CBP / p300 degraders and therapeutic uses thereof

Abstract

This disclosure relates to compounds having a structure of Formula (I): that act as degraders of CBP / p300, pharmaceutical formulations thereof, and methods of using the compounds to treat diseases and disorders, such as cancer and cancer-related diseases and disorders.

Description

CBP / P300 DEGRADERS AND THERAPEUTIC USES THEREOFFIELD[1] This disclosure relates to compounds that act as degraders of CBP / p300, pharmaceutical formulations thereof, and methods of using the compounds to treat diseases and disorders, such as cancer and cancer- related diseases and disorders.BACKGROUND[2] Prostate cancer is the most commonly diagnosed cancer type and the second leading cause of cancer- related death in American men (Siegel, et al., Ca-Cancer J. Clin. 2023, 73 (1 ), 17-48.). The majority of prostate cancers expresses the androgen receptor (AR) (Dewinter, et al. Am. J. Clin. Pathol. 1994, 144 (4), 735-746.; Chodak, et al. J. Urol. 1992, 147 (3 Part 2), 798-803.; Sadi, et al. Cancer 1991, 67 (12), 3057-3064.) and depends on AR signaling for growth and progression (Heinlein, et al. Endocr. Rev. 2004, 25 (2), 276-308.; Lonergan, et al. J. Carcinog. 2011, 10 (20), 1-12.; Fujita, et al. World J. Mens Health 2019, 37 (3), 288-295.). Anti-androgen therapies, which reduce the production of endogenous androgen or block the activity of AR receptor, can significantly slow down progression of the disease (de Bono, et al. N. Engl. J. Med. 2011, 364 (21), 1995-2005.; Chen, et al. Cell Death Dis. 2022, 13 (7), 632.). However, most advanced prostate cancers (APC), particularly castration-resistant prostate cancer (CRPC), will develop resistance to current anti-androgen therapies (Huang, et al. Front. Oncol. 2022, 12, 865350.). Some of the major resistance mechanisms include AR gene amplification, AR point mutations in the ligand-binding domain (LBD), expression of constitutively active AR splice variants (ARV), and upregulated expression of the coactivators of AR such as CREB-binding protein (CBP) / E1 A binding protein (p300) (Chen, et al. Cell Death Dis. 2022, 13 (7), 632.; Huang, et al. Front. Oncol. 2022, 12, 865350.; Galletti, et al. Cancer Treat. Rev. 2017, 57, 16-27.; Comuzzi, et al. J. Pathol. 2004, 204 (2), 159-166.; Waddell, et al. Cancers 2021, 13 (12), 2872.; Debes, et al. Cancer Res. 2003, 63 (22), 7638-7640.; Pan, et al. Clin. Cancer Res. 2021, 27 (7), 2087-2099.). When patients progress to second-generation AR targeting therapies, there are very limited treatment options (Chen, et al. Cell Death Dis. 2022, 13 (7), 632.). Consequently, there is a need to develop novel therapeutic strategies for prostate cancer patients who become resistance to current anti-androgen therapies (Chen, et al. Cell Death Dis. 2022, 13 (7), 632.; Huang, et al. Front. Oncol. 2022, 12, 865350.; Welti, et al. CancerDiscov. 2021, 11 (5), 1118-1137.).[3] The transcriptional activity of AR in prostate cancer relies on numerous coactivators(Culig, et al. World J. Urol. 2012, 30 (3), 297-302.). CBP and its homologue p300, often termed as CBP / p300 together due to their high sequence similarity and functional overlap, serve as critical transcriptional coactivators of AR (Comuzzi, et al. J. Pathol. 2004, 204 (2), 159-166.; Waddell, et al. Cancers 2021, 13 (12), 2872.; Chen, et al. Theranostics 2022, 12 (11 ), 4935-4948.). These proteins are highly expressed in human prostate cancer and their expressions are positively associated with AR signaling in prostate cancer (Comuzzi, et al. J. Pathol. 2004, 204 (2), 159-166.; Debes, et al. Cancer Res. 2003, 63 (22), 7638-7640.; Welti, et al. Cancer Discov. 2021, 11 (5), 1118-1137.). CBP / p300 is upregulated following androgen deprivation, and this upregulation is thought to be closely related toendocrine resistance (Comuzzi, et al. J. Pathol. 2004, 204 (2), 159-166.). Knockdown of CBP / p300 leads to a significant anti-proliferative effect in CRPC cell lines (Welti, et al. Cancer Discov. 2021, 11 (5), 1118-1137.), while pharmacological inhibition of the CBP / p300 functions has been found to cause tumor suppression in preclinical models of APC (Jin, et al. Cancer Res. 2017, 77 (20), 5564-5575.; Xiang, et al. J. Med. Chem. 2021,65. 785-810.; Lasko, et al. Nature 2017, 550 (7674), 128-132.; Kanada, et al. J. Med. Chem. 2022, 66, 695-715.). Taken together, these observations suggest that targeting CBP / p300 represents a promising therapeutic strategy for the treatment of advanced prostate cancer, including CRPC.[4] CBP / p300 contain a number of domains and both the bromodomain reader domain and histone acetyltransferase (HAT) domain have been extensively explored for the design of small-molecule inhibitors targeting CBP / p300 (Welti, et al. Cancer Discov. 2021, 11 (5), 1118-1137.; Jin, et al. CancerRes. 2017, 77 (20), 5564-5575.; Xiang, et al. J. Med. Chem. 2021, 65, 785-810.; Lasko, et al. Nature 2017, 550 (7674), 128-132.; Kanada, et al. J. Med. Chem. 2022, 66, 695-715.; Rasool, et al. Cancer Discov. 2021, 11 (5), 1011-1013.; He, et al. Eur. J. Med. Chem. 2021, 209, 112861.; Cochran etal. Nat. Rev. Drug Discov. 2019, 18 (8), 609-628.; Liu, et al. J. Med. Chem. 2023, 66 (3), 1678-1699.). A large number of CBP / p300 bromodomain inhibitors have been reported, including CBP30 (Hay, et al. J. Am. Soc. Chem. 2014, 136 (26), 9308-9319.; Hammitzsch, et al. Proc. Natl. Acad. Sci. 2015, 112 (34), 10768-10773.), I-CBP112 (Picaud, et al. CancerRes. 2015, 75 (23), 5106- 5119.), GNE-049 and its analogue GNE-781 (Romero, et al. J. Med. Chem. 2017, 60 (22), 9162-9183.), CCS1477 (Welti, et al. Cancer Discov. 2021, 11 (5), 1118-1137.) and Y08284 (Xiang, etal. J. Med. Chem. 2021,65. 785-810.). A number of CBP / p300 HAT domain inhibitors such as C646 (Bowers, et al. Chem. Biol. 2010, 17(5), 471-482.), A-485 (Lasko, et al. Nature 2017, 550 (7674), 128-132.; Michaelides, et al. ACS Med. Chem. Lett. 2018, 9, 28.), B026 (Liu, et al. J. Med. Chem. 2023, 66 (3), 1678-1699.) and DC-9300 (Kanada, et al. J. Med. Chem. 2022, 66, 695-715.) have also been discovered. To date, two bromodomain inhibitors, CCS1477 (Welti, et al. Cancer Discov. 2021, 11 (5), 1118-1137.) from CellCentric and FT-7051 (Armstrong et al. Mol. Cancer Ther. 2021, 20 (12_Supplement), P202-P202.) from Forma Therapeutics, have been advanced into human clinical trials for the treatment of human cancers, including prostate cancer.[5] In recent years, induced protein degradation using the proteolysis targeting chimera (PROTAC) technology has become a powerful strategy for the discovery and development of potential new therapies (Li, et al. Mol. Cancer 2022, 21 (1), 99.; Li, et al. Chem. Sci. Rev. 2022, 51 (12), 5214-5236.; Bekes, et al. Nat. Rev. Drug Discov. 2022, 21, 181-200.; Chimomas, et al. Nat. Rev. Clin. Oncol. 2023, 20 (4), 265-278.; Zhou, et al. Eur. J. Med. Chem. 2020, 203, 112539.). A number of heterobifunctional PROTAC degraders of CBP / p300, including dCBP-1, JET-209, and JQAD1 (Figure 1), have been reported (Vannam, et al. Cell Chem. Biol. 2021, 28, 503- 514.; Thomas, et al. J. Med. Chem. 2023, 66 (12), 8178-8199; Durbin, et al. Cancer Discov. 2022, 12 (3), 730- 751.). To date, no orally bioavailable CBP / p300 degrader has been reported (Vannam, et al. Cell Chem. Biol. 2021, 28, 503-514.; Thomas, et al. J. Med. Chem. 2023, 66 (12), 8178-8199; Durbin, et al. Cancer Discov. 2022, 12 (3), 730-751.). In addition, the therapeutic potential of CBP / p300 degraders has not been evaluated inprostate cancer models. Thus, a need exists for CBP / p300 degraders which may be useful in treating, e.g., prostate cancer, and may be orally bioavailable.SUMMARY[6] Provided herein are compounds having a structure of Formula (I):or pharmaceutically acceptable salts thereof, wherein: Ring A is a 4-15-membered monocyclic, bicyclic, spiro, or bridged ring; R1is H, C1-6alkyl, or halo; R2is H, Ci-ealkyl, C1-6haloalkyl, or halo; R3is H, halo, C1-6alkyl, C3- iocycloalkyl, 3-10 membered heterocycle having 1 , 2, or 3 ring heteroatoms independently selected from N, 0, and S, C6-10aryl, or 5-10 membered heteroaryl having 1 , 2, or 3 ring heteroatoms independently selected from N, 0, and S, and the cycloalkyl, heterocycle, or heteroaryl is substituted with 0-3 Ra; each Rais independently Ci-6alkyl; L is C0-4alkylene, C(0)- C0-4alkylene, Co^alkylene-NH, C(0)- C0-4alkylene-NH, C0-4alkylene-3-10 membered heterocycle, or C(0) C0-4alkylene-3-10 membered heterocycle, the heterocycle having 1 or 2 ring nitrogen atoms;X is CH or N; and Y is CH2 or C(O).[7] Further provided herein are pharmaceutical compositions comprising the compounds as disclosed herein. Also provided are methods of treating or preventing a disease or disorder associated with the CBP / p300 transcriptional co-activators of the androgen receptor in a subject, comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein.[8] Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description, taken in conjunction with the drawings. While the compounds and methods disclosed herein are susceptible of cases in various forms, the description hereafter includes specific cases with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific cases described herein.BRIEF DESCRIPTION OF THE DRAWINGS[9] FIGURE 1 shows representative, previously published CBP / p300 degraders.

[0010] FIGURE 2 shows the concentration-dependent degradation of CBP / p300 induced by compound 17 in AR+ VCaP, LNCaP and 22Rv1 prostate cancer cell line with a 4 hour treatment time.

[0011] FIGURE 3 shows the cell viability of VCaP and 22Rv1 cells after exposure to compound 17 and control compounds at various concentrations, after 4 days.

[0012] FIGURE 4 shows proteomics analysis of more than 6700 proteins after the treatment of compound 17 in VCaP cells after 4 hr.

[0013] FIGURE 5 shows the suppression of CBP / p300 regulated gene transcription of KLK3, AR, and c-Myc induced by compound 17 (called CBPD-409 in the figure) and control compounds in AR+ prostate cancer cell lines VCaP, LNCaP, and 22Rv1 at 6 h.

[0014] FIGURE 6 shows (A) CBP degradation by compound 17 (called CBPD-409 in figure) in VCaP tumor tissue; and (B) P300 degradation by compound 17 in VCaP tumor tissue.

[0015] FIGURE 7 shows the anti-tumor efficacy of compound 17 in VCaP xenograft mouse model, with Enzalutamide, CCS1477 and GNE-049included as the controls. (A) Tumor growth for each group. (B) Tumor volume increase for each group at the end of treatment (day 63). A method of two-tailed unpaired t test was used for calculating the statistical significance of the tumor volumes between groups. P < 0.05; P < 0.01 ; “***”, P < 0.001 ; “****”, P < 0.0001. (C). Summary of antitumor activity for each group at the end of the treatment. (D) Animal body weight for each group.DETAILED DESCRIPTION

[0016] Provided herein are compounds that can act as degraders of CBP / p300, such as compounds of Formulaand pharmaceutically acceptable salts thereof wherein ring A, R1, R2, R3, L, X, and Y are as described herein.Compounds of the Disclosure

[0017] Disclosed herein are compounds having a structure of Formula (I):and pharmaceutically acceptable salts thereof wherein:Ring A is a 4-15-membered monocyclic, bicyclic, spiro, or bridged ring;R1is H, C1-6alkyl, or halo;R2is H, C1-6alkyl, C1-6haloalkyl, or halo;R3is H, halo, C1-6alkyl, C3-10cycloalkyl, 3-10 membered heterocycle having 1 , 2, or 3 ring heteroatoms independently selected from N, 0, and S, C6-10aryl, or 5-10 membered heteroaryl having 1 , 2, or 3 ring heteroatoms independently selected from N, 0, and S, and the cycloalkyl, heterocycle, or heteroaryl is substituted with 0-3 Ra; each Rais independently C1-6alkyl;L is C0-4alkylene, C(0)- C0-4alkylene, C0-4alkylene-NH, C(0)- C0-4alkylene-NH, C0-4alkylene-3-10 membered heterocycle, or C(O) C0-4alkylene-3-10 membered heterocycle, the heterocycle having 1 or 2 ring nitrogen atoms;X is CH or N; andY is CH2or C(0).

[0018] In various cases, L is C(O)- C0-4alkylene-NH or Co-4alkylene-3-10 membered heterocycle, the heterocycle having 1 or 2 ring nitrogen atoms. In various cases, L is C(O)- C1-4alkylene-NH. In various cases, L is

[0019] For the compounds disclosed herein, ring A is a 4-15-membered monocyclic, bicyclic, spiro, or bridged ring, which can be carbocyclic (i.e., X is CH and no other ring atoms are heteroatoms) or can be heterocyclic (having one or more heteroatoms, e.g., 1 to 4, in the ring, and X can be either CH or N), where the ring heteroatoms, other than X being N, can independently be selected from N, 0, and S. In some cases, ring A is carbocyclic. In some cases, ring A is heterocyclic having 1 to 4 ring heteroatoms selected from N, 0, and S (with the proviso that if X is a heteroatom, it is only N). In various cases, ring A is a 6-membered monocyclic ring. In various cases the compound has a structure of Formula (II):

[0020] In various cases, ring A is an 8-15-membered spiro ring. In various cases, the compound has a structure of Formula (III):wherein each of m, n, 0, and p is independently 1 , 2, or 3.

[0021] In various cases, the compound has a structure of Formula (IV):

[0022] In various cases, the compound has a structure of Formula (V):

[0023] In various cases, X is CH. In various cases, X is N.

[0024] In various cases, the compound has a structure of Formula (VI):

[0025] In various cases, R1is H, CH3, or halo. In various cases, R1is H. In various cases, R1is F.

[0026] In various cases, R2is CHF2, CF3, CH3, H, or halo. In various cases, R2is CHF2.

[0027] In various cases, R3is 5-10 membered heteroaryl substituted with 0-3 Ra. In various cases, R3is pyrazolyl substituted with 0 or 1 Ra. In various cases, R3is

[0028] In various cases,

[0029] In various cases, Y is C(O). In various cases, Y is CH2.

[0030] In various cases,

[0031] Compounds as disclosed herein include those as provided in Table A, or a pharmaceutically acceptable salt thereof.Table A.

[0032] In some cases, a compound as disclosed herein is selected from the group consisting ofor a pharmaceutically acceptable salt of any of the foregoing.

[0033] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure. For example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this disclosure, unless only one of the isomers is specifically indicated. Therefore, single stereochemical Isomers as well as enantiomeric, diastereomeric, cis / trans, conformational, and rotational mixtures of the present compounds are within the scope of the disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein can exist as a single stereoisomer, or as a mixture of stereoisomers. Stereochemistry of the compounds shown herein indicate a relative stereochemistry, not absolute, unless discussed otherwise. As indicated herein, a single stereoisomer, diastereomer, or enantiomer refers to a compound that is at least more than 50% of the indicated stereoisomer, diastereomer, or enantiomer, and in some cases, at least 90% or 95% of the indicated stereoisomer, diastereomer, or enantiomer.

[0034] The compounds disclosed herein that have a double bond can exhibit E or Z (not shown) stereochemistry. In some cases, the compounds of Formula (I) exhibit E stereochemistry. In various cases, the compounds of Formula (I) exhibit Z stereochemistry at the double bond. The compounds of Formula (I) can have any stereochemical configuration at any sp3carbon atoms. In some cases, the compounds of the disclosure are optically pure. As used herein, “optically pure” refers to the predominant presence of one enantiomer of a compound if multiple stereochemical configurations can exist (e.g., at least 99% enantiomeric excess).

[0035] Unless otherwise indicated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0036] The compounds of the disclosure are defined herein by their chemical structures and / or chemical names. Where a compound Is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0037] The present disclosure encompasses any compound being isotopically-labelled (e.g., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H (or deuterium (D)),3H,11C,13C,14C,15N,180,170,31P,32P,35S,18F, and “Cl. In some cases, substantially all of the atoms at a position within the compound are replaced by an atom having a different atomic mass or mass number. In some cases, a portion of the atoms at a position within the compound are replaced, i.e., the compound is enriched at a position with an atom having a different atomic mass or mass number. Isotopically-labelled compounds can be prepared by methods known in the art.

[0038] As used herein, the term “alkyl" refers to straight chained and branched saturated hydrocarbon groups containing one to thirty carbon atoms, for example, one to twenty carbon atoms, or one to ten carbon atoms. The term Cnmeans the alkyl group has “n” carbon atoms. For example, Cealkyl refers to an alkyl group that has 6 carbon atoms. Cualkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (i.e., 1 to 6 carbon atoms), as well as all subgroups (e.g., 1-5, 2-5, 3-6, 1, 2, 3, 4, 5, and 6 carbon atoms). Nonlimiting examples of alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2- methylpropyl), and t-butyl (1 ,1-dimethylethyl). Unless otherwise indicated, an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.

[0039] As used herein, the term “alkylene” refers to a bivalent saturated aliphatic radical. The term Cnmeans the alkylene group has "n" carbon atoms, e.g., a C-ialkylene is CH2. For example, Ci^alkylene refers to an alkylene group having a number of carbon atoms encompassing the entire range, as well as all subgroups, as previously described for "alkyl" groups. Co alkylene refers to a direct bond - i.e., Coalkyiene-C(0)NH2refers to a C(O)NH2moiety where the carbonyl of the amide is the point of attachment.

[0040] As used herein, the term "heterocycle" refers to a non-aromatic ring which contains one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur. Additionally, heterocycles of the disclosure can be monocyclic, bicyclic, bridged, fused or spirocyclic. For example, a heterocycle can be a monocyclic, bicyclic, bridged, fused, or spirocyclic 4-15 membered ring having 1 or 2 or 3 or 4 heteroatoms selected from N, 0, and S. As another example, a heterocycle can be a 8-15 membered bicyclic, bridged, fused, or spirocyclic group having 1 or 2 or 3 or 4 ring heteroatoms selected from N, 0, and S in the bicyclic ring. Nonlimiting examples of heterocycle groups include piperidine, piperazine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, oxazepane, thiazole, pyrrole, and pyridine.

[0041] As used herein, the term "heteroaryl" refers to a cyclic aromatic ring having heteroatoms in the ring (e.g., a monocyclic aromatic ring with 5-6 total ring atoms, or a fused bicyclic ring with 10 total ring atoms), and containing one to three heteroatoms selected from nitrogen, oxygen, and sulfur atom in the aromatic ring.Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted. Heteroaryl groups can be isolated (e.g., pyridyl) or fused to another heteroaryl group (e.g., purinyl), a cycloalkyl group (e.g.,tetrahydroquinolinyl), a heterocycle group (e.g., dihydronaphthyridinyl), and / or an aryl group (e.g., benzothiazolyl, quinolyl, Isoqulnolinyl, orquinazolinyl).

[0042] As used herein, the term “halo” refers to refers to a fluoro (F), chloro (Cl), bromo (Br), or iodo (I) group.

[0043] As used herein, the term “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. In some cases, all hydrogen atoms are replaced with a halogen (i.e., a perhaloalkyl). Non-limiting examples of haloalkyl groups include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1- difluoroethyl, 2-fluoroethyl, 1 -chloro-2-fluoromethyl and 2-fluoroisobutyl.Pharmaceutically Acceptable Salts

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.

[0045] Pharmaceutically acceptable salts are well known In the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

[0046] Where the compound described herein contains a basic group, or a sufficiently basic bioisostere, acid addition salts can be prepared by 1) reacting the purified compound in its free-base form with a suitable organic or inorganic acid and 2) isolating the salt thus formed. In practice, acid addition salts might be a more convenient form for use and use of the salt amounts to use of the free basic form.

[0047] Examples of pharmaceutically acceptable, non-toxlc acid addition salts are salts of an amino group formed with Inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used In the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0048] Where the compound described herein contains a carboxyl group or a sufficiently acidic bioisostere, base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed. In practice, use of the base addition salt might be more convenient and use of the salt form inherently amounts to use of the free acid form. Salts derived from appropriate bases include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N+(Ci-4alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[0049] Basic addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. The sodium and potassium salts are usually preferred. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N’-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.

[0050] Other acids and bases, although not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0051] It should be understood that a compound disclosed herein can be present as a mixture / combination of different pharmaceutically acceptable salts. Also contemplated are mixtures / combinations of compounds in free form and pharmaceutically acceptable salts.Pharmaceutical Formulations

[0052] Also provided herein are pharmaceutical formulations that include an effective amount of compounds of the disclosure and one or more pharmaceutically acceptable excipients. As used herein, the term “formulation" is used interchangeable with “composition."

[0053] An "effective amount" includes a "therapeutically effective amount" and a 'prophylactically effective amount." The term "therapeutically effective amount" refers to an amount effective in treating and / or ameliorating a disease or condition in a subject. The term "prophylactically effective amount" refers to an amount effective inpreventing and / or substantially lessening the chances of a disease or condition in a subject. As used herein, the terms “patient" and “subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (i.e., non-human animals) and humans. Particular patients or subjects are mammals (e.g., humans). The terms “patient" and “subject” include males and females.

[0054] As used herein, the term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.

[0055] The compounds of the disclosure can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds can be administered all at once, as for example, by a bolus injection, multiple times, e.g., by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.

[0056] The compounds disclosed herein and other pharmaceutically active compounds, if desired, can be administered to a subject or patient by any suitable route, e.g., orally, topically, rectally, parenterally, (for example, subcutaneous injections, intravenous, intramuscular, intrasternal, and intrathecal injection or infusion techniques), or as a buccal, inhalation, or nasal spray. The administration can be to provide a systemic effect (e.g., eneteral or parenteral). All methods that can be used by those skilled in the art to administer a pharmaceutically active agent are contemplated. In some cases, the disclosed formulations can be administered orally or topically.

[0057] Suitable oral compositions or formulations in accordance with the disclosure include without limitation tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, syrups or elixirs. Compositions or formulations suitable for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.

[0058] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0059] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0060] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used Include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0061] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one Inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as Is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active Ingredlent(s) only, or preferentially, In a certain part of the Intestinal tract, optionally, In a delayed manner. Examples of embedding compositions that can be used Include polymeric substances and waxes.

[0062] The pharmaceutical compositions described herein may also be administered topically or transdermally, especially when the target of treatment Includes areas or organs readily accessible by topical application, Including diseases of the eye, the skin, or the lower Intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract, e.g., can be affected in a rectal suppository formulation or in a suitable enema formulation. Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, suppositories, or patches.

[0063] For topical applications, the pharmaceutical compositions may be formulated In a suitable ointment, cream, lotion, or gel, containing the active component suspended or dissolved In one or more carriers, and any needed preservatives or buffers as may be required. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated In a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

[0064] Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0065] 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. The sterile Injectable preparation may also be a sterile Injectable solution, suspension or emulsion In a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and Isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed Including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0066] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0067] In order to prolong the effect of a compound described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0068] The compounds for use in the methods of the disclosure can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical excipient. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

[0069] The compounds of the disclosure can be administered to a subject or patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient. The specific dosage and dosage range that will be used can potentially depend on a number of factors, including the requirements of the subject or patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular subject or patient is within the ordinary skill in the art.Methods of Use

[0070] The compounds disclosed herein, and pharmaceutically acceptable salts thereof, can act as degraders of CBP / p300. CBP / p300 coactivator family in humans is composed of two closely related transcriptional coactivating proteins that interact with numerous transcription factors and act to increase the expression of their target genes. CBP / p300 serve as critical transcriptional coactivators of AR (Comuzzi, et al. J. Pathol. 2004, 204 (2), 159-166.; Waddell, et al. Cancers 2021, 13 (12), 2872.; Chen, et al. Theranostics 2022, 12 (11), 4935-4948.), and these proteins are highly expressed in human prostate cancer and their expressions are positively associated with AR signaling in prostate cancer (Comuzzi, et al. J. Pathol. 2004, 204 (2), 159-166.; Debes, et al. Cancer Res. 2003, 63 (22), 7638-7640.; Welti, et al. Cancer Discov. 2021, 11 (5), 1118-1137.). Knockdown of CBP / p300 proteins or inhibition of their functions by bromodomain or HAT domain inhibitors has been shown to not only suppress AR signaling but also reduce the expression of c-Myc, another transcriptional factor and oncogene in AR+ prostate cancer cells (Welti, et al. Cancer Discov. 2021, 11 (5), 1118-1137; Jin, et al. Cancer Res. 2017, 77 (20), 5564-5575.; Xiang, et al. J. Med. Chem. 2021 , 65, 785-810.; Lasko, et al. Nature 2017, 550 (7674), 128-132.; Kanada, et al. J. Med. Chem. 2022, 66, 695-715.). Loss of CBP / p300 protein or inactivation of CBP / p300 activity leads to genome instability and renders cells more sensitive to eradication. Recently, increasing evidence demonstrates the important role of CBP / p300 in various human cancers, illustrating it as both a biomarker of cancer and a potential target for cancer therapy.

[0071] The disclosure provides a method of degrading CBP / p300 comprising contacting the CBP / p300 with a compound or salt disclosed herein or a formulation thereof, in an amount effective to degrade CBP / p300 activity. In some cases, the contacting occurs in vitro. In some cases, the contacting occurs in vivo. In some cases, thecontacting comprises administering to a subject in need thereof. As used herein, the terms “patient” and “subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (i.e., non-human animals) and humans. In some cases, the patient is a mammal (e.g., human). In some cases, the subject suffers from cancer. In some cases, the cancer is breast cancer, ovarian cancer, prostate cancer, or gastric cancer. In various cases, the cancer is prostate cancer, e.g., AR+ prostate cancer.

[0072] In some cases, the compound as disclosed herein reduces mRNA levels of AR, KLK3 (which encodes prostate specific antigen (PSA)), and / or c-Myc genes. In various cases, the compound reduces mRNA levels of each of AR, KLK3, and c-Myc genes. In various cases, the compound as disclosed herein suppresses AR signaling and / or c-Myc expression.

[0073] Another aspect of the disclosure provides a method of treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt disclosed herein or a formulation thereof. In some cases, the terms “treating”, “treat” or “treatment” and the like can include preventative (e.g., prophylactic) and palliative treatment. In some cases, the disease or disorder is cancer.Examples of treatable cancers include, but are not limited to, adrenal cancer, acinic ceil carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemis / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell proiymphocytic leukemia, B-cell lymphoma, basal ceil carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round ceil tumor, diffuse large B-cell lymphoma, dysembryoplastio neuroepithelial tumor, dysgermlnoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fete, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ ceil tumor, gestational choriocarcinoma, giant cell tibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliometosis cerebri, glucagonoma, gonadeblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoapithelioma. lymphoma, acute lymphocytic leukemia, acute myetogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer. MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton turner, mantle cell lymphoma, marginal zone B-celi lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides. myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, ollgoastrocytcma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-iymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei , renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter’s transformation, rectal cancer, sarcoma. Schwannomatosis, seminoma, Sertoli cell turner, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinome, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary’s disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom’s macraglobuiinemia, Warthin’s tumor, and Wilms' tumor.

[0074] In another embodiment, the cancer is a leukemia , for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MIL). In another embodiment the cancer is NUT-midiine carcinoma. In another embodiment the cancer is multiple myeloma, in another embodiment the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a neuroblastoma. In another embodiment the cancer is Burkitt's lymphoma, in another embodiment ths cancer is cervical cancer. In another embodiment ths cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In various cases the prostate cancer is AR+ prostate cancer. In another embodiment, the cancer is breast cancer.

[0075] Another aspect of the disclosure provides the use of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a formulation thereof in the treatment of a disease or disorder associated with aberrant CBP / p300 activity in a subject. In various cases, the disease or disorder is cancer. In some cases, the cancer is breast cancer, ovarian cancer, prostate cancer, or gastric cancer. In various cases, the cancer is prostate cancer, e.g., AR+ prostate cancer.

[0076] Also contemplated Is the use of a compound disclosed herein, or salt thereof, or a formulation comprising a compound or salt disclosed herein for the manufacture of a medicament In the treatment of cancer, such as breast cancer, ovarian cancer, prostate cancer, or gastric cancer.

[0077] In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering" of a composition to a human subject or patient shall be restricted to prescribing a controlled substance that may be administered to a human subject or patient by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.Synthesis of the Compounds of the Disclosure

[0078] The compounds of the disclosure can be synthesized by any method known in the art. For example, the compounds of the disclosure (compounds of Formula (I)) can be synthesized in line with the synthetic routes as described in the examples below.Embodiments of the Disclosure1. A compound having a structure of Formula (I):whereinRing A is a 4-15-membered monocyclic, bicyclic, spiro, or bridged ring;R1is H, C1-6alkyl, or halo;R2is H, C1-6alkyl, Ci-ehaloalkyl, or halo;R3is H, halo, C1-6alky I, C3-10cycloalkyl, 3-10 membered heterocycle having 1 , 2, or 3 ring heteroatoms independently selected from N, 0, and S, C3-10aryl, or 5-10 membered heteroaryl having 1 , 2, or 3 ring heteroatoms independently selected from N, 0, and S, and the cycloalkyl, heterocycle, or heteroaryl is substituted with 0-3 Ra; each Rais independently C1-6alkyl;L is C0-4alkylene, C(0)- C0-4alkyiene, Co^alkylene-NH, C(0)-Co^alkyiene-NH, C0-4alkylene-3-10 membered heterocycle, or C(O) C0-4alkylene-3-10 membered heterocycle, the heterocycle having 1 or 2 ring nitrogen atoms;X is CH or N; andY is CH2or C(O); or a pharmaceutically acceptable salt thereof.2. The compound or salt of embodiment 1 , wherein L is C(0)- C0-4alkylene-(NH), Co^alkylene-3-10 membered heterocycle, the heterocycle having 1 or 2 ring nitrogen atoms.3. The compound or salt of embodiment 1 or 2, wherein ring A is a 6-membered monocyclic ring.4. The compound or salt of embodiment 3, having a structure of Formula (II):5. The compound or salt of embodiment 1 or 2, wherein ring A is an 8-15-membered spiro ring.6. The compound or salt of embodiment 5, having a structure of Formula (III):wherein each of m, n, o, and p is independently 1 , 2, or 3.7. The compound or salt of any one of embodiments 1 to 6 having a structure of Formula (IV):8. The compound or salt of any one of embodiments 1 to 6, having a structure of Formula (V):9. The compound or salt of any one of embodiments 1 to 8, wherein X is CH.10. The compound or salt of embodiment 9, having a structure of Formula (VI):11. The compound or salt of any one of embodiments 1 to 8, wherein X is N.12. The compound or salt of any one of embodiments 1 to 11 , wherein R1is H, CH3, or halo.13. The compound or salt of embodiment 12, wherein R1is H.14. The compound or salt of embodiment 12, wherein R1is F.15. The compound or salt of any one of embodiments 1 to 14, wherein R2is CHF2, CF3, CH3, H, or halo.16. The compound or salt of embodiment 15, wherein R2is CHF2.17. The compound or salt of any one of embodiments 1 to 16, wherein R3is 5-10 membered heteroaryl substituted with 0-3 Ra.18. The compound or salt of embodiment 17, wherein R3is pyrazolyl substituted with 0 or 1 Ra.A19. The compound or salt of embodiment 18, wherein R3isNThe compound or salt of any one of embodiments 1 to 14, wherein R2is CHF2 and R3isThe compound or salt of any one of embodiments 1 to 20, wherein Y is C(O). The compound or salt of any one of embodiments 1 to 20, wherein Y is CH2. The compound or salt of any one of embodiments 1 to 22, wherein L is C(O)- C1-4alkylene-NH.The compound or salt of any one of embodiments 1 to 22, wherein L isThe compound or salt of embodiment 24, wherein L isThe compound or salt of any one of embodiments 1 to 11 , wherein R1is H or F; R2is CHF2; R3A compound, or a pharmaceutically acceptable salt thereof, as recited in Table A. The compound or salt of embodiment 1 having a structure of29. A pharmaceutical composition comprising the compound or salt of any one of embodiments 1 to 28 and a pharmaceutically acceptable excipient.30. A method of degrading CBP / p300 in a cell comprising contacting the cell with a compound or salt of any one of embodiments 1 to 28.31. A method of reducing mRNA levels of KLK3, AR, and / or c-Myc genes in a cell comprising contacting the cell with a compound or salt of any one of embodiments 1 to 28.32. The method of embodiment 31 , wherein the mRNA levels of each of KLK3, AR, and c-Myc genes are reduced.33. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of embodiments 1 to 28.34. The method of embodiment 33, wherein the cancer is prostate cancer.35. The method of embodiment 34, wherein the prostate cancer is AR+ prostate cancer.36. The method of any one of embodiments 33 to 35, wherein the administration is oral administration.EXAMPLES

[0079] The following examples are provided for illustration and are not intended to limit the scope of the invention.

[0080] The synthesis of compounds 1, 2, 6 and 7 is shown in Scheme 1. Compound 29 was prepared according to a reported procedure (Romero, et al. J. Med. Chem. 2017, 60 (22), 9162-9183.). N-substitution of 29 with tertbutyl 4-((methylsulfonyl)oxy)piperidine-1 -carboxylate provided compound 30 (Romero, et al. J. Med. Chem.2017, 60 (22), 9162-9183.). After deprotection of Boc by TFA, the resulting amine (31) was coupled with the appropriate carboxylic acids to give amide compounds (1 , 6). In addition, treatment of amine (31 ) with triphosgene followed by reaction with the appropriate anilines yielded the urea products (2, 7).’Reagents and conditions: (a) tert-butyl 4-((methylsulfonyl)oxy)piperidine-1 -carboxylate, CS2CO3, DMF, 80 °C; (b) TFA, DCM, rt; (c) 2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindoline-5-carboxylic acid or 2-(2,6-dioxopiperidin-3-yl)-1.3-dioxoisoindoline-4-carboxylic acid, HATU, DIPEA, DMF, rt; (d) 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1.3-dione or 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione, bis(trichloromethyl) carbonate, DIPEA, DCM / MeCN, rt to 50 °C.

[0081] The general synthesis of compounds 3-5 and 8-11 is outlined in Scheme 2. SNAr substitutions of fluorides(32) with amines (33) followed by deprotection of the t-butyl group with TFA gave acids (34), which was subjected to amide coupling with amine (31) to afford the title compounds 3-5 and 8-11.Scheme 2. General Synthesis of compounds 3-5 and 8-11a’Reagents and conditions: (a) DIPEA, DMSO, 80-90 °C; (b) TFA, DCM; (c) 31, HATU, DIPEA, DMF, rt.

[0082] The syntheses of compound 12-16 are shown in Scheme 3. Selective SNAP substitution of fluoride (32a) with 25zetidine-3-ylmethanol gave alcohol (35), which was converted to aldehyde (36) via DMP oxidation. Reductive amination of aldehyde (36) with amine (31) yielded the title compound 12. Reductive amination of amine (31) with ketones 37a and 37b followed by Boc deprotection with TFA provided compounds 38a and 38b, which were substituted with 32a to afford the title compounds (13, 16). In addition, substitution of fluoride (32a) with the appropriate ketal containing amines yielded compounds 39a and 39b. After deprotection by TFA (2% H2O), the resulting ketones (40a, 40b) were subjected to a reductive amination with amine (31) to achieve the title compounds 14 and 15.Scheme 3. Synthesis of Compounds 12-16.’Reagents and conditions: (a) 26zetidine-3-ylmethanol, DIPEA, DMSO, 80 °C; (b) DMP, DCM, rt; (c) 31,NaBH(0Ac)3, DCE, rt; (d) tert-butyl 4-oxopiperidine-1 -carboxylate or tert-butyl 3-oxoazetidine-1 -carboxylate,NaBH(OAc)3, DCE, rt; (e) TFA, DCM, rt; (f) 32a, DIPEA, DMSO, 90 °C; (g) 6,6-dimethoxy-2-azaspiro[3.3]heptane or 2,2-dimethoxy-7-azaspiro[3.5]nonane, DIPEA, DMSO, 80 °C; (h) TFA (2% H2O), rt.

[0083] The synthesis of compound 17 is shown in Scheme 4. Conversion of the alcohol group in compound 41 to a leaving group OTs (compound 42) followed by SN2substitution with pyrazole (29) gave compound 43.Selective reduction of the ester of compound 43 with DIBAL-H provided the aldehyde (44) in moderate yield. SnAr substitution of fluoride (32a) with tert-butyl piperazine-1 -carboxylate followed by deprotection of the Boc group by TFA yielded amine (45), which underwent a reductive amination with aldehyde (44) to achieve the final compound 17.Scheme 4. Synthesis of compound 17a’Reagents and conditions: (a) TsCI, DMAP, Et3N, DCM; (b) 29, Cs2CO3, DMF, 70 °C; (c) DIBAL-H (25% intoluene), DCM, -78 °C; (d) fert-butyl piperazine-1 -carboxylate, DIPEA, DMSO, 110 °C; (e) TFA, DCM; (f) NaBH(OAc)3, DCE / DMF.

[0084] The syntheses of compounds 18-20 are shown in Scheme 5. SNAP substitution of fluorides (32b and 47) with fert-butyl piperazi ne- 1 -carboxylate and subsequently deprotection of the Boc group by TFA gave amines 46 and 48, which were further reacted with aldehyde (44) to yield compounds 18 and 19, respectively. In addition, amine (50) could be synthesized via a Pd-PEPPSI-lpent catalyzed C-N coupling of fert-butyl piperazine-1 - carboxylate with bromide (49) following by Boc deprotection.50A similar reductive amination of amine (50) with aldehyde (44) obtained the title compound 20.SaReagents and conditions: (a) fert-butyl piperazine-1 -carboxylate, DIPEA, DMSO, 80 °C; (b) TFA, DCM, rt; (c) 44, NaBH(OAc)3, DCE / DMF; (d) fert-butyl piperazine-1 -carboxylate, Pd-PEPPSI-lpent, CS2CO3, 1,4-dioxane, 90 °C, 3 h.

[0085] The synthesis of final compound 21 is outlined in Scheme 6. SnAr substitution of fluoride (51) with fert- butyl piperazine-1 -carboxylate gave compound 52, which was hydrolyzed by NaOH to yield compound 53. Treatment of acid (53) with TMSCHN2 achieved methyl ester (54), which underwent an Appel reaction to provide bromide (55). Substitution of 55 with fert-butyl (S)-4,5-diamino-5-oxopentanoate followed by an intramolecular amide formation gave product 56. Boc deprotection of 56 using formic acid yielded amine (57), which wasunderwent with a reductive amination with aldehyde (44) to assemble compound 58. Treatment of compound 58 with PhSO2H achieved the final product 21.Scheme 5. Synthesis of Compound 21aaReagents and conditions: (a) tert-butyl piperazine-1 -carboxylate, DIPEA, DMSO, 120 °C; (b) NaOH, MeOH / THF / H2O, rt; (c) TMSCHN2, MeOH / EA = 1:1, -10 °C; (d) PPh3, CBr4, THF, rt; (e) tert-butyl (S)-4,5- diamino-5-oxopentanoate, DIPEA, MeCN, 80 °C; (f) HCOOH; (g) 57, NaBH(OAc)3, DCE / DMF; (h) PhSO2H, MeCN, 85 °C.

[0086] Unless otherwise noted, all commercial materials were used as received. NMR spectra were recorded on a Bruker Ascend™ 400 MHz spectrometer and calibrated using residual solvent peaks as internal references. In reported spectral data, the format (3) chemical shift (multiplicity, J values In Hz, Integration) was used with the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, hept = heptet, dd = doublet of doublets, and m = multiplet. Low resolution mass spectrometric (MS) analysis was carried out with a Waters UPLCACQUITY QDa mass spectrometer. High resolution mass experiments were operated on an Agilent Technologies 6230 TOF LC / MS instrument with APCI ionization. Flash column chromatography was performed by Teledyne CombiFlash RF+ using RediSep Rf silica gel flash column. The final compounds were all purified by a C18 reverse phase preparative HPLC column (SunFire™ Prep C18 OBD™ 5 pm, 50*100 mm) with solvent A (0.1% TFA in H2O) and solvent B (0.1% TFA in MeCN) as eluents at 60 mL / min flow rate. The purity of all the final compounds was measured and confirmed to be >95% by UPLC-MS analysis (10-100% MeCN in H2O containing 0.1% formic acid in 5 min, 1.0 mL / min flow rate) with a C18 column (ACQUITY UPLC BEH C18 1.7 pm, 2.1 * 50 mm).Biological Assays

[0087] Control Compounds. Enzalutamide was purchased from Combi-Block (QA-8520). ARV-110 was purchased from AstaTech (AT25206) and CCS1477 was purchased from MedChemExpress (HY-111784). GNE- 049 was synthesized in house according to the reported procedure. (Romero, et al, J. Med. Chem. 2017, 60 (22), 9162-9183). The purity of these compounds was determined to be >95% by UPLC.

[0088] Cell Lines and Cell Culture. All the LNCaP, VCaP, and 22Rv1 cells used were purchased from American Type Culture Collection (ATCC). Cell culture media: LNCaP cells were grown in RPM1 1640 (Invitrogen); VCaP cells were grown in DMEM with Glutamax (Invitrogen); 22Rv1 cells were grown in RPMI1640 (Invitrogen). All the cells were supplemented with 10% fetal bovine serum (Invitrogen) at 37 °C in a humidified 5% CO2 incubator.

[0089] Western Blot Analysis. Cells were lysed in RIPA lysis and extraction buffer (Thermo-Fisher Scientific, 89901) supplemented with protease inhibitor cocktail (Roche, 11697498001) and phosphatase inhibitor cocktail (Roche, 4906837001) for 30 min on ice. Lysates were centrifuged at 15,000 rpm for 10 min and supernatants were analyzed by SDS / PAGE. Samples were then transferred onto a PVDF membrane and incubated in LI-COR Intercept (TBS) Protein-Free Blocking Buffer (at rt for 1 h, followed by incubation with indicated primary antibodies overnight at 4 °C. Membranes were then incubated with secondary antibodies for 1 h at rt.Membranes were visualized and analyzed using LI-COR Odyssey.

[0090] Cell Viability Assay. Cells seeded in 96-well plates (Corning Costar) were incubated with serially diluted compounds for 4 days. Cell viability was determined using the CellTiter-Glo Luminescent Cell Viability Assay (Promega) following the manufacturer's instruction. Data points were fit with Graphpad 8.0 in a four-parameter equation to generate a concentration-response curve and DMSO controls were defined as the lowest doses ofserial diluted compounds and set as 0 on x-axis. IC50 values were calculated using a nonlinear regression analysis of the mean of 3 Independent triplicate biological assay.

[0091] Quantitative Reverse Transcrlptase-polymerase Chain Reaction (qRT-PCR). RNA was Isolated using the RNeasy Mini Kit (Qiagen). Reverse transcriptase reaction (RT) was performed with 1 pg of total RNA using the High-Capacity RNA-tocDNA Kit (Thermo Fisher Scientific) and followed by polymerase chain reaction (PCR) using TaqMan Gene Expression Master Mix(Thermo Fisher Scientific) on a QuantStudio 7 Flex Real-Time PCR System (Thermo Fisher Scientific). The relative abundance of gene expression was calculated using the comparative CT method which compares the Ct value of target gene to GAPDH(2ΔΔCT).

[0092] Proteomic Profiling: Proteomic profiling was performed as described previously (Bai, et al. Cancer Cell 2019, 36 (5), 498-511.). VCaP cells were treated with Ex. 17 at 100 nM for 4 hr, then collected, washed in PBS and lysed in RIPA buffer (Sigma, #R0278). Cell lysis samples (75 pg / condition) were proteolysed and labeled with TMT 10-plex essentially by following manufacturer’s protocol (Thermo Fisher). Briefly, upon reduction (5 mM DTT, for 30 min at 45 °C) and alkylation (15 mM 2-chloroacetamide, for 30 min at rt) of cysteines, the proteins were precipitated by adding 6 volumes of ice-cold acetone followed by overnight Incubation at - 20 °C. The precipitate was spun down, and the pellet was allowed to air dry. The pellet was resuspended In 0.1 M TEAB and overnight (-16 h) digestion with trypsin / Lys-C mix (1 :25 protease:protein; Promega) at 37 °C was performed with constant mixing using a thermomixer. The TMT 10-plex reagents were dissolved in 41 pl of anhydrous MeCN and labeling was performed by transferring the entire digest to TMT reagent vial and incubating at rt for 1 h.

[0093] Reactions were quenched by adding 8 pl of 5% hydroxylamine and a further 15 mln Incubation. Labeled samples were mixed, and dried using a vacufuge. An offline fractionation of the combined sample (~200 pg) Into 8 fractions was performed using high pH reversed-phase peptide fractionation kit according to the manufacturer’s protocol (Pierce; Cat #84868). Fractions were dried and reconstituted in 9 pl of 0.1% formic acid / 2% MeCN in preparation for LC- MS / MS analysis.

[0094] In order to obtain high accuracy in quantitation, multinotch-MS3 (McAlister, et al. Anal. Chem. 2014, 86 (14), 7150-7158) was used, which minimizes the reporter ion ratio distortion resulting from fragmentation of coisolated peptides during MS analysis. Orbitrap Fusion (Thermo Fisher Scientific) and RSLC Ultimate 3000 nano- UPLC (Dionex) was used to acquire the data. The sample (2 pl) was resolved on a PepMap RSLC C18 column (75 pm i.d. x 50 cm; Thermo Fisher Scientific) at the flowrate of 300 nl / min using 0.1% HCOOH / MeCN gradient system (2-22% MeCN in 150 min; 22-32% MeCN in 40 min; 20 min wash at 90% followed by 50 min reequilibration) and direct spray into the mass spectrometer using EasySpray source (Thermo Fisher Scientific). The mass spectrometer was set to collect one MS1 scan (Orbitrap; 60K resolution; AGC target 2x105; max IT 100 ms) followed by data-dependent, “Top Speed” (3 sec) MS2 scans (collision induced dissociation; ion trap; NCD 35; AGC 5x10^; max IT 100 ms). For multinotch-MS3, top 10 precursors from each MS2 were fragmentedby HCD followed by Orbitrap analysis (NCE 55; 60K resolution; AGO 5*10^; max IT 120 ms, 100-500 m / z scan range).

[0095] Proteome Discoverer (v2.4; Thermo Fisher Scientific) was used for data analysis. MS2 spectra were searched against SwissProt human protein database using the following search parameters: MS1 and MS2 tolerances were set to 10 ppm and 0.6 Da, respectively; carbamido- methylation of cysteines (57.02146 Da) and TMT labeling of lysine and N-termini of peptides (229.16293 Da) were considered static modifications; oxidation of methionine (15.9949 Da) and deamidation of asparagine and glutamine (0.98401 Da) were considered variable. Identified proteins and peptides were filtered to retain only those that passed ^1% FDR threshold.

[0096] Quantitation was performed using high-quality MS3 spectra (Average signal-to-noise ratio of 10 and <50% isolation interference). Proteins with high FDR confidence, S2 unique peptides and found in all samples were selected for further analysis.Design of Potent and Orally Bioavailable CBP / p300 Degraders.

[0097] For the design of a CBP / p300 PROTAC degrader with a desired potency, selectivity and oral bioavailability, a key consideration is the selection of an appropriate protein binder and a ligand for an E3 ligase or an E3 ligase complex. Among a number of classes of CBP / p300 bromodomain inhibitors reported, GNE-049 and its analogue GNE-781 are attractive ligands for the design of PROTAC degraders, as they show highly binding affinities to CBP / p300 proteins and >3000-fold selectivity over BRD4 bromodomain protein. (Romero et al, J. Med. Chem. 2017, 60 (22), 9162-9183). Furthermore, they possess excellent cell permeability and desirable pharmacokinetic (PK) properties. (Romero et al, J. Med. Chem. 2017, 60 (22), 9162-9183). Since GNE- 781 has an additional hydrogen bond donor group, which may be detrimental for achieving oral bioavailability for resulting PROTAC degraders, (Whitehurst, et al, J. Med. Chem. 2023, 66, 7594-7604; Hornberger, et al, J. Med. Chem. 2023, 66, 8281 -8287). GNE-049 was selected rather than GNE-781 as the ligand for the design of orally bioavailable CBP / p300 degraders. Thalidomide was employed as a ligand for CRBN / cullin 4A, in the initial efforts for the design of orally bioavailable CBP / p300 PROTAC degraders.

[0098] The co-crystal structure of GNE-049 in complex with the CBP bromodomain showed that GNE-049 has three solvent-exposed regions, which can be used as potential tethering sites for the design of PROTAC degraders: the N-methyl-pyrazole group, the tetrahydroquinoline moiety and the tetrahydropyran ring. (Romero et al, J. Med. Chem. 2017, 60 (22), 9162-9183). In a recent study, a similar site was employed as the N-methyl- pyrazole site for the design of a potent and efficacious CBP / p300 degrader JET-209 (Figure 1). Thomas, et al, J. Med. Chem. 2023, 66 (12), 8178-8199 In the design of dCBP-1 Vannam, et al, Cell Chem. Biol. 2021, 28, 503- 514 and degraders disclosed in a patent application from Cullgen, (W02020173440) the tetrahydropyran ring site has been employed as the tethering site for the linker. Furthermore, the structure-activity relationship (SAR) studies on this class of CBP / p300 bromodomain inhibitors have shown that the oxygen atom in the tetrahydropyran ring in GNE-049 was well tolerated with various modifications to retain high binding affinities for CBP. (Romero et al, J. Med. Chem. 2017, 60 (22), 9162-9183). In this disclosure, it was decided to explore theoxygen atom in the tetrahydropyran ring as the tethering site in the design of potent and orally active CBP / p300 degraders.

[0099] To facilitate the synthesis of PROTAC molecules, the oxygen atom in the tetrahydropyran in GNE-049 was replaced with a NH group. The first compounds synthesized were a series of potential degraders containing linkers with different lengths, by connecting to either the meta or ortho position of the phenyl ring in thalidomide (Table 1). The initial kinetic experiments revealed that the PROTAC CBP / p300 degraders were capable of reducing the levels of CBP / p300 proteins in cells within just a few hours. Thus, all of the synthesized potential degraders were evaluated for the ability to reduce CBP and p300 proteins in the AR amplified VCaP cell line by western blotting with a 4 h treatment time, and the data are presented below.

[0100] The CBP Degradation (VCap, 4h) and p300 Degradation (VCap, 4h) are shown in the table below, wherein each compound’s DC50 (the concentration needed to reduce the protein by 50%) is reported in nM. CBP / p300 degradation was tested in VCaP cell line with 4 h treatment at concentrations of 0.15-1000 nM.

[0101] Compound 1 containing only a carbonyl group in the linker did not show any significant CBP / p300 degradation at concentrations of 0.15-1000 nM. Surprisingly, just inserting an NH group into the linker of compound 1 yielded an extremely potent degrader (compound 2), which has DC50 values <0.2 nM and Dmaxvalues of ≥95% against both CBP and p300 proteins. Increasing the linker lengths by insertion of 1 , 2 or 4 methylene groups in the linker of compound 2 generated compounds 3, 4 and 5, respectively. All these 3compounds are highly potent CBP / p300 degraders with DC50 values of 0.4-0.9 nM against CBP and DC50 values of 0.4-2 nM against p300 protein. In direct comparison, compounds 3-5 are slightly less potent than compound 2.

[0102] Using the same linkers as those In compounds 1 and 2 but tethering to the ortho position of the phenyl ring In thalidomide generated compounds 6 and 7, respectively. Both compounds are Ineffective CBP / p300 degraders with DC50 values of >1 ,000 nM and Dmaxvalues of <50% at concentrations up to 1000 nM. Inserting 2- 5 methylenes into the linker of compound 7 resulted in compounds 8-11. While compound 8 is a relatively weak CBP / p300 degrader, other three compounds are highly potent and effective CBP / p300 degraders with DC50 values of 0.4-1.4 nM against CBP and 0.1 -1.2 nM against p300 and Dm« values of >90% against both proteins. Compounds 10 and 11 are equally potent and effective in inducing degradation of CBP / p300 proteins.

[0103] Hence, by tethering the linker to either the meta or ortho position in the phenyl ring in thalidomide, several highly potent and effective CBP / p300 degraders were obtained.

[0104] A series of CBP / p300 degrader molecules were designed and synthesized by replacing the NH group of compounds and flexible methylenes with a cyclic amino group and converting the amide bond to an amine group to reduce the number of hydrogen bonds, polar surface and conformational flexibility. These efforts yielded compounds 12-16.

[0105] All of compounds in 12-16 are potent and effective CBP / p300 degraders with DC50 values of 0.5-1.3 nM against CBP and 0.4-1.1 nM against p300 and achieve Dmax values of &95% against both CBP and p300 proteins.

[0106] In previous studies, a piperazine group was employed as part of the linker for the design of potent and orally efficacious PROTAC AR degraders, such as ARD-2128 (Han, et al, J. Med. Chem. 2021, 64 (17), 12831- 12854), ARD-2585 (Xiang, et al, J. Med. Chem. 2021, 64 (18), 13487-13509), and ARD-2051 (Han, et al, J. Med. Chem. 2023, 10.1021 / acs.jmedchem.3c00405). The piperazine group was also used for the design of ARV-110 and ARV-471, two clinically stage degraders against AR and estrogen receptor (ER).(Bekes, et al, Nat. Rev. Drug Discov. 2022, 21, 181-200). Accordingly, four new degraders, compounds 17-20 were designed, synthesized and evaluated using a linker containing a piperazine group within the chemical structures.

[0107] The degradation data showed that compound 17 is a highly potent and effective degrader with DC50 values of 0.2-0.3 nM and Dmaxvalues of >95% against CBP and p300 proteins with the Western blotting data shown in FIGURE 2. Changing the linker tethering position in compound 17 from the meta to ortho position of the phenyl ring in thalidomide generated compound 18, which is a weak and ineffective CBP / p300 degrader. Installation of a F substitution on the phenyl ring of thalidomide in compound 17 yielded compound 19. While compound 19 is still a potent and effective CBP / p300 degrader, it is 4-6 times less potent than compound 17 in inducing degradation of CBP and p300 proteins. Replacement of the thalidomide moiety in compound 17 with a lenalidomide moiety led to compound 20, which is an extremely potent CBP / p300 degrader with DC50 values of <0.1 nM and Dmaxvalues of >95%.Oral Bioavailabilitv

[0108] The goal was to identify orally active CBP / p300 degraders.

[0109] Male ICR mice were purchased from Sino-British SIPPR / BK Lab Animal Ltd., Shanghai, China. One group of three mice was dosed intravenously (IV) with a dose level of 1 mg / kg, and a second group of three mice was dosed orally with a dose level of 3 mg / kg. The animals were fasted prior to oral administration and food supply to the animals dosed orally were resumed 4 hours post-administration. The drug solution was freshly prepared before administration. For the IV route, each compound was formulated in 100% PEG200 as a clear solution, a dosage volume of 5 mL / kg, and a theoretical concentration of 0.2 mg / mL. For the oral route, each was formulated in 100% PEG200 as a clear solution, a dosage volume of 10 mL / kg, and a theoretical concentration of 0.3 mg / mL. Blood samples were collected at the following time points: 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr and 24 hr post dose administration. 200 μl (for rat) or 30 pl (for mouse) of blood was collected and the samples were be placed in tubes containing heparin sodium and stored on ice. The samples were centrifuged at -6800 G for 6 min at 2-8 °C and the resulting plasma was transferred to appropriately labeled tubes within 1 hr of blood collection / centrifugation then stored frozen at -80 °C. The data of this experiment are shown in the below table.aOral plasma exposures evaluated in male SCID mice at a dose of 5 mg / kg using a 100% PEG200 formulation. bBelow the limit of quantification. cC alculated using ChemDraw Professional 16.0.

[0110] Compounds 2, 3, 4, and 10 show a very low oral exposure all employ a NH group to connect to the phenyl ring in thalidomide and contain a flexible linker. They also have an amide bond in their linkers. Previousstudies have shown that reducing the number of hydrogen bond donors, polar surface area and conformational flexibility in PROTAC degraders can lead to dramatic improvement in their oral bioavailability. (Han, et al, J. Med. Chem. 2023, 10.1021 / acs.jmedchem.3c00405). Thus, analysis of compounds 12-16 for their bioavailability was performed, as each were designed to replace the NH group and flexible methylenes (of compounds 2, 3, 4, and 10) with an amine bond and reduced hydrogen bonds, polar surface and conformational flexibility.

[0111] While compound 12 has a modest oral exposure, each of compounds 13-16 have a much-improved oral exposure over compounds 2, 3, 4, and 10. In particular, compound 16 achieves an excellent oral exposure.

[0112] To shed light on potential factors, which may influence the oral bioavailability of compounds in 12-16, their pKa, CLogP and total polar surface area (tPSA) were calculated. As expected, these compounds have the same calculated tPSA values and very similar calculated CLogP values. However, the calculated pKa value for compound 16 is 7.6, which is significantly different from those for other 4 compounds. This data suggested that the basicity of the amine group in the linker of these degrader molecules may have a major effect on the oral bioavailability.

[0113] The oral exposure of compounds 17 and 20 in mice were evaluated with the data shown in the table above. The data showed the while compound 17 achieves an excellent oral exposure, compound 20 has only a moderate oral exposure.

[0114] Compounds 17 and 20 have very similar pKa values (8.2 for compound 17 and 8.3 for compound 20), very similar CLogP values (3.3-3.5), but compound 17 has a higher calculated tPSA than compound 20 due to the presence of the extra carbonyl group. Because a lower tPSA value is expected to improve oral exposure, the much better oral bioavailability for compound 17 than compound 20 cannot be simply explained by the difference in their tPSA values.

[0115] Compound 17 is a highly potent and effective CBP / p300 degrader and has an excellent oral exposure in mice. Compound 17 was also evaluated for Its full pharmacokinetics In mice with the data summarized In the table below.Pharmacokinetics Analysis

[0116] Method development and biological samples analysis for the test articles (Sodium heparin anticoagulant) were be performed by Testing Facility by means of LC-MS / MS. The analytical results were confirmed using quality control samples for intra-assay variation. The accuracy of >66.7% of the quality control samples was between 80-120% of the known value(s). Standard set of parameters including TIB (elimination half-life), AUC(0- t) (area-under-the-curve), Vss(volume of distribution at steady state), Cl (clearance), Cmax (maximum drug concentration), F (oral bioavailability) were calculated using Phoenix WinNonlin 7.0 (Pharsight, USA).

[0117] Permeability and Efflux Ratio Determination in Caco-w Cells: Caco-2 cell were seeded onto polyethylene membranes (PET) in 96-well Falcon insert systems at 2 x 105 cells / cm2and cultured for 21 -28 days for confluent cell monolayer formation. The cell culture media was changed every 3-4 days. Testcompounds were diluted with the transport buffer (HBSS or HBSS with BSA) from a 10 mM stock solution to a concentration of 10 pM and applied to the apical or basolateral side of the cell monolayer. Permeation of the test compounds from A to B direction or B to A direction was determined in duplicate over a 120 min incubation at 37°C and 5% CO2 with a relative humidity of 95%. In addition, the efflux ratio of each compound was also determined. Test and reference compounds were quantified by LC-MS / MS analysis based on the peak area ratio of analyte / IS. The apparent permeability coefficient Papp(cm / s) was calculated using the equation: Papp = (dCr / dt) x VrI (A x Co), where dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time (S); Vris the solution volume in the receiver chamber (0.1 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport, i.e. 0.0804 cm2for the area of the monolayer; Co is the initial concentration in the donor chamber. The efflux ratio was calculated using the equation: Efflux Ratio = Papp(BA) / Papp(AB). LC / MS / MS Condition is as follows: detection method, LC-MS / MS-20 (TQ-6500+); matrix, HBSS; internal standard, Tolbutamide; MS conditions, positive ion ESI for Atenolol & Propranolol & Ex. 17 and negative ion ESI for Digoxin & Tolbutamide; mobile phase, A = 0.1% FA in H2O, B = 0.1% FA in MeCN; column, ACQUITY UPLC HSS T3 1.8pm (50 mm*2.10 mm).

[0118] PK / PD and Efficacy Studies in Mice: For determination of oral exposures for CBP / p300 degraders, each compound was administered in non-tumor-bearing male CB17 SCID mice (Charles River Laboratories) via oral gavage using 100% PEG200 as the dosing vehicle. Animals were sacrificed at indicated time-points with 3 mice for each time-point for each compound, and 300 pL of blood was collected from each animal and were stored at -80 °C until analysis.

[0119] To grow VCaP xenograft tumors, male CB17 SCID mice (Charles River Laboratories) were injected subcutaneously with 5 * 106VCaP cells in 5 mg / mL Matrigel (Corning).

[0120] For PK / PD studies, tumor-bearing SCID mice were administered with vehicle control or Compound 17 via oral gavage using 100% PEG200 as the dosing vehicle (dosing volume / mouse weight = 10 pL / g) when tumors reached 200-400 mm3. Mice were sacrificed at indicated time-points, and blood samples and tumor tissues were harvested for analysis. At each time point, 3 mice were euthanized with CO2 and 250-300 pL of blood were collected by cardiac puncture. The blood samples were put into 1.5 mL microfuge tubes containing Heparin sodium and placed on wet ice, and then centrifuged at 15,000 rpm for 10 min. A minimum of 100 pL of blood plasma was collected from the upper layer, leaving the blood cells behind in the microfuge tube. The plasma was transferred into a fresh 1.5 mL microfuge tube and kept frozen at -80 °C for drug concentration analysis. The tumor samples from each mouse were divided into two parts. One part was immediately frozen in liquid nitrogen, ground into fine powder, placed on dry ice and stored in -80 °C for Western blot analysis. Western blots were performed as detailed in the previous section. Another part was placed in tared Precellys® 2 mL Hard Tissue tubes with Homogenizing Ceramic Beads 16859 (Cayman Chem), weighed, snap frozen in LN2 and stored at -80 °C for drug concentration analysis.

[0121] To prepare tumor samples for LC-MS analysis, mixed ultrapure water, and MeCN solution (4:1) were added to the defrosted tumor tissue samples 5:1 , v / w, In order to facilitate homogenization with a Precellys evolution homogenizer at 4 °C. The homogenized tissues solution was denatured using cold MeCN (1 :3, v / v) with vortex and centrifuged at 13000 rpm 4 °C for 10 min. Following protein precipitation, the final supernatants were collected for LC-MS analysis.

[0122] To determine drug concentrations In plasma and tumor samples, a LC-MS / MS method was developed and validated. This method consisted of a Shlmadzu HPLC system, and chromatographic separation of a test compound was achieved using a Waters column (ACQUITY UPLC BEH C18 1.7 pm, 2.1 * 50 mm). An AB Sciex QTrap 5500 mass spectrometer equipped with an electrospray ionization source (Applied Biosystems, Toronto, Canada) In the positive-ion multiple reaction monitoring mode was used for detection. For example, the precursor / product ion transitions were monitored at m / z 863.63 for Ex. 17 and internal standard, respectively, in the positive electrospray ionization mode. The mobile phases used on HPLC were 0.1% formic acid in purified water (A) and 0.1% formic acid in MeCN (B). The flow rate was set at 0.4-0.6 mL / min and injection volume was 5-10 μL.Table

[0123] Compound 17 has a good overall PK profile in mice, characterized with a very low clearance (Cl = 1.7 mL / min / kg), a low to moderate volume distribution at steady state (Vss= 0.4 L / kg), a good half-life with both intravenous (T1 / 2= 2.8 h) and oral routes of administration (T1 / 2 = 2.6 h), an excellent oral exposure (Cm® = 2494 ng / mL and AUC = 15472 h‘ng / mL), and an overall oral bioavailability of 50% (F = 50%).

[0124] To understand the excellent oral bioavailability achieved by compound 17, its passive permeability in Caco-2 cells was determined. Surprisingly, despite its high molecular weight of 863, compound 17 has a good permeability (PapP(A-B)= 2.9 x 10-6cm / s) and shows no efflux issue (ER = 1.2). The good Caco-2 permeability for compound 17 is consistent with its excellent oral bioavailability.CBP / p300 Degradation in AR+ Prostate Cell Lines

[0125] The VCaP prostate cancer cell line has AR gene amplification, the LNCaP cell line carries an AR T878A mutation and the 22Rv1 cell line has a high level of ARv7 variant expression. (Prekovic, et al, Mol. Cancer Ther.2016, 15 (7), 1702-1712; Hille, et al, Cells 2019, 8 (9), 1067). The alternations of AR in these three cell lines represent three major and distinct resistance mechanisms to current AR targeted therapies. Because compound 17 is highly potent and effective in inducing CBP / p300 degradation in the VCaP cell line, its ability to reduce thelevels of CBP / p300 proteins in LNCaP and 22Rv1 cell lines was evaluated, with the data summarized below, with cells treated with compound 17 for four hours then analyzed.

[0126] In both the LNCaP and 22Rv1 cell lines, compound 17 achieves similar DC50values (0.2-0.4 nM) and Dmaxof ≥90% against both CBP and p300 proteins.Cell Growth Inhibition of AR+ Cell Lines

[0127] Based upon its potent and effective CBP / p300 degradation, compound 17 was tested for its ability to inhibit cell growth In the VCaP, LNCaP and 22Rv1 cell lines. Enzalutamide was included as an AR antagonist approved by the FDA for the treatment of human prostate cancer, ARV-110, an AR PROTAC degrader currently in clinical trial for the treatment of human prostate cancer, CCS1477, a CBP / p300 bromodomain inhibitor currently in clinical trials for the human prostate cancer, and GNE-049. Cells were treated for 4 days, and cell viability was determined by CellTiter-Glo luminescent assay. These data are summarized in the below table and in FIGURE 3.Table

[0128] Compound 17 potently and effectively inhibited cell growth in all these three AR+ cancer cell lines and achieved IC50 values of 2.0 nM, 1.2 nM and 1.6 nM in the VCaP, 22Rv1 and LNCaP cell lines, respectively. In comparison, GNE-049 displayed IC50values of 216 nM, >1 pM and 7.0 pM in the VCaP, 22Rv1 and LNCaP cell line, respectively. Hence, compound 17 is at least 100-times more potent than GNE-049 in inhibition of cell growth in each of these three cell lines. While CCS1477 is more potent than GNE-049, compound 17 is still >25- times more potent than CCS1477 in each of these three cell lines. Compound 17 is also >50-times more potentthan ARV-110, the AR degrader currently in clinical development. In addition, compound 17 is >1 ,000-times more potent than Enzalutamide.Selectivity Assessment of Compound 17 Against other Proteins

[0129] To investigate the degradation selectivity of compound 17 over other proteins on a global level, a whole proteomic analysis in the VCaP cell line was performed. Multiplexed quantitative proteomics analysis was performed after the treatment of compound 17 (100 nM) in VCaP cells for 4 h. The data were provided as the representative of three biological replicates, and P value: two-sided student’s t-test.. Proteins with P values less than 0.05 (y axis) and fold decreases greater than 2 (x axis) were p300 and CBP only (as shown In FIGURE 4). Although compound 17 was highly effective in inducing degradation in the VCaP cells with a DCso value of 0.3 nM and was capable of reducing CBP / p300 by S95% at concentrations as low as 3 nM, cells were treated with compound 17 at 100 nM for 4 hr for proteomic analysis to capture any potential off-target degradation of other proteins.

[0130] The data showed that compound 17 reduced the levels of p300 protein by 79% and the levels of CBP by 50%. Importantly, compound 17 did not reduce the levels of any of the other 6706 proteins analyzed, including other bromodomain containing proteins such as BRD1-4 and BRD7-9. Taken together, the proteomic data demonstrated that compound 17 is a highly selective degrader of CBP / p300 over more than 6,700 other proteins.Analysis of AR, c-Myc, and KLK3 in AR+ Prostate Cell Lines

[0131] Knockdown of CBP / p300 proteins or inhibition of their functions by bromodomain or HAT domain inhibitors were shown to not only suppress AR signaling but also reduce the expression of c-Myc, another transcriptional factor and oncogene in AR+ prostate cancer cells. (Welti, et al, Cancer Discov. 2021 , 11 (5),1118-1137; Jin, et al, Cancer Res. 2017, 77 (20), 5564-5575; Xiang, et al, J. Med. Chem. 2021, 65, 785-810; Lasko, et al, Nature 2017, 550 (7674), 128-132; Kanada, et al, J. Med. Chem. 2022, 66, 695-715). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses of AR, KLK3, which encodes prostatespecific antigen (PSA), and c-Myc in the VCaP, LNCaP and 22Rv1 cell lines was performed. ARV-110 (100 nM), enzalutamide (1,000 nM), GNE-049 (1,000 nM) and CCS1477 (1,000 nM) were included as the controls in the qRT-PCR experiments. Concentration-dependent suppression of CBP / P300-regulated gene transcription induced by compound 17 (CBPD-409) in VCaP, LNCaP, and 22Rv1 cell lines at 6 h, with ARV-110, Enzalutamide, GEN-049, and CCS1477 included as the controls. A method of two-tailed unpaired t test was used for calculating the statistical significance P value. The data are shown in FIGURE 5.

[0132] Compound 17 is highly potent and effective in reducing the mRNA levels of AR, KLK3, and c-Myc genes in a dose-dependent manner In each of these three AR+ prostate cancer cell lines. In the VCaP cell line, compound 17 has a significant effect in suppressing the expression of AR, KLK3, and c-Myc genes at 0.1 nM and reduces the mRNA levels of KLK3, AR and c-Myc genes by 57%, 77% and >95%, respectively at 1 nM. In the LNCaP cell line, compound 17 has a significant effect in suppressing the expression of AR, KLK3, and c-Myc genes at 1 nM and reduces the mRNA levels of KLK3, AR and c-Myc genes by 70%, 67% and >95%,respectively, at 10 nM. In the 22Rv1 cell line, compound 17 has a significant effect in suppressing the expression of KLK3, and c-Myc genes at 1 nM and reduces the mRNA levels of KLK3, AR and c-Myc genes by 75%, 43% and >95%, respectively at 10 nM.

[0133] In comparison, ARV-110 (100 nM) effectively reduces the mRNA levels of KLK3 gene in each of these 3 cell lines but the reduction is less than that achieved by compound 17 at 1 nM. While ARV-110 (100 nM) has a moderate effect in reducing the mRNA levels of AR and c-Myc in the VCaP cell line, it has no or minimal effect on reducing the mRNA levels of AR and c-Myc in the LNCaP and 22Rv1 cell lines. Enzalutamide (1000 nM) has a very similar effect as compared to ARV-110 (100 nM) in each of these three cell lines on KLK3 and c-Myc but has no or minimal effect on AR mRNA level in each of these three cell lines.

[0134] GNE-049 (1 ,000 nM) and CCS1477 (1 ,000 nM) are similarly effective on reduction of the mRNA levels of KLK3, AR and c-Myc genes in each of these cell lines as compared to the effects observed for compound 17 at 10 nM.

[0135] Taken together, these data demonstrated that compound 17 is highly potent and effective in suppressing the AR signaling and c-Myc expression in each of these three AR+ prostate cancer cell lines.Pharmacodynamic Effects of Compound 17 in Tumors

[0136] Compound 17 was evaluated for its pharmacodynamic effect in the VCaP xenograft tumors in mice with the data summarized in FIGURE 6, in line with the methods described above. PD evaluation of compound 17 (CBPD-409) in VCaP xenograft mouse mode was performed. Tumor-bearing SCID mice were administered with vehicle control or compound 17 (1 mg / kg or 3 mg / kg) via oral gavage using 100% PEG200 as the dosing vehicle. Mice were sacrificed at each time point (3 h or 24 h), and blood samples and tumor tissues were harvested for analysis. Tumor tissue was analyzed by western blot for CBP and p300 proteins with tubulin used as the loading control. Each group consisted of 3 mice / tumors. A method of two-tailed unpaired t test was used for calculating P value.

[0137] The data clearly showed that a single oral administration of compound 17 at both 1 and 3 mg / kg was capable of reducing both CBP and p300 proteins by >95% at 3 and 24 h time-points.

[0138] The drug concentrations in both plasma and tumor tissues of compound 17 were determined in mouse plasma and VCaP xenograft tumor tissue, with the data summarized below.TableBLQ - below the limit of quantification

[0139] Consistent with the PK parameters, compound 17 has a reasonable drug exposure in both plasma and tumors but has a lower exposure in the tumor tissue than in plasma. With 1 mg / kg oral dosing, compound 17 attained plasma drug concentrations of 95 ng / ml and 16 ng / ml at 3 and 24 h time-points, respectively. With 3 mg / kg oral dosing, compound 17 has plasma drug concentrations of 355 ng / ml and 21 ng / ml at 3 and 24 h timepoints, respectively. At 1 and 3 mg / kg, compound 17 had tumor concentrations of 30 ng / ml and 141 ng / ml, respectively, at 3 h time-point but showed no detectable drug level at 24 h time-point.

[0140] Taken together, the PK / PD data showed that even with transient drug exposure in the tumor tissue, a single PO dose of compound 17 was able to achieve >95% of CBP / p300 depletion with the effect persisting for at least 24 hr.

[0141] Based upon its promising PD effect, compound 17 was evaluated for its antitumor efficacy in the VCaP xenograft model, with Enzalutamide, CCS1477 and GNE-049 included as controls in the efficacy experiment. Because compound 17 at 1 mg / kg induced nearly complete and persistent CBP / p300 depletion in the VCaP tumor tissue, it was evaluated with a daily (QD), 5 days weekly schedule at 0.3 and 1 mg / kg, as well as less frequent dosing schedule (every other day, QOD) at 1 mg / kg. All other compounds were dosed with a daily, 5 days weekly schedule. All the drugs were administrated to 7-8 mice via oral garage using 100% PEG200 as the dosing vehicle. The data are summarized in FIGURE 7: (A) Tumor growth for each group. (B) Tumor volume increase for each group at the end of treatment (day 63). A method of two-tailed unpaired t test was used for calculating the statistical significance of the tumor volumes between groups. “*”, P < 0.05; P < 0.01 ; “***”, P < 0.001 ; “****”, P < 0.0001. (C). Summary of antitumor activity for each group at the end of the treatment. (D) Animal body weight for each group.

[0142] At the end of treatment (day 63), compound 17 dosed at 0.3 and 1 mg / kg daily, 5 days a week for 5 weeks via oral gavage inhibited tumor growth by 73% and 87%, respectively. Compound 17 dosed at 1 mg / kg every other day (day 1, 3 and 5 out of a week) via oral gavage also effectively inhibited tumor growth by 71%. In comparison, oral administration of Enzalutamide at 20 mg / kg could not slow down the tumor growth when the tumors become large (>1000 mm3) and did not show any significant tumor growth suppression at the end of the treatment (day 63), while it achieved some tumor growth inhibition during the treatment. Two CBP / p300 bromodomain inhibitors, CCS1477 (20 mg / kg, PO) and GNE-049 (30 mg / kg, PO) inhibited tumor growth by 42% and 46%, respectively, at the end of the treatment. Of significance, compound 17 was well tolerated and did not induce significant weight loss or other signs of toxicity during the entire experiment (FIGURE 7D).

[0143] Taken together, the efficacy data in the VCaP tumor model demonstrated that compound 17 is effective in inhibition of tumor growth at both QD and QOD dosing schedules. In direct comparison, compound 17 at both 0.3 and 1 mg / kg daily dosing or 1 mg / kg dosed every other day is more efficacious than enzalutamide at 20 mg / kg, CCS1477 at 20 mg / kg, and GNE-049 at 30 mg / kg.

[0144] It should be appreciated that all combinations of the foregoing concepts and implementations and additional concepts and implementations discussed in greater detail below are contemplated as being part of the inventive subject matter disclosed herein and may be employed in any suitable combination to achieve the benefits as described herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are contemplated as being part of the inventive subject matter disclosed herein

[0145] The foregoing description is given for clearness of understanding only, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the invention may be apparent to those having ordinary skill in the art.

[0146] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise” and variations such as “comprises” and “comprising" will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0147] Throughout the specification, where compositions are described as including components or materials, it is contemplated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise. Likewise, where methods are described as including particular steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise. The invention illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not specifically disclosed herein.

[0148] The practice of a method disclosed herein, and individual steps thereof, can be performed manually and / or with the aid of or automation provided by electronic equipment. Although processes have been described with reference to particular cases, a person of ordinary skill in the art will readily appreciate that other ways of performing the acts associated with the methods may be used. For example, the order of various of the steps may be changed without departing from the scope or spirit of the method, unless described otherwise. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional stepsAII patents, publications and references cited herein are hereby fully incorporated by reference. In case of conflict between the present disclosure and incorporated patents, publications and references, the present disclosure should control.

Claims

What Is claimed Is:

1.

1. A compound having a structure of Formula (I):whereinRing A is a 4-15-membered monocyclic, bicyclic, spiro, or bridged ring;R1is H, C1-6alkyl, or halo;R2is H, C1-6alkyl, C1-6haloalkyl, or halo;R3is H, halo, C1-6alkyl, C3-10cycloalkyl, 3-10 membered heterocycle having 1 , 2, or 3 ring heteroatoms independently selected from N, 0, and S, C6-10aryl, or 5-10 membered heteroaryl having 1 , 2, or 3 ring heteroatoms independently selected from N, 0, and S, and the cycloalkyl, heterocycle, or heteroaryl is substituted with 0-3 Ra; each Rais independently C1-6alkyl;L is C0-4alkylene, C(0)- C0-4alkylene, Co-ialkylene-NH, C(0)- C0-4alkylene-NH, C0-4alkylene-3-10 membered heterocycle, or C(O) C0-4alkylene-3-10 membered heterocycle, the heterocycle having 1 or 2 ring nitrogen atoms;X is CH or N; andY is CH2or C(O); or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 , wherein L is C(0)- C0-4alkylene-NH or Cwalkylene-3-10 membered heterocycle, the heterocycle having 1 or 2 ring nitrogen atoms.

3. The compound or salt of claim 1 or 2, wherein ring A is a 6-membered monocyclic ring.

4. The compound or salt of claim 3, having a structure of Formula (II):

5. The compound or salt of claim 1 or 2, wherein ring A is an 8-15-membered spiro ring.

6. The compound or salt of claim 5, having a structure of Formula (III):wherein each of m, n, o, and p is independently 1 , 2, or 3.

7. The compound or salt of any one of claims 1 to 6 having a structure of Formula (IV):

8. The compound or salt of any one of claims 1 to 6, having a structure of Formula (V):

9. The compound or salt of any one of claims 1 to 8, wherein X is CH.

10. The compound or salt of claim 9, having a structure of Formula (VI):

11. The compound or salt of any one of claims 1 to 8, wherein X is N.

12. The compound or salt of any one of claims 1 to 11, wherein R1is H, CH3, or halo.

13. The compound or salt of claim 12, wherein R1is H.

14. The compound or salt of claim 12, wherein R1is F.

15. The compound or salt of any one of claims 1 to 14, wherein R2is CHF2, CF3, CH3, H, or halo.

16. The compound or salt of claim 15, wherein R2is CHF2.

17. The compound or salt of any one of claims 1 to 16, wherein R3is 5-10 membered heteroaryl substituted with 0-3 Ra.

18. The compound or salt of claim 17, wherein R3is pyrazolyl substituted with 0 or 1 Ra.

19. The compound or salt of claim 18, wherein R3is20. The compound or salt of any one of claims 1 to 14, wherein R2is CHF2and R3is21. The compound or salt of any one of claims 1 to 20, wherein Y is C(O).

22. The compound or salt of any one of claims 1 to 20, wherein Y is CH2.

23. The compound or salt of any one of claims 1 to 22, wherein L is C(O)-C1-4alkylene-NH.The compound or salt of any one of claims 1 to 22, wherein L isThe compound or salt of claim 24, wherein L isof any one of claims 1 to 11 , wherein R1is H or F; R2is CHF2; R3is27. A compound, or a pharmaceutically acceptable salt thereof, as recited in Table A.

28. The compound or salt of claim 1 having a structure of29. A pharmaceutical composition comprising the compound or salt of any one of claims 1 to 28 and a pharmaceutically acceptable excipient.

30. A method of degrading CBP / p300 in a cell comprising contacting the cell with a compound or salt of any one of claims 1 to 28.

31. A method of reducing mRNA levels of KLK3, AR, and / or c-Myc genes in a cell comprising contacting the cell with a compound or salt of any one of claims 1 to 28.

32. The method of claim 31 , wherein the mRNA levels of each of KLK3, AR, and c-Myc genes are reduced.

33. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of claims 1 to 28.

34. The method of claim 33, wherein the cancer is prostate cancer.

35. The method of claim 34, wherein the prostate cancer is AR+ prostate cancer.

36. The method of any one of claims 33 to 35, wherein the administration is oral administration.

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