[0372] Synthesis of 1 was reported in WO2021 / 55756, 2021, Al.

[0373] Synthesis of 1A was reported in WO2023 / 278759, 2023, Al.

[0374] A mixture of 2-chloro-4-(l-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (500 mg, 1.24 mmol, 1.0 eq, trifluoroacetate), l-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (389 mg, 1.24 mmol, 1.0 eq), t-BuOK (1 M, 3.71 mL, 3.0 eq), Pd2(dba)s (113 mg, 123.82 pmol, 0.1 eq) and Xantphos (143 mg, 247.63 pmol, 0.2 eq) in toluene (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 h under N2 atmosphere. The mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (80 mL x 2), dried with anhydrous sodium sulfate, fdtered and concentrated in vacuum. The residue was purified by silica gel chromatography (20% - 80% ethyl acetate in petroleum ether). Compound 2- chloro-4-[8-[4-[4-(dimethoxymethyl)-l-piperidyl]phenyl]-l-methyl-2,8-diazaspiro[4.5]decan-2- yl] benzonitrile (450 mg, 69% yield) was obtained as a yellow solid.

[0375] LC-MS: MS (ESH): & = 0.514 min, m / z = 523.4 [M + H+]

[0376] To a solution of 2-chloro-4-[8-[4-[4-(dimethoxymethyl)-l-piperidyl]phenyl]-l-methyl-2,8- diazaspiro[4.5]decan-2-yl]benzonitrile (150 mg, 286.75 pmol, 1.0 eq) in DCM (5 mL) was added TFA (3.07 g, 26.93 mmol, 2 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure. Compound 2-chloro-4-[8-[4-(4-formyl-l-piperidyl)phenyl]-l-methyl-2,8- diazaspiro[4.5]decan-2-yl]benzonitrile (130 mg) was obtained as a yellow gum and directly used in the next step without further purification.

[0377] LC-MS: MS (ESC): & = 0.479 min, m / z = 477.4 [M + H+]

[0378] To a solution of 2-chloro-4-[8-[4-(4-formyl-l-piperidyl)phenyl]-l-methyl-2,8- diazaspiro[4.5]decan-2-yl]benzonitrile (130 mg) in DCE (5 mL) was added NMM (99 mg, 981.18 pmol, 108 pL, 5.0 eq) and 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 (100 mg, 196.24 pmol, 1.0 eq). The mixture was stirred at 25 °C for 5 min. Then NaBH(OAc)3 (125 mg, 588.71 pmol, 3.0 eq) was added and the mixture was stirred at 25 °C for another 12 h. The mixture was poured into water (30 mL). The aqueous phase was extracted with dichloromethane (30 mL x 2). The combined organic phase was washed with brine (30 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-Thin-layer chromatography (SiCL, dichloromethane : methanol = 10: 1) and further purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; gradient: 23%-43% B over 15 min). Compound 4-[8-[4-[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]phenyl]-l-methyl-2,8-diazaspiro[4.5]decan-2-yl]-2 -chloro-benzonitrile (84.67 mg, 87.23 pmol, 44% yield over two steps) was obtained as a blue solid.

[0379] 'H NMR (400 MHz, CDCL): 8 = 7.54 (d, J = 6.0 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.08 - 7.00 (m, 1H), 6.90 (br d, J = 11.6 Hz, 5H), 6.69 - 6.38 (m, 3H), 4.31 - 4.11 (m, 2H), 4.09 - 3.98 (m, 1H), 3.96 (d, J = 2.0 Hz, 3H), 3.91 (br t, J = 5.6 Hz, 1H), 3.78 - 3.64 (m, 4H), 3.54 (br d, J = 3.6 Hz, 2H), 3.43 - 3.36 (m, 1H), 3.35 - 3.28 (m, 1H), 3.24 - 3.18 (m, 1H), 3.11 (br d, J = 12.8 Hz, 5H), 2.91 - 2.84 (m, 2H), 2.81 (br t, J = 5.6 Hz, 1H), 2.75 (brt, J = 5.6 Hz, 1H), 2.63 (br s, 2H), 2.46 (br d, J = 5.2 Hz, 2H), 2.39 (br d, J = 6.8 Hz, 1H),2.35 - 2.21 (m, 3H), 2.18 - 2.01 (m, 8H), 1.98 - 1.81 (m, 4H), 1.79 - 1.66 (m, 2H), 1.62 (br s, 2H), 1.49 - 1.31 (m, 2H), 1.13 (d, J = 6.4 Hz, 3H).

[0380] LC-MS: MS (ESI+): & = 1.627 min, m / z = 486.1 [M / 2 + H+]Example 2: Synthesis of 4-[(3S)-8-[6-[[l-[[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]cyclohexyl]methyl] -2,2-dimethyl-4- piperidyl]oxy]pyridazin-3-yl]-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]-2 -chloro-benzonitrile (Compound

[0381] Synthetic route of compound AR intermediate [4.5] was reported in WO2021 / 55756 A 1.

[0382] Synthesis of 4A:

[0383] To a solution of l-(3-iodo-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (542 mg, 1.86 mmol, 1.0 eq) in DMF (14 mL) was added CS2CO3 (1.82 g, 5.59 mmol, 3.0 eq) and [4-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclohexyl] methane sulfonate (901 mg, 2.79 mmol, 1.5 eq). The mixture was stirred at 110 °C for 16 h. Water (50 mb) was added to the mixture and it was extracted with EtOAc (20 ml., x 3). The combined organics were washed with brine (20 ml.,), dried over anhydrous sodium sulfate, filtered, and concentrated under reduce pressure to give a residue. The residue was purified p / vp-HPLC (column: Phenomenex luna C 18 150*40mm* 15um;mobile phase: [water(FA)-ACN];gradient:85%-100% Bover 10 min). Compound l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-iodo-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone (377 mg, 670 pmol, 36% yield) was obtained as a white solid.

[0384] LC-MS: MS (ESI+): & = 2.838 min, m / z = 518.3 [M + H+]

[0385] A mixture of l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-iodo-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone (627 mg, 1.21 mmol, 1.0 eq), 7-(difluoromethyl)-6-(l-methylpyrazol- 4-yl)-l,2,3,4-tetrahydroquinoline (319 mg, 1.21 mmol, 1.0 eq), t-BuXPhosPd G3 (96 mg, 121 pmol, 0.1 eq) and t-BuOK (I M, 3.63 mL, 3 eq) in 2-methylbutan-2-ol (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The mixture was fdtered and the fdtrate was concentrated under reduce pressure to give the crude product. The residue was purified by column chromatography (SiCF. petroleum ether / ethyl acetate=20 / l to 0 / 1). Compound 1 -[ 1 -[4-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-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 (306 mg, 469 pmol, 39% yield) was obtained as a yellow solid.

[0386] LC-MS: MS (ESC): & = 0.739 min, m / z = 653.3 [M + H+]

[0387] To a solution of l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-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 (306 mg, 469 pmol, 1.0 eq) in MeOH (6 mL) was added NH4F (87 mg, 2.34 mmol, 5.0 eq). The mixture was stirred at 25 °C for 16 h .The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiCF. ethyl acetate / methanol = 10: 1). Compound l-[3-[7- (difluoromethyl)-6-( 1 -methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] - 1 - [4- (hydroxymethyl)cyclohexyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (204 mg, 378 pmol, 81% yield) was obtained as a yellow solid.

[0388] LC-MS: MS (ESC): & = 0.508 min, m / z = 539.4 [M + H+]

[0389] A solution of oxalyl dichloride (141 mg, 1.11 mmol, 98 pL, 3.0 eq) in DCM (3 mL) was cooled to -78 °C under N2 atmosphere. DMSO (116 mg, 1.49 mmol, 116 pL, 4.0 eq) was added slowly into the mixture. The mixture was stirred at -78 °C for 0.5 h. Then the solution of l-[3-[7-(difluoromethyl)-6-(l- methylpyrazol-4-yl)-3 ,4-dihydro-2H-quinolin- 1 -yl] - 1 -[4-(hydroxymethyl)cyclohexyl] -6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone (200 mg, 371 pmol, 1.0 eq) in DCM (3 mL) was added to the mixture. The mixture was stirred at -78 °C for 0.5 h. Then EtsN (225 mg, 2.23 mmol, 310, 6.0 eq) was added into the mixture. The mixture was stirred at -78 °C for 0.5 h. The reaction mixture contained compound 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-l-yl]cyclohexanecarbaldehyde (199 mg) as a yellow liquid was used in next step directly without further purificationLC-MS: MS (ESC): & = 0.566 min, m / z = 537.3 [M + H+]

[0390] Synthesis of Compound 122:

[0391] To a solution of tert-butyl 4-hydroxy-2,2-dimethyl-piperidine-l -carboxylate (4.80 g, 20.93 mmol,1.0 eq), 3-chloro-6-iodo-pyridazine (6.04 g, 25.12 mmol, 1.2 eq) in THF (100 mL) was added t-BuOK (1 M,31.4 mL, 1.5 eq) at 25 °C. The mixture was stirred at 60 °C for 5 hours. The reaction mixture was quenched by saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( Si O2- petroleum ether / ethyl acetate=50 / l to 10 / 1). Tert-butyl 4-(6-iodopyridazin-3-yl)oxy-2,2-dimethyl- piperidine-1 -carboxylate (6.50 g, 15.0 mmol, 72% yield) was obtained as a white solid.

[0392] LC-MS: MS (ESH): & = 0.654 min, m / z = 337.9 [M -55+ H+]

[0393] To a mixture of tert-butyl 4-(6-iodopyridazin-3-yl)oxy-2,2-dimethyl-piperidine-l-carboxylate (600 mg, 1.4 mmol, 1.0 eq) and 2-chloro-4-[(3S)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]benzonitrile (482 mg, 1.7 mmol, 1.2 eq) in dioxane (10 mL) was added Xantphos Pd G4 (133 mg, 138 pmol, 0.1 eq) and t- BuONa (2 M, 1.4 mL, 2.0 eq) under N2 atmosphere. The mixture was stirred at 90 °C for 3 h. The mixture was concentrated and purified by column chromatography (SiCL, PE / EA = 0% - 40%) to afford compound tert-butyl 4-[6-[(3S)-2-(3-chloro-4-cyano-phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl]pyridazin-3- yl] oxy-2, 2-dimethyl -piperidine- 1 -carboxylate (455 mg, 51% yield) as a brown solid.

[0394] LC-MS: MS (ESL): & = 2.566 min, m / z = 595.3 [M + H]+

[0395] To a solution of tert-butyl 4-[6-[(3S)-2-(3-chloro-4-cyano-phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-8-yl]pyridazin-3-yl]oxy-2,2-dimethyl-piperidine-l-carboxylate (455 mg, 764 pmol, 1.0 eq) in DCM (6 mL) was added TFA (2.3 g, 20.2 mmol, 1.5 mL, 26.4 eq). The mixture was stirred at 25 °C for 0.5 h. NaHCOs aqueous solution was added to reaction mixture until pH = 7-8. Then the mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford compound 2-chloro-4-[(3S)-8-[6- [(2, 2-dimethyl -4-piperidyl)oxy]pyridazin-3-yl]-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]benzonitrile (378 mg) as a yellow solid.

[0396] LC-MS: MS (ESL): & = 0.786 min, m / z = 495.2 [M + H]+

[0397] To a solution of 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]cyclohexanecarbaldehyde (149 mg, 278 pmol, 1.0 eq) and 2-chloro-4-[(3S)-8-[6-[(2,2-dimethyl-4-piperidyl)oxy]pyridazin-3-yl]-3-methyl-2,8- diazaspiro[4.5]decan-2-yl]benzonitrile (180 mg, 333 pmol, 1.2 eq) in DCM (3 mL) was added EtsN (56 mg, 555 pmol, 77 pL, 2.0 eq). The mixture was stirred at 0 °C for 10 min. Then NaBH(OAc)s (294 mg, 1.4 mmol, 5.0 eq) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. NaHCCL aqueous solution was added to reaction mixture until pH = 7-8. Then the mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product. The crude product was purified by column chromatography (SiCL, DCM / MeOH = 0% - 10%) and then purified by prep-TLC (DCM / MeOH = 10: 1) to afford compound 4-[(3S)-8-[6-[[l-[[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]cyclohexyl]methyl]-2,2-dimethyl-4-piperidyl]oxy]pyridazin-3-yl]-3-methyl-2,8-diazaspiro[4.5]decan-2-yl] -2 -chloro-benzonitrile (108 mg, 37% yield over two steps) as an off-white solid.

[0398] 'H NMR (400 MHz, CD3OD) 5 = 7.63 (s, 1H), 7.53 - 7.44 (m, 2H), 7.34 (d, J= 9.6 Hz, 1H), 7.10 (d, J= 8.8 Hz, 1H), 6.92 (d, J= 9.6 Hz, 1H), 6.77 - 6.41 (m, 4H), 4.24 (d, J= 7.6 Hz, 2H), 4.15 - 4.00 (m, 2H), 3.93 (s, 3H), 3.91 - 3.79 (m, 2H), 3.71 - 3.63 (m, 2H), 3.62 - 3.41 (m, 5H), 3.36 (d,J= 10.4 Hz, 1H), 2.95 - 2.78 (m, 5H), 2.35 (dd, J= 7.6, 13.2 Hz, 1H), 2.19 (s, 3H), 2.12 - 1.94 (m, 8H), 1.89 - 1.74 (m, 7H), 1.69 - 1.54 (m, 6H), 1.28 (d, J= 6.0 Hz, 6H), 1.24 - 1.11 (m, 6H).

[0399] LC-MS: MS (ESI+): & = 2.422 min, m / z = 1015.7 [M + H]+Example 3: Synthesis of 4-[(3S)-8-[6-[[l-[[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]cyclohexyl]methyl] -2,2-dimethyl-4- piperidyl]oxy]pyridazin-3-yl]-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]-2 -chloro-benzonitrile (Compound 123)

[0400] Synthesis of 1 was reported in WO2022 / 161414 Al.

[0401] To a solution of l-(3-iodo-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (10.83 g, 37.21 mmol, 1.0 eq) in DMF (100 mL) was added CS2CO3(36.40 g, 111.6 mmol, 3.0 eq) and [4-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclohexyl] methanesulfonate (18.00 g, 55.81 mmol, 1.5 eq). The mixture was stirred at 110 °C for 12 hours. The reaction mixture was diluted with water (500 mL) and extracted with EA (300 mL x 2). The combined organic layers were washed with brine (500 mL), dried over filtered, and filtrate was concentrated under vacuum to give a residue. It was purified by prep-HPLC (PAcondition:column: Phenomenex luna C18 (250x70mm, 10 um);mobile phase: [H2O(0.225% FA)- ACN];gradient:80%-100% B over 20.0 min) to afford l-[l-[4-(hydroxymethyl)cyclohexyl]-3-iodo-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (6.50 g, 16.12 mmol, 43% yield) was obtained as a white solid.

[0402] LC-MS: MS (ESI+): & = 0.659 min, m / z = 404.1 [M + H+]

[0403] To a solution of l-[l-[4-(hydroxymethyl)cyclohexyl]-3-iodo-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-5-yl]ethanone (6.50 g, 16.10 mmol, 1.0 eq) in DCM (60 mL) was added TBSC1 (2.43 g, 16.10 mmol, 1.0 eq) and imidazole (2.19 g, 32.24 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. It was purified by flash silica gel chromatography (0-37% ethyl acetate in petroleum ether) to afford 1 -[ 1 -[4-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (5.20 g, 10.05 mmol, 62% yield) as a white solid.

[0404] 'H NMR (400 MHz, CDC13): 4.48 - 4.18 (m, 2H), 3.95 - 3.84 (m, 2H), 3.71 (t, J = 5.6 Hz, 1H), 3.45 (d, J= 6.0 Hz, 2H), 2.80 - 2.63 (m, 2H), 2.19 (s, 3H), 2.04 - 1.87 (m, 6H), 1.64 (s, 3H), 1.57 (t, J= 2.8, 6.0, 11.6 Hz, 1H), 1.19 - 1.01 (m, 2H), 0.90 (s, 9H), 0.08 - 0.02 (m, 6H).

[0405] LC-MS: MS (ESI+): & = 0.650 min, m / z = 518.2 [M + H+]

[0406] A mixture of l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-iodo-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.00 g, 1.93 mmol, 1.0 eq), 7-(difluoromethyl)-6-(l-methylpyrazol-4- yl)-l,2,3,4-tetrahydroquinoline (763 mg, 2.90 mmol, 1.5 eq), CS2CO3 (1.57 g, 4.83 mmol, 2.5 eq), CPhos Pd G3 (312 mg, 386.46 pmol, 0.2 eq) in 2-methylbutan-2-ol (13 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 h. The reaction mixture was fdtered, and the fdtrate was concentrated under vacuum to give a residue. It was purified by flash silica gel chromatography (0-65% ethyl acetate in petroleum ether) to afford l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-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 (1.10 g, 1.68 mmol, 87% yield) as a yellow solid.

[0407] 'H NMR (400 MHz, CDCI3): 7.53 (d, J= 5.6 Hz, 1H), 7.40 (d, J= 6.8 Hz, 1H), 7.01 (d, J= 22.0 Hz, 1H), 6.86 (d, J= 2.8 Hz, 1H), 6.52 (d,J= 10.8 Hz, 1H), 4.25 (s, 1H), 4.18 - 4.08 (m, 2H), 3.95 (d, J= 2.4 Hz, 3H), 3.93 - 3.81 (m, 2H), 3.77 - 3.71 (m, 2H), 3.46 (d, J= 6.0 Hz, 2H), 2.97 - 2.64 (m, 4H), 2.05 (s, 3H), 2.12 - 2.03 (m, 1H), 2.02 - 1.90 (m, 6H), 1.62 - 1.50 (m, 1H), 1.19 - 1.03 (m, 2H), 0.91 (s, 9H), 0.10 - 0.03 (m, 6H).

[0408] LC-MS: MS (ESI+): & = 1.169 min, m / z = 653.3 [M + H+]

[0409] To a solution of l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-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 (1.60 g, 2.45 mmol, 1.0 eq) in MeOH (20 mL) was added KF (1.42 g, 24.51 mmol, 10.0 eq). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. It was purified by flash silica gel chromatography (0-8% methanol in dichloromethane) to afford l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -y 1] - 1 -[4-(hydroxymethyl)cyclohexyl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin-5 -yl]ethanone (1.2 g, 2.23 mmol, 91% yield) as a yellow solid.

[0410] 'H NMR (400 MHz, CDC13): 7.66 - 7.50 (m, 1H), 7.47 - 7.37 (m, 1H), 7.10 - 6.96 (m, 1H), 6.86 (d, J= 3.6 Hz, 1H), 6.71 - 6.32 (m, 1H), 4.34 - 4.08 (m, 2H), 3.95 (s, 3H), 3.92 - 3.85 (m, 1H), 3.77 - 3.66 (m, 2H), 3.60 - 3.44 (m, 2H), 3.04 - 2.57 (m, 4H), 2.16 (s, 2H), 2.14 - 1.90 (m, 9H), 1.68 (s, 4H), 1.26 (t, J= 7.2 Hz, 1H), 1.20 - 1.08 (m, 1H).

[0411] LC-MS: MS (ESI+): & = 0.873 min, m / z = 539.3 [M + H+]

[0412] A solution of oxalyl dichloride (636 mg, 5.01 mmol, 9.0 eq) in DCM (5 mL) was cooled to -78 °C under N2 atmosphere, DMSO (435 mg, 5.57 mmol, 435 pL, 10.0 eq) was added slowly into the mixture, the mixture was stirred at -78 °C for 0.5 hour, then the solution of l-[3-[7-(difhroromethyl)-6-(l-methylpyrazol- 4-yl)-3 ,4-dihydro-2H-quinolin- 1 -yl] - 1 -[4-(hydroxymethyl)cyclohexyl] -6,7-dihydro-4H-pyrazolo [4,3 - c]pyridin-5-yl]ethanone (300 mg, 557 pmol, 1.0 eq) in DCM (5 mL) was added to the mixture, the mixture was stirred at -78 °C for 0.5 hour. Then EtsN (1.13 g, 11.14 mmol, 20.0 eq) was added into the mixture. The reaction mixture contained product 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]cyclohexanecarbaldehyde (298 mg) was used for next step without purification.

[0413] LC-MS: MS (ESI+): & = 0.889 min, m / z = 537.3 [M + H+]

[0414] To a solution of 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]cyclohexanecarbaldehyde (200 mg, 373 pmol, 1.0 eq) and 2-chloro-4-[(3S)-8-[6-[(2,2-dimethyl-4-piperidyl)oxy]pyridazin-3-yl]-3-methyl-2,8- diazaspiro[4.5]decan-2-yl]benzonitrile (250 mg, 410 pmol, 1.1 eq) in DCM (5 mL) was added NaBH(OAc)s (395 mg, 1.86 mmol, 5.0 eq) and EtsN (75 mg, 745 pmol, 2.0 eq) at 0 °C, the mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. It was purified by prep-HPLC (LA condition: column: Phenomenex luna C 18 150*40mm* 15um;mobile phase: [H2O(0.225% FA)-ACN];gradient:22%-52% B over 15.0 min) and prep-HPLC (basic condition: column: Waters Xbridge C18 150*25mm*5um;mobile phase: [H20(0.05% NH3H20)-ACN];gradient:75%-100% B over 11.0 min) to afford 4-[(3S)-8-[6-[[l-[[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]cyclohexyl]methyl]-2,2-dimethyl-4-piperidyl]oxy]pyridazin-3-yl]-3-methyl-2,8- diazaspiro[4.5]decan-2-yl]-2 -chloro-benzonitrile (109.2 mg, 106.50 pmol, 28% yield over two steps) was obtained as a yellow solid.

[0415] 'H NMR (400 MHz, CDCI3): 7.54 (d, J= 6.0 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.08 - 6.94 (m, 2H), 6.88 - 6.74 (m, 2H), 6.69 - 6.35 (m, 2H), 6.48 - 6.33 (m, 1H), 5.39 - 5.24 (m, 1H), 4.25 (s, 1H), 4.12 (s, 1H), 4.04 - 3.97 (m, 1H), 3.97 - 3.94 (m, 3H), 3.93 - 3.85 (m, 2H), 3.77 - 3.41 (m, 7H), 3.34 (s, 2H), 2.93 - 2.83 (m, 2H), 2.82 - 2.78 (m, 1H), 2.77 - 2.70 (m, 2H), 2.48 - 2.27 (m, 3H), 2.19 - 2.14 (m, 2H), 2.12 - 1.92 (m, 9H), 1.92 - 1.75 (m, 4H), 1.60 (s, 9H), 1.30 (d, J = 6.0 Hz, 3H), 1.26 (s, 1H), 1.14 - 0.99 (m, 6H)

[0416] LC-MS: MS (ESL): & = 2.788 min, m / z = 1015.9 [M + H+]Example 4: Synthesis of 4-[(3S)-8-[6-[[l-[[4-[5-acetyl-3-[7-methyl-6-(l-methylpyrazol-4-yl)-3,4-dihydro- 2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl]cyclohexyl]methyl] -4- piperidyl]oxy]pyridazin-3-yl]-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]-2 -chloro-benzonitrile (Compound

[0417] Synthesis of 1 was report in US2005 / 54658 Al

[0418] Synthesis of 1A was report in Journal of Medicinal Chemistry, 2024, vol. 67, # 7, p. 5275 - 5304.

[0419] Synthesis of 5A was described in Example 5.

[0420] Synthesis of 2A:

[0421] To a solution of 7-methyl-l,2,3,4-tetrahydroquinoline (5.00 g, 34.0 mmol, 1.0 eq) in DMF (70 mL) was added NBS (5.44 g, 30.6 mmol, 0.9 eq) in DMF (15 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h under N2. The mixture was poured into water (50 mL). The mixture was poured into iced water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3), dried with anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 0). Compound 6-bromo-7-methyl-l,2,3,4-tetrahydroquinoline (5.60 g, 24.8 mmol, 73% yield) was obtained as a yellow solid.

[0422] 'H NMR (400 MHz, CHLOROFORM -d) 5 = 7.09 (s, 1H), 6.36 (s, 1H), 3.30 - 3.26 (m, 2H), 2.75 - 2.70 (m, 2H), 2.26 (s, 3H), 1.97 - 1.90 (m, 2H)

[0423] To a solution of 6-bromo-7-methyl-l,2,3,4-tetrahydroquinoline (5.60 g, 24.8 mmol, 1.0 eq) and 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (7.00 g, 33.6 mmol, 1.4 eq) in dioxane (70 mb) was added Pd(dppf)C12 (1.81 g, 2.48 mmol, 0.1 eq) and a solution of K2CO3 (6.85 g, 49.5 mmol, 2.0 eq) in H2O (14 mb). The reaction mixture was stirred at 110 °C for 12 h under N2. The mixture was poured into iced water (300 mb). The aqueous phase was extracted with ethyl acetate (80 mb x 3). The combined organic phase was washed with brine (80 mb), dried with anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate= 3 / 1 to 0 / 1). Compound 7-methyl-6-(l-methylpyrazol-4-yl)-l,2,3,4-tetrahydroquinoline (3.51 g, 15.4 mmol, 62% yield) was obtained as a off-white solid.

[0424] LC-MS: MS (ESI+): & = 0.456 min, m / z = 228.2 [M + H+]

[0425] Synthesis of Compound 125:

[0426] To a solution of [4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl] methane sulfonate (3.20 g, 9.90 mmol, 1.2 eq) and l-(3-iodo-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (2.41 g, 8.27 mmol, 1.0 eq) in DMF (40 mb) was added K2CO3 (3.43 g, 24.8 mmol, 3.0 eq) and The mixture was stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was poured into water 500 mb, and then extracted with ethyl acetate (200 mb x 2). The combined organic layers were washed with brine (200 mb), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA column: YMC-Gel SiL-HG 250mm x 70mm x 10um;mobile phase: [Hexane- EtOH];gradient:5%-45% B over 15 min) Compound 1 -[ 1 -[4-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.26 g, 2.43 mmol, 29% yield) was obtained as colorless oil.

[0427] LC-MS: MS (ESC): & = 0.754 min, m / z = 518.1 [M + H+]

[0428] To a solution of l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-iodo-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.26 g, 2.43 mmol, 1.0 eq) and 7-methyl-6-(l-methylpyrazol-4- yl)-l,2,3,4-tetrahydroquinoline (719 mg, 3.17 mmol, 1.3 eq) in 2-methylbutan-2-ol (25 mL) was added CS2CO3 (1.98 g, 6.09 mmol, 2.5 eq) and CPHOS PD G3 (236 mg, 292 pmol, 0.1 eq). The reaction mixture as stirred at 90 °C for 12 h under N2. The reaction mixture was poured into iced water 150 mL, and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate 10 / 1 to 2 / 1). Compound l-[l-[4- [[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-[7-methyl-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H- quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.30 g, 2.11 mmol, 87% yield) was obtained as yellow solid.

[0429] LC-MS: MS (ESC): & = 0.690 min, m / z = 617.3 [M + H+]

[0430] To a solution of l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-[7-methyl-6-(l- methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.30 g, 2.11 mmol, 1.0 eq) in THF (13 mL) was added TBAF (1 M, 4.21 mL, 2.0 eq). The mixture wasstirred at 45 °C for 12 h. The reaction mixture was poured into water 50 mL, and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate =10 / 1 to 0 / 1). Compound 1 -[ 1 -[4- (hydroxymethyl)cyclohexyl]-3-[7-methyl-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-6,7- dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (1.00 g, 1.99 mmol, 94% yield) was obtained as yellow oil.

[0431] LC-MS: MS (ESC): & = 0.528 min, m / z = 503.3 [M + H+]

[0432] To a solution of TFAA (653 mg, 3.11 mmol, 432 pL, 5.2 eq) in DCM (20 mL) was added DMSO (360 mg, 4.61 mmol, 360 pL, 7.7 eq) in DCM (2 mL) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 0.5 h. Then l-[l-[4-(hydroxymethyl)cyclohexyl]-3-[7-methyl-6-(l-methylpyrazol-4-yl)- 3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (300 mg, 597 pmol, 1.0 eq) in DCM (2 mL) was added to the mixture at -78 °C. The mixture was stirred at -78 °C for 0.5 h under N2 atmosphere. Then EtsN (785.11 mg, 7.76 mmol, 1.08 mL, 13.0 eq) in DCM (2 mL) was added at -78 °C. The mixture was stirred at 0 °C for 1.5 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate =10 / 1 to 0 / 1). Compound 4-[5-acetyl-3-[7-methyl-6-(l-methylpyrazol-4-yl)-3,4- dihydro-2H-quinolin- 1 -yl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin- 1 -yl]cyclohexanecarbaldehyde (298 mg, 595 pmol, 98% yield) was obtained as yellow oil.

[0433] LC-MS: MS (ESC): & = 0.532 min, m / z = 501.3 [M + H+]

[0434] To a solution of 2-chloro-4-[(3S)-3-methyl-8-[6-(4-piperidyloxy)pyridazin-3-yl]-2,8- diazaspiro[4.5]decan-2-yl]benzonitrile (371 mg, 638 pmol, 1.1 eq) in DCM (5 mL) was added ET3N (602 mg, 5.95 mmol, 829 pL, 10.0 eq), 4-[5-acetyl-3-[7-methyl-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H- quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-l-yl]cyclohexanecarbaldehyde (298 mg, 595 pmol, 1.0 eq) and NaBH(OAc)3 (631 mg, 2.98 mmol, 5.0 eq) at 0 °C and stirred at 25 °C for 12 h. The mixture was poured into iced water (30 mL). The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiCL, dichloromethane / methanol =10 / 1). The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 x 40mm x 15um;mobile phase: [H2O(0.225% FA)-ACN];gradient:22%-52% B over 15.0 min). Compound 4-[(3S)-8- [6-[[l-[[4-[5-acetyl-3-[7-methyl-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4H- pyrazolo[4,3-c]pyridin-l-yl]cyclohexyl]methyl]-4-piperidyl]oxy]pyridazin-3-yl]-3-methyl-2,8- diazaspiro[4.5]decan-2-yl]-2 -chloro-benzonitrile (144.39 mg, 151 pmol, 25% yield) was obtained as off- white solid.

[0435] 'H NMR (400 MHz, CHLOROFORM-d) 5 = 8.39 - 8.35 (m, 1H), 7.61 - 7.50 (m, 1H), 7.47 - 7.35 (m, 2H), 7.11 - 7.02 (m, 1H), 7.02 - 6.92 (m, 1H), 6.90 - 6.75 (m, 1H), 6.64 - 6.55 (m, 1H), 6.51 - 6.41 (m, 1H), 6.40 - 6.30 (m, 1H), 5.44 - 5.19 (m, 1H), 4.12 (s, 1H), 4.05 - 3.96 (m, 2H), 3.95 - 3.92 (m, 3H), 3.90 (t,J= 5.6 Hz, 1H), 3.73 (s, 1H), 3.68 - 3.55 (m, 4H), 3.54 - 3.43 (m, 2H), 3.34 (s, 2H), 3.30 - 3.01 (m, 3H), 2.96 (s, 2H), 2.86 - 2.75 (m, 3H), 2.71 (t, J= 5.6 Hz, 1H), 2.41 - 2.27 (m, 4H), 2.26 - 2.15 (m, 8H), 2.10 - 2.06 (m, 2H), 2.02 (s, 2H), 1.97 - 1.89 (m, 3H), 1.88 - 1.79 (m, 4H), 1.77 - 1.69 (m, 2H), 1.67 - 1.57 (m, 3H), 1.30 (d, J= 6.0 Hz, 3H)

[0436] LC-MS: MS (ESI+): & = 2.723 min, m / z = 951.9 [M + H+]Example 5: Synthesis of 4-[(3S)-8-[6-[[l-[[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]cyclohexyl]methyl] -4- piperidyl]oxy]pyridazin-3-yl]-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]-2 -chloro-benzonitrile (Compound135)

[0437] Synthesis of 2A was reported in Journal of Medicinal Chemistry, 2023, vol. 66, # 18, p. 13280 - 13303.

[0438] Synthesis of 5A was reported in Journal of Medicinal Chemistry, 2024, vol. 67, # 7, p. 5275 - 5304.

[0439] Synthesis of 6A was reported in Journal of Cell Chemical Biology, 2021, vol. 28, # 4, p. 503 - 12,514.

[0440] To a solution of 3,6-diiodopyridazine (5.00 g, 15.1 mmol, 1.0 eq) and tert-butyl 4- hydroxypiperidine -1 -carboxylate (3.34 g, 16.6 mmol, 1.1 eq) in THF (70 mL) was dropwise added t-BuOK (1 M, 16.6 mL, 1.1 eq) dropwise at 25 °C under N2. The mixture was stirred at 60 °C for 2 h under N2. The reaction mixture was poured into iced with H2O (200 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, dichloromethane / ethyl acetate = 1 / 1).Compound tert-butyl 4-(6-iodopyridazin-3-yl)oxypiperidine-l-carboxylate (6.00 g, 14.81 mmol, 98% yield) was obtained as a brown solid.

[0441] LC-MS: MS (ESI+): & = 0.621 min, m / z = 349.9 [M - 55]

[0442] 'H NMR (400 MHz, CHLOROFORM -d) 5 = 7.66 (d, J=9.2 Hz, 1 H) 6.66 (d, J=9.2 Hz, 1 H) 5.40 (m, 1 H) 3.77 - 3.88 (m, 2 H) 3.20 - 3.29 (m, 2 H) 2.02 - 2.11 (m, 2 H) 1.76 (m, 2 H) 1.47 (s, 9 H)

[0443] To a solution of 2-chloro-4-[(3S)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]benzonitrile (3.26 g, 8.07 mmol, 1.0 eq) and tert-butyl 4-(6-iodopyridazin-3-yl)oxypiperidine-l -carboxylate (3.27 g, 8.07 mmol, 1.0 eq) in dioxane (70 mL) was added t-BuONa (2 M, 12.11 mL, 3.0 eq) and Xantphos Pd G4 (593 mg, 616 pmol, 0.08 eq). The reaction mixture was stirred at 90 °C for 0.5 h under N2. The mixture was poured into iced water (150 mL). The aqueous phase was extracted with ethyl acetate (70 mL x 3). The combined organic phase was washed with brine (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / l to 1 / 1). Compound tert-butyl 4-[6-[(3S)-2-(3-chloro-4-cyano-phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-8-yl]pyridazin-3-yl]oxypiperidine-l-carboxylate (3.60 g, 6.35 mmol, 79% yield) was obtained as a brown solid.

[0444] LC-MS: MS (ESI+): & = 0.909 min, m / z = 567.3 [M + H+];

[0445] To a solution of tert-butyl 4-[6-[(3S)-2-(3-chloro-4-cyano-phenyl)-3-methyl-2,8- diazaspiro[4.5]decan-8-yl]pyridazin-3-yl]oxypiperidine-l-carboxylate (4.60 g, 8.11 mmol, 1.0 eq) DCM (30 mL) was added TFA (16.05 g, 141 mmol, 10.5 mL, 17.4 eq). The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give a residue. Compound 2-chloro-4-[(3S)-3-methyl-8-[6-(4- piperidyloxy)pyridazin-3-yl]-2,8-diazaspiro[4.5]decan-2-yl]benzonitrile (4.70 g) was obtained as a brown gum and directly used in the next step without further purification.

[0446] LC-MS: MS (ESI+): & = 0.782 min, m / z = 467.2 [M + H+]

[0447] To a solution of [4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl] methane sulfonate (29.92 g, 92.8 mmol, 1.5 eq) andl-(3-iodo-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (18.00 g, 61.8 mmol, 1.0 eq) in DMF (250 mL) was added CS2CO3 (80.59 g, 247 mmol, 4.0 eq). The reaction mixture as stirred at 110 °C for 3 h under N2. The mixture was poured into iced water (2500 mL). The aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (500 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by semi-preparative reverse phase HPLC (column: Welch Ultimate XB-CN 250 x 70mm x lOum; mobile phase: [Heptane-EtOH (0.1%NH3H2O)]; B%: 15%, isocratic elution mode). Compound l-[ l-[4-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-iodo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (10.00 g, 19.32 mmol, 31% yield) was obtained as a white solid.

[0448] LC-MS: MS (ESI+): & = 1.141 min, m / z = 518.2 [M + H+]

[0449] To a solution of l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-3-iodo-6,7-dihydro- 4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (4.00 g, 7.73 mmol, 1.0 eq), CS2CO3 (6.30 g, 19.3 mmol, 2.5 eq) and 7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-l,2,3,4-tetrahydroquinoline (2.68 g, 10.2 mmol, 1.3 eq) in tert-amyl alcohol (70 mL) was added CPhos Pd G3 (623 mg, 773 pmol, 0.1 eq). The reaction mixture as stirred at 90 °C for 12 h under N2. The mixture was poured into iced water (300 mL). The aqueous phasewas extracted with ethyl acetate (90 mL x 3). The combined organic phase was washed with brine (100 mL), dried with anhydrous sodium sulfate, fdtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane / methyl alcohol = 60 / 1 to 40 / 1). Compound l-[l-[4- [[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-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 (3.50 g, 4.40 mmol, 57% yield) was obtained as a light yellow solid.

[0450] LC-MS: MS (ESI+): & = 1.173 min, m / z = 653.4 [M + H+]

[0451] To a solution of l-[l-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexyl]-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 (6.60 g, 10.1 mmol, 1.0 eq) in THF (80 mL) was added TBAF (1 M, 18.2 mL, 1.8 eq). The reaction mixture as stirred at 40 °C for 12 h. The mixture was poured into iced water (500 mL). The aqueous phase was extracted with DCM (70 mL x 3). The combined organic phase was washed with brine (80 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane / methyl alcohol = 60 / 1 to 30 / 1). Compound l-[3-[7- (difluoromethyl)-6-( 1 -methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin- 1 -yl] - 1 - [4- (hydroxymethyl)cyclohexyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]ethanone (4.8 g, 8.91 mmol, 88% yield) was obtained as a light yellow solid.

[0452] LC-MS: MS (ESC): & =0.470 min, m / z = 539.4 [M + H+]

[0453] To a solution of (COC1)2 (5.04 g, 39.7 mmol, 3.48 mL, 5.4 eq) in DCM (100 mL) was slowly dropwise added DMSO (5.22 g, 66.8 mmol, 5.22 mL, 9.0 eq) in DCM (10 mL) at -78 °C and stirred at -78 °C for 0.5 h under N2 atmosphere. Then l-[3-[7-(difluoromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H- quinolin- 1 -yl] - 1 -[4-(hydroxymethyl)cyclohexyl] -6,7-dihydro-4H-pyrazolo [4,3 -c]pyridin-5 -yl]ethanone (4.00 g, 7.43 mmol, 1.0 eq) in DCM (8 mL) was slowly dropwise added at -78 °C and stirred at -78 °C for 1 h under N2 atmosphere. EtsN (10.11 g, 100 mmol, 13.9 mL, 13.5 eq) in DCM (8 mL) was added to the above reaction mixture at -78 °C and stirred at 0 °C for 1.5 h under N2. Compound 4-[5-acetyl-3-[7- (difhioromethyl)-6-(l-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-l-yl]-6,7-dihydro-4H-pyrazolo[4,3- c]pyridin-l-yl]cyclohexanecarbaldehyde (4.00 g, crude) in reaction solution was obtained as a light yellow liquid and used into the next step without further purification.

[0454] LC-MS: MS (ESC): & =0.897 min, m / z = 537.3 [M + H+]

[0455] To a solution of 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]cyclohexanecarbaldehyde (4.00 g) and EtsN (3.77 g, 37.3 mmol, 5.19 mL, 5.0 eq) in DCM (50 mL) was added 2-chloro-4-[(3S)-3-methyl-8-[6-(4- piperidyloxy)pyridazin-3-yl]-2,8-diazaspiro[4.5]decan-2-yl]benzonitrile (4.50 g, 9.64 mmol, 1.3 eq) in DCM (10 mL) and NaBH(OAc)3 (4.74 g, 22.4 mmol, 3.0 eq) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 1 h. The mixture was poured into ice-water (400 mL). The aqueous phase was extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel columnchromatography (dichloromethane / methyl alcohol = 30 / 1 to 10 / 1 to tetrahydrofuran / petroleum ether = 4 / 1). Compound 4-[(3S)-8-[6-[[l-[[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] cyclohexyl]methyl] -4-piperidyl]oxy]pyridazin-3 - yl]-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]-2-chloro-benzonitrile (3244.8 mg, 3.25 mmol, 44% yield over two steps) was obtained as a white solid.

[0456] 'H NMR (400 MHz, CHLOROFORM -d) 5 = 7.53 (d, J=5.6 Hz, 1 H) 7.36 - 7.45 (m, 2 H) 6.96 - 7.08 (m, 2 H) 6.77 - 6.90 (m, 2 H) 6.35 - 6.69 (m, 3 H) 5.17 (m, 1 H) 4.25 (s, 1 H) 4.12 (s, 1 H) 3.94 - 4.04 (m, 4 H) 3.84 - 3.93 (m, 2 H) 3.66 - 3.80 (m, 3 H) 3.53 - 3.65 (m, 2 H) 3.41 - 3.53 (m, 2 H) 3.34 (s, 2 H) 2.66 - 2.93 (m, 6 H) 2.25 - 2.35 (m, 2 H) 2.11 - 2.23 (m, 5 H) 1.95 - 2.10 (m, 10 H) 1.74 - 1.91 (m, 4 H) 1.61 (m, 5 H) 1.29 (d, J=6.0 Hz, 3 H) 1.07 (m, 2 H)

[0457] LC-MS: MS (ESI+): & = 2.724 min, m / z = 987.8 [M + H+]Example 6: Synthesis of 5-[(3S)-8-[6-[[l-[[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] cyclohexyl] methyl] -4-piperidyl] oxy] pyridazin-3-yl]-3-methyl-2,8-diazaspiro [4.5] decan-2-yl] quinoline-8-carbonitrile (Compound 171)

[0458] Synthesis of 1A was reported in Journal of Medicinal Chemistry, 2023, vol. 66, # 13, p. 8822 - 8843.

[0459] Synthesis of 7A was described in Example 5.

[0460] Synthesis of 3:

[0461] To a mixture of 5-bromoquinoline-8-carbonitrile (5.0 g, 21.5 mmol, 1.0 eq) and tert-butyl (3S)-3- methyl-2,8- diazaspiro [4.5] decane-8-carboxylate (8.2 g, 32.2 mmol, 1.5 eq) in DMA (50 mb) was added DIPEA (8.3 g, 64.7 mmol, 11.2 mb, 3.0 eq), the mixture was stirred at 130 °C for 12 h. Then the reaction mixture was diluted with water (100 mb) and extracted with EtOAc (100 mb x 3). The combined organic layers were washed with brine (100 mb), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, DCM / MeOH =200 / 1 to 100 / 1). Compound tert-butyl (3S)-2-(8-cyano-5-quinolyl)-3-methyl-2,8-diazaspiro [4.5] decane-8- carboxylate (4.0 g, 9.84 mmol, 45% yield) was obtained as a yellow solid.

[0462] LC-MS: MS (ESC): & = 0.655 min, m / z = 407.2 [M + H+]

[0463] To a mixture of tert-butyl (3S)-2-(8-cyano-5-quinolyl)-3-methyl-2,8-diazaspiro [4.5] decane-8- carboxylate (4.0 g, 9.84 mmol, 1.0 eq) in DCM (40 mb) was added TEA (12.3 g, 107 mmol, 8 mb, 10.9 eq), the mixture was stirred at 25 °C for 12 h. The mixture was concentrated to give a residue. The residue was diluted with DCM (20 mb) and adjusted to pH about 8 by sat. NaHCOs, extracted with DCM (20 mb * 3). The combined organic layers were dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give a crude product. Compound 5-[(3S)-3-methyl-2,8-diazaspiro [4.5] decan-2 -yl] quinoline-8-carbonitrile (3.0 g) was obtained as a yellow solid and directly used into the next step without further purification.

[0464] LC-MS: MS (ESC): & = 0.482 min, m / z = 307.1 [M + H+]

[0465] Synthesis of Compound 171:

[0466] To a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (5.0 g, 24.8 mmol, 1.0 eq) and 3,6- dichloropyridazine (7.4 g, 49.7 mmol, 2.0 eq) in THF (50 mb) was added dropwise tBuOK (1 M, 37.3 mb,1.5 eq) at 25 °C under N2. After addition, the mixture was stirred at this temperature for 15 min. The resulting mixture was stirred at 60 °C for 4 h under N2. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (150 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. Then the residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 3 / 1). Compound tert-butyl 4-(6-chloropyridazin-3-yl) oxypiperidine- 1 -carboxylate (4.2 g, 13.4 mmol, 53% yield) was obtained as a white solid.

[0467] LC-MS: MS (ESI+): & = 0.574 min, m / z = 258.1 [M - tBu+]

[0468] A mixture of 5-[(3S)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl]quinoline-8-carbonitrile (1.5 g, 4.90 mmol, 1.0 eq), tert-butyl 4-(6-chloropyridazin-3-yl)oxypiperidine-l-carboxylate (2.3 g, 7.34 mmol, 1.5 eq), Xantphos Pd G4 (471 mg, 489 pmol, 0.1 eq), tBuONa (2 M, 7.34 mL, 3.0 eq) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL * 2). The combined organic layers were washed with brine (100 ml * 2), dried over Na2SC>4, 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 1 / 1). Compound tert-butyl 4-[6-[(3S)-2-(8-cyano-5-quinolyl)- 3-methyl-2,8-diazaspiro[4.5]decan-8-yl]pyridazin-3-yl]oxypiperidine-l-carboxylate (1.5 g, 2.57 mmol, 52% yield) was obtained as a yellow solid.

[0469] LC-MS: MS (ESI+): & = 0.504 min, m / z = 584.3 [M + H+]

[0470] To a solution of tert-butyl 4-[6-[(3S)-2-(8-cyano-5-quinolyl)-3-methyl-2,8-diazaspiro [4.5] decan- 8-yl] pyridazin-3-yl] oxypiperidine -1 -carboxylate (1.66 g, 2.84 mmol, 1.0 eq) in DCM (15 mL) was added TLA (6.7 g, 58.9 mmol, 4 mL, 20.7 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give a residue. Compound 5-[(3S)-3-methyl-8-[6-(4-piperidyloxy) pyridazin-3-yl]-2,8- diazaspiro [4.5] decan-2-yl] quinoline-8-carbonitrile (1.38 g) was obtained as a yellow solid and directly used into the next step without further purification.

[0471] LC-MS: MS (ESI+): & = 0.399 min, m / z = 484.2 [M + H+]

[0472] To a solution of 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]cyclohexanecarbaldehyde (199 mg) in DCM (2 mL) was added EtsN (375 mg, 3.71 mmol, 516 pL, 10.0 eq), 5-[(3S)-3-methyl-8-[6-(4- piperidyloxy)pyridazin-3-yl]-2,8-diazaspiro[4.5]decan-2-yl]quinoline-8-carbonitrile (179 mg, 370 pmol, 1.0 eq) and NaBH(OAc)3 (392 mg, 1.85 mmol, 5.0 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm* lOum; mobile phase: [H2O (0.225% LA)-ACN]; gradient: 19%-49% B over 10.0 min). Compound 5-[(3S)-8-[6-[[l-[[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-l-yl] cyclohexyl] methyl] -4-piperidyl] oxy]pyridazin-3-yl]-3-methyl-2,8-diazaspiro [4.5] decan-2-yl] quinoline-8-carbonitrile (171.76 mg, 44% yield over two steps) was obtained as a yellow solid.

[0473] 'H NMR (400 MHz, DMSO = 8.97 - 8.90 (m, 1H), 8.66 - 8.58 (m, 1H), 8.19 (s, 1H), 8.10 -8.00 (m, 1H), 7.75 (s, 1H), 7.55 - 7.47 (m, 2H), 7.36 - 7.30 (m, 1H), 7.09 (s, 1H), 6.96 - 6.63 (m, 4H), 5.04 - 4.86 (m, 1H), 4.37 - 4.24 (m, 1H), 4.21 - 4.08 (m, 2H), 4.06 - 3.92 (m, 2H), 3.86 (s, 3H), 3.76 - 3.66 (m, 2H), 3.61 - 3.53 (m, 3H), 3.45 - 3.41 (m, 4H), 2.87 - 2.82 (m, 3H), 2.80 - 2.63 (m, 3H), 2.38 - 2.32 (m, 1H), 2.18 - 2.05 (m, 6H), 2.02 - 1.93 (m, 5H), 1.92 - 1.76 (m, 6H), 1.75 - 1.61 (m, 4H), 1.50 (s, 3H), 1.41 - 1.33 (m, 1H), 1.22 - 1.13 (m, 3H), 1.09 - 0.95 (m, 2H).

[0474] LC-MS: MS (ESI+): &= 2.617 min, m / z = 1004.8 [M+H+]

[0475] The compounds below were synthesized in a similar manner as described in the Examples.Example A-l: Oral Solution

[0476] To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s), optional buffer(s) and taste masking excipients) to provide a 20 mg / mL solution.Example A-2: Oral Tablet

[0477] A tablet is prepared by mixing 20-50% by weight of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.Example A-3: Oral Capsule

[0478] To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

[0479] In another embodiment, 10-500 mg of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is placed into Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and thecapsule is closed.Example B-l: Ternary Complex Formation AssayPreparation of mouse anti-AR antibody coated 96 well plates

[0480] Black MaxiSorp plates: coat with 50 uL of mouse 1 / 50 diluted AR antibody (Monoclonal Antibody (AR 441 from Thermo Fisher); diluted in phosphate buffered saline (PBS). Spin the liquid to the bottom of the wells, if necessary. Incubate overnight at 4 °C. Next day, wash 3 times with 200 uL of TBST. Block with 200 uL of blocking buffer (5% BSA in TBST) at room temperature for 2 hours (BSA: A4503 or A2153 from Sigma). Wash plates 3 times with TBST. Plates are ready for lysates Preparation of dimerizer treated lysates

[0481] Culture cells in 96 wells at 5 OK VCaP cells / well for at least 3 days. Plate in 5% Omega charcoal stripped FBS in total volume of 200 uL. Treat with bifunctional for 1.5 hours by adding 1 uL of 200x stock in DMSO. Aspirate media / compound. Add and pipet-to-mix 70 uL of lx AlphaLisa Lysis Buffer to each well (Perkin Elmer, AlphaLISA SureFire Ultra, diluted in water). Pipet up and down when adding lysis buffer to disrupt cells. Let lysis proceed for 30 min at 4 °C.Sandwich ELISA

[0482] Transfer 50 uL of lysate to MaxiSorp plates coated with antibody and subsequently blocked with BSA. Incubate for 1 hour at room temperature. Flick out the lysates. Wash 3 times with TBST. Add 75 uL of rabbit CBP or p300 antibody to each well (diluted 1:5000 in blocking buffer (5% BSA in TBST). CBP antibody: (D6C5) Rabbit mAb #7389; p300 antibody: (D8Z4E) Rabbit mAb #86377. Incubate overnight at 4 °C. Wash 3 times with 300uL TBST, each time on shaker for 5-10 min. Prepare goat anti-rabbit antibody conjugated to HRP (1 / 100K dilution in blocking buffer) Invitrogen Catalog number: 32260. Add 75 uL of HRP-conjugated goat anti -rabbit antibody. Incubate at room temperature for 1 hour. Flick out the HRP- antibody mixture. Wash 7-8 times with TBST, each time on shaker for 10 min. Later washes try to overflow the wells so that no residual HRP remains bound to the sides of the well. Prepare and add 75 uL / well of QuantaRed Enhance Chemifluore scent HRP Substrate solution. Immediately read fluorescence on BMG ClarioStar (ex: 570 / em 585), and repeat the read in 5 minutes and 15 minutes.

[0483] Results of the ternary complex formation assay for representative compounds are shown in Table 2.Table 2*A is EC50 <1 nM; B is EC50 >1 nM and <10 nM; C is ECso MO nM and <100 nM; D is EC50 active and>100 nMExample B-2: VCaP Growth Inhibition Assay

[0484] VCaP cells (ATCC Cat#CRL-2876) are plated at IxlO4cells per well of a white plastic 96-well cluster plate (Thermo Scientific Nunc Cat#165306) in lOOuL phenol red-free DMEM (Gibco Cat#21063- 029) media with 5% CSS (Omega Scientific Cat#FB-04). Cluster plates are returned to the incubator (37*C / 5% CO2) for 72 hours prior to treatment. Just prior to treatment, lOOuL of phenol red-free DMEM / 5%CSS and 60pM R1881 (Sigma Cat#R0908-10mg) was added to each well of the cluster plates (Final R1881 concentration = 30pM). Compounds (200X) were added to each well in a volume of luL, with serial dilutions (1:5) from 20uM to 2pM (final concentrations in well are lOOnM to lOfM). Cluster plates are returned to the incubator for 9 days.

[0485] After the 9-day treatment period, media was removed from the cluster plates by inversion and lOOuL room temperature CTG reagent (Promega Cat#G7573) is added to each well. The cluster plates are placed on a shaker and incubated at room temperature for 20 minutes. Following this shaking / incubation, cluster plates are read on a luminometer (BMG ClarioStar). IC50 values are obtained by graphing the RLU data vs. compound concentration with nonlinear regression 4-parameter logistic curves (GraphPad Prism).

[0486] Results of the VCaP growth inhibition assay are shown for representative compounds in Table 3. Table 3** ++++ is IC50 active and > 100 nM; +++ is 100 nM < IC50 > 1 nM; ++ is 1 nM < IC50 > 0.1 nM; + is IC50 <0.1 nMExample B-3: NanoBRET Cellular Assay

[0487] NanoBRET™ Histone H3 3 / CBP-BD Interaction Assay Reagents and FuGENE® HDTransfection Reagents were purchased from Promega. Reference compound SGC-CBP-30 was purchased from MedChem Express. HEK293 cell line was purchased from American Type Culture Collection (Manassas, VA). HEK293 cells were cultured in EMEM media supplemented with 10% FBS, 100 pg / ml ofpenicillin, and 100 pg / ml of streptomycin. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0488] HEK293 cells were transfected with 2 ug of Histone H3.3-HaloTag Fusion Vector DNA plus 0.05 ug of CBP-BD-NanoLuc fusion vector. The transfected cells were treated with NanoBRET™ 618 Ligand and test compounds (starting at 1 uM, 10-dose with 3-fold dilution) or with reference compound SGC-CBP- 30 (starting at 10 uM, 10-dose with 3-fold dilution) for 22 hours. Cellular Histone H3.3 / CBP-BD Interaction was measured by NanoBRET assay. Curve fits were performed only when % NanoBret signal at the highest concentration of compounds was less than 55%.

[0489] Results of the NanoBRET assay are shown in Table 4.Table 4CompoundTransfection for NanoBRET™ Histone H3.3 / CBP-BD Interaction Assay1. Culture HEK293 cells appropriately prior to assay.2. Remove medium from cell flask by aspiration, trypsinize and allow cells to dissociate from the flask bottom.3. Neutralize trypsin using cell culture medium, count cells to estimate density and resuspend to a final density of 4 * 105cells / ml in cell culture medium.4. Plate 2 ml of cells into each well of a six-well plate.5. Allow the cells to attach and recover overnight at 37°C, 5% CO2.6. Prepare a transfection mixture consisting of the following DNA amounts:2pg of Histone H3.3-HaloTag 0.05pg of NanoLuc-CBP-BD7. Add 1 OOpl of Opti-MEM® I Reduced Serum Medium, no phenol red, to the transfection mixture, and mix well.8. Add 8 pl of FuGENE® HD Transfection Reagent and incubate at room temperature for 10 minutes.9. Add transfection mixture to wells with attached cells, and express proteins for 24 hours at 37°C, 5% CO2.Replating Transfected HEK293 Cells into Multiwell Plates and Adding HaloTag® NanoBRET™ 618 Ligand1. For each well in a six-well plate, remove medium from cells, and wash with 1ml of PBS. Discard.2. Add 0.25% trypsin-EDTA and incubate at room temperature until cells lift from well bottom.3. Add cell culture medium to neutralize trypsin, mix to collect and resuspend cells, and transfer cell suspension to a 15ml conical tube.4. Spin cells down at 125 x g for 5 minutes. Discard cell culture medium and resuspend in an equal volume of assay medium (Opti-MEM® I Reduced Serum Medium, no phenol red + 4% FBS).5. Count to estimate cell density and adjust density to 2 x 105cells / ml in assay medium.6. Divide cells into two pools and add HaloTag® NanoBRET™ 618 Ligand or DMSO vehicle as follows: Experimental samples (+ ligand): Add 1 pl of O.lmM HaloTag® NanoBRET™ 618 Ligand per milliliter of cells (100 nM final concentration). No-acceptor controls (- ligand): Add Ipl of DMSO per milliliter of cells (0. 1% DMSO final concentration). Deliver compounds to the 384-well plate with Echo 550.7. For NanoBRET™ measurements with / without compound treatment, dispense 25 pl of each pool of the cells prepared in Step 6 in duplicate to reach the requested final test concentrations (starting at 1 or 10 pM, 10-dose with 3 -fold dilution).8. Incubate plates at 37°C, 5% CO2 22 hours.Adding NanoBRET™ Nano-Gio® Substrate and Taking NanoBRET™ Measurements1. Prepare a 5X solution of NanoBRET™ Nano-Gio® Substrate in Opti-MEM® I Reduced Serum Medium, no phenol red.2. Add substrate to cells and shake plate to mix for 30 seconds.3. Measure donor emission (460nm) and acceptor emission (600nm) within 10 minutes of substrate addition using an Envision 2104 Multilabel Reader.NanoBRET™ Calculations1. Divide the acceptor emission value (e.g., 600nm) by the donor emission value (e.g., 460nm) for each sample to generate raw NanoBRET™ ratio values.2. Determine the mean NanoBRET™ ratio for each set of samples: Experimental samples with HaloTag®NanoBRET™ 618 Ligand and no-acceptor control samples.3. The IC50 curves were plotted and IC50 values were calculated using the GraphPad Prism program based on a sigmoidal dose-response equation.

Claims

CLAIMSWHAT IS CLAIMED IS:A heterobifunctional conditional inhibitor compound of CBP / p300 that has the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:SB-CBP / p300 is a silent binder of human CREB-binding protein (CBP) or human ElA-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:1) a head group A3that occupies the ligand-binding domain (LBD) of AR and is covalently attached to a core moiety; and2) an optional tail moiety covalently attached to the core moiety; wherein the core comprises an optionally substituted spiro bicyclic heterocycloalkyl having the structure of Formula (C):, Formula (C); wherein: the head group A3is covalently attached at position (A); the optional tail moiety comprises a ring D that is covalently attached to the nitrogen (*), 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 s R3; s is 1, 2, or 3; w is 2 or 3; k is 0 or 1; m is 0, 1, 2, or 3; each R2is independently hydrogen, halogen, C1-C6alkyl, C1-C6fluoroalkyl, -CN, OH, -OR4, or - N(R5)2; 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 C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C ,- 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; and wherein 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. 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; 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 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; and w is 2; and s is 1; k is 0; and m is 1; andhydrogen, -CH,. or -CH2CH3; and the head group A3of B-AR forms hydrogen bonds with the side chains of Gin 711 and Arg752 of the LBD of AR. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein SB- CBP / p300 further comprises a moiety that interacts with Argl 173 in the bromodomain of CBP or Asnl 137 in the bromodomain of p300. The compound of claim 2 or 3, 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-CBP / p300 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.

5. The compound of claim 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the acetyl-lysine mimetic moiety that binds in the acetyl-lysine (KAc) binding site of the bromodomain of CBP / p300 comprises: l-(l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-l-one; or N-methyl-l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide; wherein the acetyl-lysine mimetic moiety optionally further comprises:1) a moiety at the 1-position of the l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl group that occupies the lipophilic shelf (LPF) region of the bromodomain of CBP / p300; or2) a moiety that at the 3-position of the l,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl group occupies the BC Loop region of the bromodomain of CBP / p300; or3) both 1) and 2).6 The compound of any one of claims 2-4, 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; is the point of attachment to the optional linker that covalently connects a) to b); or R32comprisesand the optional linker that covalently connects a) to b) is attached to R32; each R28is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, -C(=O)Rb, or -C(=0)N(Rb)2; each R34is independently hydrogen or substituted or unsubstituted C1-C6alkyl; each R35is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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 G-Gcycloalkyl. 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 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 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- substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- 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 , substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted substituted or unsubstituted monocyclic 3- to 8-memberedheterocycloalkyl, 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. The compound of claim 6, 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 C1-C6alkyl, substituted or unsubstitutedsubstituted or unsubstituted stituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstitutedsubstituted or unsubstituted 3- to 12-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;y is 1 or 2;Z is -NRC-, -0-, or -S-;Rcis hydrogen or substituted or unsubstituted C1-C6alkyl;R26is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6lfuoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- Gcycloalkyl, 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 G-Gcycloalkyl. 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 C1-C6alkyl;R29is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-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 bstituted or unsubstituted C1-C6heteroalkyl;C is substituted or unsubstitutedsubstituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rais independently substituted or unsubstituted substituted or unsubstituted C1-substituted or unsubstituted substituted or unsubstituted G-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 substituted or unsubstituted G-C6heteroalkyl, substituted or unsubstituted substituted or unsubstituted monocyclic 3- to 8-memberedheterocycloalkyl, 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.The compound of claim 6 or 7, 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:unsubstituted. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R27is 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 aryl, substituted or unsubstituted heteroaryl, -CN, -OH, or -ORa; and each Rais independently substituted or unsubstituted C1-C6alkyl.

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

12. The compound of any one of claims 9-11, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises13. The compound of claim 9 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein:

14. The compound of claim 9 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein:The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein themoiety comprising an acetyl-lysine mimetic comprises; each R28is independently hydrogen or substituted or unsubstituted C1- C6alkyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic compriseseach 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.

17. The compound of any one of claims 15, or a pharmaceutically acceptable salt or solvate thereof, wherein:

18. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein themoiety comprising an acetyl-lysine mimetic comprises19. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises20. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises:

21. The compound of claim 18 or 20, or a pharmaceutically acceptable salt or solvate thereof, wherein:Tl. The compound of claim 6. 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 C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, or substituted or unsubstituted C1-C6heteroalkyl;R34is hydrogen or substituted or unsubstituted C1-C6alkyl; each R38is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted , substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstitutedsubstituted 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; r is 0, 1, 2, 3, or 4;23. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein the24. The compound of claim 23, or a pharmaceutically acceptable salt or solvate thereof, wherein:

25. The compound of claim 6. or a pharmaceutically acceptable salt or solvate thereof, wherein the moiety comprising an acetyl-lysine mimetic comprises26. The compound of claim 24 or 25, wherein:

27. The compound of any one of claims 2-4, wherein SB-CBP / p300 has the structure of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof:Formula (Illb) wherein: each X is independently -CR27- or -N-; each R27is independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted orunsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C’s-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, -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 C1-C6alkyl, substituted or unsubstituted C1- 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.The compound of any one of claims 2-4, wherein SB-CBP / p300 has the structure of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof:Formula (IIIc) wherein:R26is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- 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, substituted or unsubstituted G-Gcycloalkyl. 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 C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, -C(=O)Ra, or -C(=O)N(Rb)2;Z is -NRC-, -O-, or -S-;Rcis hydrogen or substituted or unsubstituted C1-C6alkyl; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G- 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.

29. The compound of any one of claims 2-4, wherein SB-CBP / p300 has the structure of Formula (Illd- 1) or (IIId-2), or a pharmaceutically acceptable salt or solvate thereof:wherein:R26is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted or substituted or unsubstituted 3- to8-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 G-Gcycloalkyl. 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 C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- Cscycloalkyl, 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 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;Y is -C(R30)2- or C(=O); 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.

30. The compound of any one of claims 2-4, wherein SB-CBP / p300 has the structure of Formula (Hie) , or a pharmaceutically acceptable salt or solvate thereof:Formula (Hie)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, substituted or unsubstituted G-Gcycloalkyl. 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 C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, -C(=O)Rb, or -C(=O)N(Rb)2;R32is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G- Gcycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;Ring A is absent or substituted or unsubstituted G-Gcycloalkyl. substituted or unsubstituted 3- to 8- membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rais independently substituted or unsubstituted G-Galkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted G-C6heteroalkyl, substituted or unsubstituted G- 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 G-Galkyl, substituted or unsubstituted G-Gfluoroalkyl, substituted or unsubstituted G-C6heteroalkyl, substituted or unsubstituted G-C, cycloalkyl. 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.

31. The compound of any one of claims 2-4, wherein SB-CBP / p300 has one of the following structures:

32. The compound of any one of claims 2-4, wherein SB-CBP / p300 has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein:

34. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein:is or35. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein:is36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein: A3is 4-cyanophenyl; 3-fluoro-4-cyanophenyl; 3-chloro-4-cyanophenyl; 3-methoxy-4- cyanophenyl; 3-methyl-4-cyanophenyl; 3-trifluroromethyl-4-cyanophenyl; 3-trifluroromethoxy-4- cyanophenyl; 5-fluoro-6-cyanopyridin-3-yl; 5-chloro-6-cyanopyridin-3-yl; 5-methoxy-6-cyanopyridin-3-yl; 5-methyl-6-cyanopyridin-3-yl; 5-trifluroromethyl-6-cyanopyridin-3-yl; 5- trifhiroromethoxy-6-cyanopyridin-3-yl; [l,2,4]triazolo[4,3-b]pyridazin-6-yl; or 3 -(trifluoromethyl) - [ 1 ,2,4]triazolo [4,3 -b]pyridazin-6-yl .

37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein:each X1is independently -CR1- or -N-;X4is -CR1d- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or - SR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, or -CN; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl, pyridinyl, pyridazinyl, or pyrimidinyl, each of which is optionally substituted with 1 or 2 R1.

38. The compound of claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein: one X1is -CR1- and the other X1is -CR1- or -N-;R1ais -CN; R1bis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; each R1cis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, or -CF3; R1dis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto 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.

39. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein:The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein A3is selected from:each X1is independently -CR1- or -N-;X4is -CRd- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, or -CN; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl or pyridinyl optionally substituted with 1 or 2 R1; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; and each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl.

41. The compound of any one of claims 1 -35, or a pharmaceutically acceptable salt or solvate thereof, wherein A3is selected from:each X1is independently -CR1- or -N-;X4is -CRd- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or -SR4; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl or pyridinyl optionally substituted with 1 or 2 R1; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; and each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl.The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein A3is selected from:one X1is -CR1- and the other X1is -CR1- or -N-; R1ais -CN, -NO2, -C(=O)NH2or -C(=O)NH(CH3); R1bis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, -OCH2CH3or -CN; each R1cis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, or -CF3; each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, -CH2CF3, -OH, -OCF3, -OCH3, or -OCH2CH3.

43. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein A3is selected from:

44. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein A3is:

45. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein A3is:

46. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof,wherein the head group and core of B-AR is:

47. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein the head group and core of B-AR is:

48. The compound of claim 46 or 47, wherein:B-AR further comprises a tail moiety that is covalently attached to position (*), wherein the tail moiety is a 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 s R3; s is 1, 2, or 3; each R3is independently hydrogen, F, Cl, Br, I, -CH3, -CDs, - CH2CH3, -CH2F, -CHF2, -CFS, -CH2CH2F, -CH2CHF2, - CH2CFS, -OH, -OCFS, -OCHS, -OCH2CHS OCDs, -OCH2CDS, -CN, -C(=O)NH2, -C(=O)NH(CHS), or -C(=O)NH(CD3).

49. The compound of claim 48, wherein ring D is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein ring D is optionally substituted with s R3; s is 1, 2, or 3; each R3is independently hydrogen, F, Cl, Br, I, -CH3, -CDs, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, - CH2CHF2, - CH2CF3, -OH, -OCFS, -OCH3, -OCH2CH3, -OCDS, -OCH2CD3, or -CN.

50. The compound of any one of claims 47-49, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR further comprises a tail moiety that is covalently attached to position (*), wherein the51. The compound of any one of claims 47-49, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR further comprises a tail moiety that is covalently attached to position (*), wherein theeach R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1- C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2.

52. The compound of claim 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has one of the following structures:

53. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has the structure of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof:Formula (Va) wherein: each X is independently -CR3- or -N-; R1ais -CN; R1bis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or -CN; R1dis hydrogen, F, Cl, Br, I, -CH3, -CH2F, -CHF2, or -CF3; each R2is -CH3; 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 C1-C6alkyl, or C1-C6fluoroalkyl; each R5is independently hydrogen, substituted or unsubstituted C1-C6alkyl, C1-C6fluoroalkyl.

54. The compound of claim 53, or a pharmaceutically acceptable salt or solvate thereof, wherein: R1bis hydrogen, F, Cl, -CH3, -CF3, -OCF3, or -OCH3;R1dis hydrogen, F, Cl, -CH3, or -CF3.

55. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein B-AR has the structure of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof:Formula (IVb) wherein: each X is independently -CR3- or -N-; each R1is 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); each R2is hydrogen or C1-C4alkyl; each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1- C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2; each R4is independently C1-C4alkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl; and m is 0, 1, or 2.

56. The compound of claim 55, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R1is independently hydrogen, F, Cl, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3.

57. The compound of any one of claims 53-56, or a pharmaceutically acceptable salt or solvate thereof,Z R3Cl each 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.

58. A heterobifunctional conditional inhibitor compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I), wherein:SB-CBP / p300 has the structure:R28is -C(=O)CH3, -C(=O)CH2CH3, -C(=O)NH2, -C(=O)NH(CH3), or -C(=O)NH(CH2CH3); each R35is independently hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl; m is 0, 1, 2, 3, or 4;R32is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3- C12cycloalkyl, or substituted or unsubstituted 3- to 12-membered heterocycloalkyl, wherein L is covalently attached to R32if R26or R27are not L; or R32is L if R26or R27are not L;p is 0, 1, 2, or 3;X2is -CR30- or N, wherein at most two X2are -N-; X3is -CR27- or -N-;Z1is -NRC- or -O-; Rcis hydrogen or C1-C6alkyl;R27is hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-Cscycloalkyl, 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;R26is hydrogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-Cscycloalkyl, or substituted or unsubstituted 3- to 8-membered heterocycloalkyl; or R26is L if R32or R27are not L; or R27is L if R26or R32are not L; each R30is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, -CN, -OH, or -ORa; q is 0, 1, 2, 3, or 4; each Rais independently C1-C4alkyl, C1-C6fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl,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- C6cycloalkyl, 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;attached at position (A), and L is attached at position * ; each X1is independently -CR1- or -N-; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or - OR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, or -CN; each R1is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1- C4fluoroalkyl, -CN, -OH, or -OR4; each R2is hydrogen or C1-C4alkyl; each X is independently -CR3- or -N-; each R3is independently hydrogen, halogen, substituted or unsubstituted C1-C4alkyl, C1- C4fluoroalkyl, -CN, -OH, -OR4, or -N(R5)2; each R4is independently substituted or unsubstituted C1-C4alkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, substituted or unsubstituted C1-C4alkyl, C1-C4fluoroalkyl; and each s is 1, 2, or 3.

59. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein: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, wherein L is covalently attached to R32if R26or R27are not L; or R32is L if R26or R27are not L;R27is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3- Cscycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CN, - OH, or -ORa; each Rais independently substituted or unsubstituted C1-C6alkyl;or R26is L if R32or R27are not L; or R27is L if R26or R32are not L.

60. The compound of claim 58, 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;substituted 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.

61. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein:wherein L is covalently attached to the nitrogen of R32group if R26orR27are not L; or R32is L if R26or R27are not L;The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein:is the point of attachment to the optional linker.

63. The compound of any one of claims 58-62, or a pharmaceutically acceptable salt or solvate thereof, wherein the head group is:R1bis hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, -OCH2CH3, -OCD3, -OCH2CD3, or -CN; R1cis hydrogen, F, Cl, Br, -CH3, -CD3, -CH2F, -CHF2, or -CF3; each R1is independently hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, -CH2CF3, -OH, -OCF3, -OCH3, -OCD3, or -OCH2CH3.

64. The compound of any one of claims 58-62, or a pharmaceutically acceptable salt or solvate thereof, wherein the head group is selected from:

65. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein:with F, -CH3, -CH2F, -CHF2, or -CF3, wherein L is covalently attached to the nitrogen of the R32group if R26or R27are not L; or R32is L if R26or R27are not L;at least one X2is -CR30- and at most two X2are -N-;X3is -CR27- or -N-;R27is hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3- C6cycloalkyl, 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;or R27is L if R26or R32are not L;R26is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl. or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R26is L if R32or R27are not L; each R30is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -ORa; Rais C1-C4alkyl;each R2is hydrogen or -CH3; each R3is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, -OCH3, or - CN.

66. The compound of claim 65, or a pharmaceutically acceptable salt or solvate thereof, wherein:

67. The compound of any one of claims 65-66, or a pharmaceutically acceptable salt or solvate thereof, wherein:wherein L is covalently attached to the nitrogen of the R32group ifR26or R27are not L; or R32is L if R26or R27are not L; 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-;R27is hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3- C6cycloalkyl, 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;or R27is L if R26or R32are not L;R26is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, substituted or unsubstituted C3-C6cycloalkyl. or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R26is L if R32or R27are not L;and each R30is independently hydrogen, halogen, C1-C4alkyl, C1-C4fluoroalkyl, -CN, -OH, or -ORa.

68. The compound of any one of claims 65-66, or a pharmaceutically acceptable salt or solvate thereof, wherein:Z1is -NH- or -O-; is the point of attachment to the optional linker.

69. The compound of claim 58 or 63-68, wherein SB-CBP / p300 has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

70. The compound of any one of claims 58 or 63-67, wherein SB-CBP / p300 has one of the following structures:salt or solvate thereof.

71. The compound of any one of claims 58 or 63-67, or a pharmaceutically acceptable salt or solvate thereof, wherein SB-CBP / p300 has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

72. The compound of any one of claims 58 or 63-67, or a pharmaceutically acceptable salt or solvate thereof, wherein SB-CBP / p300 has one of the following structures:pharmaceutically acceptable salt or solvate thereof.

73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent.

74. The compound of any one of claims 1-72, 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- C1ocycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or combinations thereof.

75. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof, wherein L is absent or, wherein: each A is independently absent, substituted or unsubstituted monocyclic C3-C1ocycloalkyl, substituted or unsubstituted bridged bicyclic C3-C1ocycloalkyl, substituted or unsubstituted fused bicyclic C3-C1ocycloalkyl, substituted or unsubstituted spiro bicyclic C3-C1ocycloalkyl, 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, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, or substituted or unsubstituted Cs-C6cycloalkyl; and each R2bis independently hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6fluoroalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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);each 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 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.

76. The compound of claim 75, or a pharmaceutically acceptable salt or solvate thereof, wherein:independently unsubstituted or substituted with x R2b;The compound of claim 76, or a pharmaceutically acceptable salt or solvate thereof, wherein:

78. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof, wherein L has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.

79. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof, wherein L has one of the following structures:or a pharmaceutically acceptable salt or solvate thereof.The compound of any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof, wherein L has one of the following structures:acceptable salt or solvate thereof.

81. The compound of any one of claims 1 -72, or a pharmaceutically acceptable salt or solvate thereof, wherein L has one of the following structures:solvate thereof.

82. A compound that is a heterobifunctional conditional inhibitor of CBP / p300 that has the structure of Formula (VI):pharmaceutically acceptable salt or solvate thereof, wherein,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 C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, substituted or unsubstituted C’s-Cscycloalkyl. or substituted or unsubstituted 3- to 8-membered heterocycloalkyl;X3is -CR27- or -N-;R27is hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, substituted or unsubstituted G-Gcycloalkyl. 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 C1-C6heteroalkyl, -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 C2- C1ocycloalkyl, 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, C1-C4alkyl, C1-C4deuteroalkyl, C1-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 G-Gcycloalkyl. 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 C3Gcycloalkyl. 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.each X1is independently -CR1- or -N-;X4is -CR1d- or -N-; each R1is independently hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; R1ais -CN, -NO2, -C(=O)R5, -C(=O)OR5, or -C(=O)N(R5)2; R1bis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, -OR4, or - SR4; R1cis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, or -CN; R1dis hydrogen, halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4fluoroalkyl, -CN, -OH, or -OR4; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto form a phenyl, pyridinyl, pyridazinyl, or pyrimidinyl optionally substituted with 1 or 2 R1; each X is independently -CR3- or -N-; 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 C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl; each R5is independently hydrogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4fluoroalkyl;83. The compound claim 82, or a pharmaceutically acceptable salt or solvate thereof, wherein:

84. The compound of claim 82 or 83, or a pharmaceutically acceptable salt or solvate thereof, wherein: one X1is -CR1- and the other X1is -CR1- or -N-; R1ais -CN; R1bis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; each R1cis hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, or -CF3; R1dis hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -OH, -OCF3, or -OCH3; or R1band R1dare taken together with the intervening carbon atoms between R1band R1dto 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.

5. The compound of any one of claims 82-84, or a pharmaceutically acceptable salt or solvate thereof,each R3is independently hydrogen, F, Cl, Br, I, -CH3, -CD3, -CH2CH3, -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, - CH2CF3, -OH, -OCFs, -OCHs, -OCH2CH3, -OCDs, -OCH2CD3, -CN, -NH2-NH(CHs), -NH(CH3)2, -NH(CDS) or -N(CD3)2.

86. The compound of any one of claims 82-84, or a pharmaceutically acceptable salt or solvate thereof,each R3is independently hydrogen, F, Cl, -CH3, -CDs, -CH2F, -CHF2, -CFs, -OH, -OCF3, -OCH3, - OCD3, or -CN.

87. The compound of any one of claims 82-86, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R30is independently hydrogen, F, Cl, Br, I, -CH3, -CDs, -CFs, -CH2F, -CHF2, -CH2CH3, - CD2CH3, -CH2CD3, - CD2CD3, -CH2CF3, -CF2CF3, -CH2CH2F, -CH2CHF2, -OCHs, -OCDs, -OCFs -OCH2F, -OCHF2, -OCH2CH3, -OCD2CH3, -OCH2CD3, -OCD2CD3, -OCH2CF3, -OCF2CF3, - OCH2CH2F, -OCH2CHF2, or -CN.

88. The compound of claim 87, or a pharmaceutically acceptable salt or solvate thereof, wherein:

89. The compound of any one of claims 82-88, 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; or90. The compound of any one of claims 82-88, 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 .

91. The compound of any one of claims 82-88, 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(CHS), -C(=O)NH(CDS), -C(=O)NH(CFS), -C(=O)NH(CH2F), -C(=O)NH(CHF2), -C(=O)NH(CHS), -C(=O)NH(CH2CHS), -C(=O)NH(CD2CDS), -C(=O)NH(CH2CFS), -C(=O)NH(CF2CFS), -C(=O)NH(CH2CH2F), or -C(=O)NH(CH2CHF2); orR26is hydrogen, -CHs, -CH2CH3, -CH2(CHs)2, -(CHs)3, -CDs, -CFs, -CH2F, -CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

92. The compound of any one of claims 82-91, or a pharmaceutically acceptable salt or solvate thereof, wherein:R30is hydrogen, -CH3, -CDs, -CFs, -CH2F, -CHF2, or -CN.

93. The compound of any one of claims 82-86, or a pharmaceutically acceptable salt or solvate thereof, wherein:

4. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:or cyclopropyl;R2a, or R2a, R2ais hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, or cyclopropyl.

95. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:

96. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:

97. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:

98. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:

99. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:

100. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:or a pharmaceutically acceptable salt or solvate thereof.

101. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:

102. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:

103. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvatethereof, wherein: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.

104. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvate thereof, wherein:

105. The compound of any one of claims 82-93, or a pharmaceutically acceptable salt or solvateor a pharmaceutically acceptable salt or solvate thereof.

107. A ternary complex comprising: a. CBP / p300; b. Androgen receptor (AR); and c. a heterobifunctional conditional inhibitor compound of any one of claims 1-106, wherein CBP / p300 and AR are present in a cell of interest (COI) and the relative abundance of AR in the COI is greater than the relative abundance of CBP / p300 in the COI.

108. A method of selectively inhibiting the activity of CBP / p300 in a cell of interest (COI) of a mammal comprising administering a compound of any one of claims 1-106, or a pharmaceutically acceptable salt or solvate thereof, wherein the COI expresses the androgen receptor (AR).

109. The method of claim 108, wherein the compound of any one of claims 1-106, or a pharmaceutically acceptable salt or solvate thereof, inhibits the activity of CBP / p300 in the COI but does not inhibit the activity of CBP / p300 in cells expressing CBP / p300 and not expressing the AR.

110. The method of claim 109, wherein AR is overexpressed, overactive or both overexpressed andoveractive in the COI.

111. 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 1-106, or a pharmaceutically acceptable salt or solvate thereof.

112. The method of claim 111, wherein the cancer is an androgen dependent cancer.

113. The method of claim 111, wherein the cancer is prostate cancer.

114. 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 1-106, or a pharmaceutically acceptable salt or solvate thereof.

115. The method of claim 114, wherein 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.

116. A pharmaceutical composition comprising a compound of any one of claims 1-106, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

Images