Imidazopipeazine inhibitors of transcription-activating proteins

Abstract

The present disclosure relates to heterocyclic compounds and methods that may be useful as inhibitors of transcriptional activator proteins, such as CBP and P300, for the treatment or prevention of diseases such as proliferative diseases, inflammatory disorders, autoimmune diseases, and fibrotic diseases.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority from U.S. Provisional Patent Application No. 63 / 086,728, filed on 2 October 2020, which is incorporated herein by reference for all purposes.

[0002] Novel imidazopiperazine compounds and compositions, as well as their uses as pharmaceuticals for treating diseases, are disclosed herein. Methods for inhibiting the activity of transcription-activating proteins such as CBP and P300 in human or animal subjects for treating diseases such as cancer are also provided. [Background technology]

[0003] Chromatin is the combination of DNA and proteins found in the nucleus of eukaryotes, and it constitutes chromosomes. Chromatin can be classified into either heterochromatin (condensed) or euchromatin (elongated). The main protein components of chromatin are called histones, which act as a scaffold for packaging and compressing DNA into a smaller volume to fit into the nucleus. Histones are involved in the processes of mitosis and meiosis and are thought to play a crucial role in DNA expression and replication. Importantly, histones undergo post-translational modifications ("PTMs") at various amino acid sites, which regulate chromatin structure and affect transcription. These modifications provide a mechanism for "epigenetics," that is, the regulation of gene activity and expression that does not arise from direct changes in the DNA sequence.

[0004] Lysine residue acetylation is a post-translational modification (PTM) widely involved in cell signaling and disease biology. Lysine acetylation, particularly abundant in nuclear macromolecular complexes, plays a key role in chromatin regulation and transcriptional control. In cells, the primary "leaders" of the acetyl-lysine mark are bromodomains (BRDs), a diverse family of evolutionarily conserved protein-protein interaction modules that specifically recognize and bind to acetylated lysine residues. Bromodomains, along with enzymes that "write" (histone acetyltransferases, HATs) and "erase" (histone deacetylases, HDACs) acetylated lysine residues on histone and non-histone proteins, tightly regulate gene expression, thereby controlling cellular phenotypes, including proliferation, cell differentiation, and metabolism. Beyond chromatin, many other proteins, such as p53, undergo post-translational modifications and may also be recognized by bromodomain proteins. Because chromatin-mediated processes are often disregulated in cancer, targeting epigenetic leader proteins such as BET (a dual BRD4 containing a protein), CREBBP, ATAD2A, SMARCA2 / 4, and 3-element motif-containing 24 (TRIM24) makes them promising drug targets. As exemplified by the development of selective inhibitors of the bromodomain BET family, conserved BRD folds represent a promising pocket for the development of small, pharmaceutically active molecules.

[0005] Histone acetyltransferase paralogs, cyclic adenosine monophosphate response element binding proteins, binding proteins (CBP, CREBBP, or CREB binding proteins), and 300kDa adenovirus E1A binding proteins (P300 or EP300) are highly homologous and are two closely related multi-domain transcriptional activators containing both histone acetyltransferase (HAT) and bromodomains, playing crucial roles in histone acetylation. These are essential transcriptional coactivators indispensable to numerous cellular processes and are involved in several human pathological conditions, including cancer.

[0006] CBP and P300 bind to chromatin via their bromodomains, and once associated with chromatin, this complex mobilizes further transcriptional machinery to regulate gene expression, triggering the recruitment of various transcription proteins. In addition to chromatin, CBP / P300 has been shown to bind to non-histone proteins; for example, CBP has been described as recognizing acetylated p53 at K382 after DNA damage. Several studies have linked CBP / P300 to the development, maintenance, and / or progression of cancer and tumor immunity, and therefore CBP / P300 inhibitors are a target of current efforts to develop anticancer drugs. In particular, CBP has been found to regulate the expression of MYC, a transcription factor and oncogene that is widely upregulated in many human cancers, suggesting a potential therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies, as well as solid tumors.

[0007] In addition, CBP and P300 are known co-activators of the androgen receptor (AR) and are involved in enhancing the response to androgens. Consistently, CBP / P300 has been proposed to play an oncogenic role in prostate cancer, and upregulation of both proteins has been observed in tumors. CBP inhibitors selectively inhibit growth in several hematological malignancies and lineage-specific tumor types, including androgen receptor-positive prostate cancer. CBP inhibitors inhibit the androgen receptor transcription program in both androgen-sensitive and castration-resistant prostate cancer, thereby inhibiting tumor growth in prostate cancer xenograft models.

[0008] CBP is also relevant to cancer immunotherapy, and the ability of CBP bromodomain inhibitors to impair Treg differentiation and suppression has been described. This activity may constitute a novel small molecule approach to enhance the response to cancer immunotherapy. [Overview of the project] [Means for solving the problem]

[0009] Compounds and pharmaceutical compositions (some of which were found to bind to CBP and P300 and inhibit their interaction) were discovered along with methods for synthesizing and using these compounds (including methods for treating patients' CBP and P300-mediated diseases by administering the compounds). [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 shows the changes in (a) tumor volume (vertical axis, mm3) and (b) percentage change in body weight over time, in response to treatment of DOHH2 xenografts with (i) the vehicle and (ii) the compound of Example 1. [Modes for carrying out the invention]

[0011] Compounds having the following structural formula I: [ka] Or a salt thereof is provided herein. (In the formula, X1 is N, and X2 is CH; R 1 The R is selected from cyclopropyl, tetrahydro-2H-pyran-4-yl, and 2-oxabicyclo[2.2.2]octan-4-yl, any one of which may contain one or two R 5 Substituted by the group; R 2 It is methyl; R 3 The R is selected from pyridine-3-yl and thiazole-5-yl, and optionally contains one or two R 7 Substituted by the group; R 4 is selected from H and fluoro; Each R 5 The elements are independently selected from alkyl, alkoxy, cyano, carboxy, halo, haloalkyl, haloalkoxyl, hydroxy, and oxo; R 7Each occurrence of -C(O)NR 8 R 9 is independently selected from and alkyl, and R 8 and R 9 is independently selected from hydrogen and alkyl).

[0012] Certain compounds disclosed herein may have useful CBP or P300 inhibitory activity and may be used in the treatment or prevention of diseases or conditions in which CBP or P300 plays an active role. Accordingly, in a broad aspect, certain embodiments also provide a pharmaceutical composition comprising one or more of the compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide a method for inhibiting CBP or P300. Other embodiments provide a method for treating a CBP- or P300-mediated disorder in a patient needing such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound or composition according to this specification. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for treating a disease or condition improved by inhibition of CBP and P300.

[0013] In certain embodiments, R 1 is selected from cyclopropyl, tetrahydro-2H-pyran-4-yl, 2-oxabicyclo[2.2.2]octan-4-yl.

[0014] In certain embodiments, R 3 is selected from pyridin-3-yl and thiazol-5-yl and is optionally substituted by one or two R 7 groups. In certain embodiments, R 3 is selected from pyridin-3-yl and thiazol-5-yl and is optionally substituted by one R 7 group. In certain embodiments, R 3R is selected from 6-(methylcarbamoyl)pyridine-3-yl, 2-methylthiazole-5-yl, 2,4-dimethylthiazole-5-yl, 6-methylpyridine-3-yl, and 2-(methylcarbamoyl)thiazole-5-yl. In certain embodiments, R 3 teeth, [ka] Selected from. In a particular embodiment, R 3 teeth, [ka] That is the case.

[0015] Compounds having the following structural formula I: [ka] Or a salt thereof is also provided herein. (In the formula, X1 is N, and X2 is CH; R 1 This can be any one or two R 5 It is a tetrahydro-2H-pyran-4-yl substituted with a group; R 2 It is methyl; R 3 This can be any one or two R 7 It is a thiazole-5-yl substituted with a group; R 4 is selected from H and fluoro; Each R 5 The elements are independently selected from alkyl, alkoxy, cyano, carboxy, halo, haloalkyl, haloalkoxyl, hydroxy, and oxo; R 7 Each occurrence is -C(O)NR 8 R 9 and selected independently from alkyl, and R 8 and R 9(The element is independently selected from hydrogen and alkyl).

[0016] Compounds having the following structural formula II: [ka] Or a salt thereof is also provided herein. (In the formula, X1 is N, and X2 is CH; R 1 This can be any one or two R 5 It is a tetrahydro-2H-pyran-4-yl substituted with a group; R 2 It is methyl; R 3 The R is selected from pyridine-3-yl and thiazole-5-yl, and optionally contains one or two R 7 Substituted by the group; R 4 is selected from H or fluoro; Each R 5 The elements are independently selected from alkyl, alkoxy, cyano, carboxy, halo, haloalkyl, haloalkoxyl, hydroxy, and oxo; R 7 Each occurrence is -C(O)NR 8 R 9 and selected independently from alkyl, and R 8 and R 9 (The element is independently selected from hydrogen and alkyl).

[0017] In a particular embodiment, R 1 It is tetrahydro-2H-pyran-4-yl.

[0018] In a particular embodiment, R 2 It is methyl.

[0019] In a particular embodiment, R 3 It is thiazole-5-yl, and optionally one R 7It is replaced by the group. In certain embodiments, R 3 R is selected from 2-methylthiazole-5-yl, 2,4-dimethylthiazole-5-yl, 6-methylpyridine-3-yl, and 2-(methylcarbamoyl)thiazole-5-yl. In certain embodiments, R 3 teeth, [ka] Selected from. In a particular embodiment, R 3 teeth, [ka] That is the case.

[0020] In a particular embodiment, R 7 is -C(O)NR 8 R 9 In certain further embodiments, R 7 It is -C(O)NHCH3.

[0021] In a particular embodiment, R 7 C 1~6 It is alkyl. In certain further embodiments, R 7 It is methyl.

[0022] In a particular embodiment, R 8 and R 9 These are independently hydrogen and C 1~6 Selected from alkyl. In certain further embodiments, R 8 and R 9 This is independently selected from hydrogen and methyl.

[0023] In a particular embodiment, R 8 and R 9 At least one of them is hydrogen. In a particular embodiment, R 8 and R 9 Many of them, or at least one, is hydrogen.

[0024] Embodiments are also provided in which any of the above embodiments may be combined with any one or more of these embodiments, but the combinations are not mutually exclusive.

[0025] As used herein, two embodiments are defined as “mutually exclusive” if one is distinct from the other. For example, an embodiment in which two groups are bonded to form a cycloalkyl group is mutually exclusive to an embodiment in which one group is ethyl and the other is hydrogen. Similarly, an embodiment in which one group is CH2 is mutually exclusive to an embodiment in which the same group is NH.

[0026] Compounds selected from the examples disclosed herein are also provided.

[0027] This disclosure also relates to a method for inhibiting the function of at least one CBP, comprising the step of contacting CBP with a compound or salt thereof described herein. Cellular phenotype, cell proliferation, CBP activity, changes in biochemical output produced by active CBP, CBP expression, or binding of CBP to a natural binding partner can be monitored. Such methods may be modes of disease treatment, biological assays, cellular assays, biochemical assays, etc.

[0028] This disclosure also relates to a method for inhibiting at least one function of P300, comprising the step of contacting P300 with a compound or salt thereof described herein. This method can monitor cellular phenotype, cell proliferation, P300 activity, changes in biochemical output produced by active P300, P300 expression, or binding of P300 to a natural binding partner. Such methods may include a mode of disease treatment, a biological assay, a cellular assay, a biochemical assay, and the like.

[0029] A method for treating a CBP-mediated disease is also provided herein, comprising administering a therapeutically effective amount of one of the compounds disclosed herein, or a salt thereof, to a patient in need thereof.

[0030] A method for treating a P300-mediated disease is also provided herein, comprising administering a therapeutically effective amount of one of the compounds disclosed herein, or a salt thereof, to a patient in need.

[0031] In certain embodiments, the disease is a proliferative disorder.

[0032] In certain embodiments, the disease is cancer.

[0033] Compounds disclosed herein or salts thereof, for use as pharmaceuticals, are also provided herein.

[0034] Compounds disclosed herein or salts thereof are also provided herein for use as pharmaceuticals for the treatment of CBP-mediated diseases.

[0035] This specification also provides compounds disclosed herein or salts thereof for use as agents for the treatment of P300-mediated diseases.

[0036] The use of the compounds disclosed herein or salts thereof as pharmaceuticals is also provided.

[0037] The use of the compounds disclosed herein or salts thereof as agents for the treatment of CBP-mediated diseases is also provided.

[0038] The use of the compounds disclosed herein or salts thereof as pharmacopoeias for the treatment of P300-borne diseases is also provided.

[0039] Compounds disclosed herein or salts thereof are also provided for use in the manufacture of agents for treating CBP-mediated diseases.

[0040] Compounds disclosed herein or salts thereof are also provided for use in the manufacture of pharmaceuticals for the treatment of P300-borne diseases.

[0041] The use of the compounds disclosed herein or salts thereof for the treatment of CBP-mediated diseases is also provided.

[0042] The use of the compounds disclosed herein or salts thereof for the treatment of P300-borne diseases is also provided.

[0043] This specification also provides a method for inhibiting CBP, which includes contacting CBP with a compound or salt thereof disclosed herein.

[0044] A method for inhibiting P300 is also provided herein, which includes contacting P300 with a compound disclosed herein or a salt thereof.

[0045] This specification also provides a method for achieving an effect in a patient, comprising administering to the patient a therapeutically effective amount of the compound or salt thereof disclosed herein, the effect being selected from cognitive enhancement.

[0046] In certain embodiments, the CBP-mediated disease is cancer.

[0047] In certain embodiments, the P300-mediated disease is cancer.

[0048] A method for modulating CBP-mediated function in a subject is also provided, comprising administering a therapeutically effective amount of a compound or salt thereof disclosed herein.

[0049] A method for modulating P300-mediated function in a subject is also provided, comprising administering a therapeutically effective amount of the compound disclosed herein or a salt thereof.

[0050] Pharmaceutical compositions comprising the compounds disclosed herein or salts thereof together with a pharmaceutically acceptable carrier are also provided.

[0051] In certain embodiments, the pharmaceutical composition is formulated for oral administration.

[0052] In certain embodiments, the pharmaceutical composition is formulated for parenteral administration.

[0053] In certain embodiments, the oral pharmaceutical composition is selected from tablets and capsules.

[0054] Abbreviations and definitions As used herein, the following terms have the meanings indicated.

[0055] When a range of values ​​is disclosed and the notation "n1...~n2" or "between n1... and n2" (where n1 and n2 are numbers) is used, unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range includes the values ​​at both ends, and may be integers or consecutive. For example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. Compare this to the range "1 to 3 μM (micromoles)" as an example, which is intended to include 1 μM, 3 μM, and all significant digits in between (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0056] As used herein, the term “about” is intended to indicate that the numerical value it modifies represents such a value as a variable within the margin of error. Where no specific margin of error, such as the standard deviation relative to the mean, is given in a chart or table of data, the term “about” should be understood to mean the range that may encompass the stated value, and also the range that may be included by rounding up or down to that number, taking significant figures into account.

[0057] As used herein, the term “acyl” refers, alone or in combination, to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclic, or any other carbonyl group, wherein the atom bonded to the carbonyl is carbon. “Acetyl” refers to the -C(O)CH3 group. “Alkylcarbonyl” or “alkanoyl” refers to an alkyl group bonded to the parent molecule via a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0058] As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon radical, either alone or in combination, having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkenyl may contain 2 to 6 carbon atoms. The term “alkenylene” refers to a carbon-carbon double bond system bonded at two or more positions, such as ethenylene [(-CH=CH-),(-C::C-)]. Suitable examples of alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, and 1,4-butadienyl. Unless otherwise specified, the term “alkenyl” may include an “alkenylene” group.

[0059] As used herein, the term “alkoxy,” either alone or in combination, refers to an alkyl ether radical, where the term alkyl is defined below. Suitable examples of alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0060] As used herein, the term “alkyl” refers, alone or in combination, to a linear or branched alkyl radical containing 1 to 20 carbon atoms. In certain embodiments, the alkyl may contain 1 to 10 carbon atoms. In further embodiments, the alkyl may contain 1 to 8 carbon atoms. The alkyl may optionally be substituted as defined below. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and nonyl. As used herein, the term “alkylene” refers, alone or in combination, to a saturated aliphatic group derived from a linear or branched saturated hydrocarbon, such as methylene(-CH2-), bonded at two or more positions. Unless otherwise specified, the term “alkyl” may include an “alkylene” group.

[0061] As used herein, the term "alkylamino" refers, either alone or in combination, to an alkyl group bonded to the parent molecule via an amino group. Suitable alkylamino groups may be mono- or dialkylation-forming groups, such as N-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-ethylmethylamino.

[0062] As used herein, the term "alkylidene," either alone or in combination, refers to an alkenyl group in which one carbon atom of a carbon-carbon double bond is attached to the part to which the alkenyl group is bonded.

[0063] As used herein, the term "alkylthio," either alone or in combination, refers to an alkylthioether (RS-) radical, where the term alkyl is as defined above, and sulfur may be oxidized singly or doubly. Suitable examples of alkylthioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, and ethanesulfinyl.

[0064] As used herein, the term “alkynyl” refers to a linear or branched hydrocarbon radical, either alone or in combination, having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkynyl contains 2 to 6 carbon atoms. In further embodiments, the alkynyl contains 2 to 4 carbon atoms. The term “alkynylene” refers to a carbon-carbon triple bond bonded at two positions, such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, buty-1-yl, buty-2-yl, pentyn-1-yl, 3-methylbuty-1-yl, and hexyn-2-yl. Unless otherwise specified, the term “alkynyl” may include an “alkynylene” group.

[0065] As used herein, the terms “amide” and “carbamoyl” refer, either alone or in combination, to an amino group (or vice versa) attached to the parent molecule via a carbonyl group, as described below. As used herein, the term “C-amide” refers, either alone or in combination, to a -C(O)N(RR') group, where R and R' are as defined herein or as defined by the specified “R” group. As used herein, the term “N-amide” refers, either alone or in combination, to an RC(O)N(R')- group, where R and R' are as defined herein or as defined by the specified “R” group. As used herein, the term “acylamino” refers, either alone or in combination, to an acyl group attached to the parent molecule via an amino group. An example of an “acylamino” group is acetylamino (CH3C(O)NH-).

[0066] As used herein, the term "amino" alone or in combination refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may optionally be substituted themselves. Furthermore, R and R' may combine to form a heterocycloalkyl, either of which may optionally be substituted.

[0067] As used herein, the term “aryl,” either alone or in combination, refers to a carbocyclic aromatic system containing one, two, or three rings, where such polycyclic systems are condensed. The term “aryl” encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[0068] As used herein, the terms "arylalkenyl" or "aralkenyl" refer to an aryl group bonded to the parent molecule via an alkenyl group, either alone or in combination.

[0069] As used herein, the terms "arylalkoxy" or "aryloxy," either alone or in combination, refer to an aryl group bonded to the parent molecule via an alkoxy group.

[0070] As used herein, the terms "arylalkyl" or "aralkyl," either alone or in combination, refer to an aryl group bonded to the parent molecule via an alkyl group.

[0071] As used herein, the terms "arylalkynyl" or "aralkynyl" refer to an aryl group bonded to the parent molecule via an alkynyl group, either alone or in combination.

[0072] As used herein, the terms “arylalkanoyl,” “alalkanoyl,” or “aloyl,” either alone or in combination, refer to acyl radicals derived from aryl-substituted alkanecarboxylic acids such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, and 4-chlorohydrocinnamoyl.

[0073] As used herein, the term aryloxy refers to an aryl group, either alone or in combination, bonded to the parent molecule via an oxy linkage.

[0074] As used herein, the terms “benzo” and “benz,” either alone or in combination, refer to the divalent radical C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.

[0075] As used herein, the term "carbamate" refers to an ester (-NHCOO-) of carbamic acid that can be bonded to the parent molecule from either a nitrogen or acid terminus, either alone or in combination, and may be optionally substituted as defined herein.

[0076] As used herein, the term "O-carbamyl," either alone or in combination, refers to the -OC(O)NRR' group, where R and R' are as defined herein.

[0077] As used herein, the term “N-carbamyl” refers, either alone or in combination, to the ROC(O)NR'- group, where R and R' are as defined herein.

[0078] As used herein, the term "carbonyl" includes formyl [-C(O)H] when used alone, and a -C(O)- group when used in combination.

[0079] As used herein, the terms "carboxyl" or "carboxy" refer to the -C(O)OH or the corresponding "carboxylate" anion (as in the case of carboxylate salts). The "O-carboxyl" group refers to the RC(O)O- group, where R is as defined herein. The "C-carboxyl" group refers to the -C(O)OR group, where R is as defined herein.

[0080] As used herein, the term "cyano," either alone or in combination, refers to -CN.

[0081] As used herein, the terms “cycloalkyl,” or alternatively “carbocyclic,” either alone or in combination, refer to saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl groups, where each cyclic portion contains 3 to 12 carbon atom ring members and may optionally be a benzo-condensed ring system as defined herein. In certain embodiments, the cycloalkyl group may contain 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, and adamantyl. As used herein, “bicyclic” and “tricyclic” are intended to include both condensed ring systems, e.g., decahydronaphthalene, octahydronaphthalene, and polycyclic (multicentric) saturated or partially unsaturated types. The latter type of isomer is commonly exemplified by bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0082] As used herein, the term "ester" refers, either alone or in combination, to a carboxyl group that bridges two carbon-carbon bonded groups.

[0083] As used herein, the term "ether" refers, either alone or in combination, to an oxy group that bridges two carbon-carbon bonded moieties.

[0084] As used herein, the terms "halo" or "halogen," either alone or in combination, refer to fluorine, chlorine, bromine, or iodine.

[0085] As used herein, the term "haloalkoxy" refers to a haloalkyl group, either alone or in combination, bonded to the parent molecule via an oxygen atom.

[0086] As used herein, the term “haloalkyl” refers, alone or in combination, to an alkyl radical having the meaning defined above, in which one or more hydrogens are substituted by a halogen. In particular, monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals are included. For example, a monohaloalkyl radical may have an iodine, bromo, chloro, or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more identical halo atoms or combinations of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. “Haloalkylene” refers to a haloalkyl group bonded at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), and chloromethylene (-CHCl-).

[0087] As used herein, the term "heteroalkyl" refers to a stable linear, branched, or combination thereof, consisting of a specified number of carbon atoms and 1 to 3 heteroatoms selected from N, O, and S, either alone or in combination, which are fully saturated or contain 1 to 3 degrees of unsaturation, where the N and S atoms may optionally be oxidized, and the N heteroatom may optionally be quaternized. The heteroatoms may be located at any internal position of the heteroalkyl group. For example, up to two heteroatoms may be consecutive, such as -CH2-NH-OCH3.

[0088] As used herein, the term “heteroaryl” refers, alone or in combination, to a 3- to 15-membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system, where all fused rings are aromatic and contain at least one atom selected from N, O, and S. Accordingly, the term “heteroaryl” includes, for example, pyridine, thiophene, quinoline, and phenanthridine. Accordingly, the term “heteroaryl” does not include, for example, indoline and 2,3-dihydrobenzofuran. In certain embodiments, the heteroaryl may contain 1 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl may contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl may contain 5 to 7 atoms. The term also includes fused polycyclic groups in which a heterocyclic ring is fused with an aryl ring, and a heteroaryl ring is fused with another heteroaryl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazonyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolidinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, and quinazolinyl. Exemplary tricyclic heterocyclic groups include carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, and phenanthridinyl.

[0089] As used herein, the terms “heterocycloalkyl” and interchangeably “heterocyclic” refer to saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) monocyclic, bicyclic, or tricyclic heterocyclic groups, each containing at least one heteroatom as a ring member, either alone or in combination, where each of the heteroatoms may be independently selected from nitrogen, oxygen, and sulfur. Accordingly, the term “heterocycloalkyl” excludes fully aromatic ring systems such as pyridine, pyrimidine, quinoline, and acridine. Thus, the term “heterocycloalkyl” includes partially aromatic bicyclic and larger ring systems such as 1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline, and indoline. In certain embodiments, the heterocycloalkyl may contain 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl may contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl group may contain 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl group may contain 3 to 7 ring members in each ring. In yet another embodiment, the heterocycloalkyl group may contain 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocyclic" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic and benzo-condensed ring systems, and both terms also include systems in which a heterocyclic ring is condensed to an aryl group or an additional heterocyclic group as defined herein. Examples of heterocyclic groups include azilidinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrosinnolinyl, dihydrobenzodioxynyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, and thiomorpholinyl. Unless otherwise prohibited, heterocyclic groups may be substituted as desired.

[0090] Certain compounds in this disclosure may contain diazanaphthalene groups, which may be understood as derivatives of naphthalene, in which two non-bridgehead CH groups are replaced with nitrogen. The term “diazanaphthalene” encompasses the four isomers of benzodiazines, which have both nitrogen atoms in the same ring, and the six isomers of naphthyridines, which have nitrogen atoms on different rings.

[0091] As used herein, the term "hydrazinyl," either alone or in combination, refers to two amino groups linked by a single bond, i.e., -NN-.

[0092] As used herein, the term "hydroxy" refers to -OH, either alone or in combination.

[0093] As used herein, the term "hydroxyalkyl" refers to a hydroxyl group, either alone or in combination, that is bonded to the parent molecule via an alkyl group.

[0094] As used herein, the term "imino" refers, either alone or in combination, to =N-.

[0095] As used herein, the term "iminohydroxy," either alone or in combination, refers to =N(OH) and =NO-.

[0096] The phrase "in the main chain" refers to the longest chain of nearest or adjacent carbon atoms starting from the bond site of a group to any one of the compounds of the formulas disclosed herein.

[0097] The term "isocyanato" refers to the -NCO group.

[0098] The term "isothiocyanate" refers to the -NCS group.

[0099] The term "atomic chain" refers to the longest possible straight chain of atoms, independently selected from carbon, nitrogen, oxygen, and sulfur.

[0100] As used herein, the term “inferior” means, alone or in combination, that it contains 1 to 6 carbon atoms (i.e., C1 to C6 alkyl groups), unless otherwise defined.

[0101] As used herein, the term “lower aryl” means, alone or in combination, phenyl or naphthyl, both of which may be optionally substituted as provided.

[0102] As used herein, the term “lower heteroaryl” means, alone or in combination, either 1) a monocyclic heteroaryl having five or six ring members, of which one to four ring members may be heteroatoms selected from N, O, and S, or 2) a bicyclic heteroaryl having either of five or six ring members in a fused ring, with one to four heteroatoms selected from N, O, and S between them.

[0103] As used herein, the term “lower cycloalkyl” means, alone or in combination, a monocyclic cycloalkyl (i.e., C3-C6 cycloalkyl) having 3 to 6 ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0104] As used herein, the term “lower heterocycloalkyl” means, alone or in combination, a monocyclic heterocycloalkyl (i.e., C3-C6 heterocycloalkyl) having 3 to 6 ring members, of which 1 to 4 may be heteroatoms selected from N, O, and S. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.

[0105] As used herein, the term “lower amino” alone or in combination refers to -NRR', where R and R' are independently selected from hydrogen and lower alkyl, and either of these may be optionally substituted.

[0106] As used herein, the term “mercaptyl” refers, either alone or in combination, to an RS- group, where R is as defined herein.

[0107] As used herein, the term "nitro," either alone or in combination, refers to -NO2.

[0108] As used herein, the terms "oxy" or "oxa" refer to -O-, either alone or in combination.

[0109] As used herein, the term "oxo," either alone or in combination, refers to =O.

[0110] The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[0111] As used herein, the term “perhaloalkyl” refers, either alone or in combination, to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0112] As used herein, the terms "sulfonate," "sulfonic acid," and "sulfonic" refer, either alone or in combination, to the -SO3H group and its anion (when sulfonic acid is used in the form of a salt).

[0113] As used herein, the term "sulfanil," either alone or in combination, refers to -S-.

[0114] As used herein, the term "sulfinyl," either alone or in combination, refers to -S(O)-.

[0115] As used herein, the term "sulfonyl," either alone or in combination, refers to -S(O)2-.

[0116] The term "N-sulfonamide" refers to the RS(=O)2NR'- group, where R and R' are as defined herein.

[0117] The term "S-sulfonamide" refers to the -S(=O)2NRR' group, where R and R' are as defined herein.

[0118] As used herein, the terms “thia” and “thio,” either alone or in combination, refer to ethers in which an -S- group or oxygen is substituted with sulfur. Oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definitions of thia and thio.

[0119] As used herein, the term "thiol" refers, either alone or in combination, to an -SH group.

[0120] As used herein, the term "thiocarbonyl" alone includes thioformyl-C(S)H, and when combined with other terms, refers to the -C(S)- group.

[0121] The term "N-thiocarbamyl" refers to the ROC(S)NR'- group, where R and R' are as defined herein.

[0122] The term "O-thiocarbamyl" refers to the -OC(S)NRR' group, where R and R' are as defined herein.

[0123] The term "thiocyanate" refers to the -CNS group.

[0124] The term "trihalomethanesulfonamide" refers to the X3CS(O)2NR- group, where X is a halogen and R is as defined herein.

[0125] The term "trihalomethanesulfonyl" refers to the X3CS(O)2- group, where X is a halogen.

[0126] The term "trihalomethoxy" refers to the X3CO- group, where X is a halogen.

[0127] As used herein, the term “trisubstituted silyl” refers, either alone or in combination, to a silicone group whose three free valencies are substituted by a group as defined herein in the definition of a substituted amino. Examples include trimethylilyl, tert-butyldimethylsilyl, and triphenylsilyl.

[0128] Any definition herein may be used in combination with any other definition to describe a complex structural group. By convention, the suffix of any such definition is the element bonded to the parent part. For example, the complex group alkylamide may represent an alkyl group bonded to the parent molecule via an amide group, and the term alkoxyalkyl may represent an alkoxy group bonded to the parent molecule via an alkyl group.

[0129] When a base is defined as "null," it means that this base does not exist.

[0130] The term "optionally substituted" means that the preceding group may be substituted or unsubstituted. If substituted, the substituents of the "optionally substituted" group may include, alone or in combination, one or more substituents independently selected from the following groups or a specific set of designated groups: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower halo Lucoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamide, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amide, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Where structurally feasible, two substituents may be linked together to form a condensed 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic ring consisting of 0 to 3 heteroatoms, for example, methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), completely substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between complete and monosubstituted (e.g., -CH2CF3). When a substituent is described without limitation on substitution, both substituted and unsubstituted forms are included. When a substituent is limited to "substituted," the substituted form is specifically intended. Furthermore, different sets of substituents may be defined for a particular part as needed, in which case the optional substitution would often be as defined immediately after the phrase "optionally substituted with."

[0131] The terms R or R', appearing alone and without a number designation, refer to a portion selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether the R group has a number designation or not, R, R', and R n All R groups, all substituents, and all terms, including (where n = (1, 2, 3, ..., n)), should be understood to be independent of all others with respect to selection from the group. If any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) appears more than once in a formula or general structure, its definition in each appearance is independent of its definition in all other appearances. Those skilled in the art will further recognize that certain groups can be bonded to the parent molecule or occupy a position in the elemental chain from either end as described. For example, an asymmetric group such as -C(O)N(R)- can be bonded to the parent at either carbon or nitrogen.

[0132] The compounds disclosed herein contain chiral centers. These centers are denoted by the symbols "R" or "S" depending on the stereochemistry of substituents around the chiral carbon atom. It should be understood that this disclosure encompasses all stereochemical isomers, including diastereomers, enantiomers, and epimer forms, as well as d-isomers and l-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or they can be prepared by preparing a mixture of enantiomer products, followed by separation such as conversion to a diastereomer mixture, and then by separation or recrystallization, chromatography techniques, direct separation of enantiomers in a chiral chromatography column, or any other suitable method known in the art. Starting compounds for specific stereochemistrys are commercially available or can be prepared and divided by techniques known in the art. Furthermore, the compounds disclosed herein may exist as geometric isomers. This disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as suitable mixtures thereof. Furthermore, compounds can exist as tautomers, and all tautomers are provided herein. In addition, the compounds disclosed herein can exist in non-solvated forms and in solvated forms with pharmaceutically acceptable solvents such as water and ethanol. Generally, the solvated forms are considered equivalent to the non-solvated forms.

[0133] The term "bond" refers to a covalent bond between two atoms, or between two parts when the atoms bonded together are considered part of a larger substructure. Unless otherwise specified, a bond can be a single, double, or triple bond. In molecular diagrams, a dashed line between two atoms indicates that an additional bond may or may not exist at that position.

[0134] As used herein, the term “disease” is intended to be generally synonymous with and interchangeable with the terms “disorder,” “syndrome,” and “condition” (in the case of a medical condition), all of which describe an abnormal condition of one of the body or organs of a human or animal that impairs normal function, is usually manifested by prominent signs and symptoms, and causes a decline in lifespan or quality of life in the human or animal.

[0135] The term “combination therapy” means the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described herein. Such administrations include the concurrent administration of these therapeutic agents substantially simultaneously (e.g., in a single capsule having fixed ratios of active ingredients, or in multiple separate capsules for each active ingredient). Furthermore, such administrations also include the sequential use of each type of therapeutic agent. In any case, the treatment plan will provide the beneficial effects of drug combination in the treatment of the conditions or disorders described herein.

[0136] As used herein, “CBP inhibitor” refers to a compound that binds to and inhibits the bromodomain of CBP with measurable affinity and activity. In certain embodiments, the CBP inhibitor exhibits an IC50 related to CBP activity of approximately 100 μM or less, more typically approximately 50 μM or less, as measured with CBP (assay name) as commonly described herein. “IC50” is the concentration of the inhibitor that reduces the activity of the bromodomain of CBP to half of its maximum level. Certain compounds disclosed herein have been found to exhibit inhibition against CBP. In certain embodiments, the compound exhibits a CBP-related IC50 of about 20 μM or less as measured by the CBP assay described herein; in further embodiments, the compound exhibits a CBP-related IC50 of about 5 μM or less; in yet further embodiments, the compound exhibits a CBP-related IC50 of about 200 nM or less; in yet further embodiments, the compound exhibits a CBP-related IC50 of about 50 nM or less; in yet further embodiments, the compound exhibits a CBP-related IC50 of about 10 nM or less; and in yet further embodiments, the compound exhibits a CBP-related IC50 of about 2 nM or less.

[0137] As used herein, “P300 inhibitor” refers to a compound that binds to and inhibits the bromodomain of P300 with measurable affinity and activity. In certain embodiments, the P300 inhibitor exhibits an IC50 related to P300 activity, measured by P300 (assay name) as commonly described herein, of about 100 μM or less, more typically about 50 μM or less. “IC50” is the concentration of the inhibitor that reduces the activity of the bromodomain of P300 to half of its maximum level. Certain compounds disclosed herein have been found to exhibit inhibition against P300. In certain embodiments, the compound exhibits a P300-related IC50 of about 20 μM or less as measured by the P300 assay described herein; in further embodiments, the compound exhibits a P300-related IC50 of about 5 μM or less; in even further embodiments, the compound exhibits a P300-related IC50 of about 200 nM or less; in even further embodiments, the compound exhibits a P300-related IC50 of about 50 nM or less; in even further embodiments, the compound exhibits a P300-related IC50 of about 10 nM or less; and in even further embodiments, the compound exhibits a P300-related IC50 of about 2 nM or less.

[0138] In some embodiments, certain compounds disclosed herein interfere with the association of CBP and / or EP300 with histones, particularly acetylated lysine in histones. In some embodiments, certain compounds disclosed herein inhibit the binding of CBP and / or EP300 to chromatin (e.g., histone-associated DNA). In some embodiments, certain compounds disclosed herein inhibit and / or reduce the binding of the CBP bromodomain and / or EP300 bromodomain to chromatin (e.g., histone-associated DNA). In some embodiments, certain compounds disclosed herein do not affect the association of other domains of CBP and / or EP300 with chromatin. In some embodiments, certain compounds disclosed herein bind to CBP and / or EP300 primarily (e.g., exclusively) through contact and / or interaction with the CBP bromodomain and / or EP300 bromodomain. In some embodiments, certain compounds disclosed herein bind to CBP and / or EP300 via contact and / or interaction with the CBP bromodomain and / or EP300 bromodomain, as well as additional CBP and / or EP300 residues and / or domains. Methods for assaying chromatin association are known in the art and include, but are not limited to, chromatin fractionation, BRET assay (Promega), FRAP assay, chromatin immunoprecipitation (ChIP), biophysical binding assay, and / or histone-associated assay. See, for example, Das et al., BioTechniques 37:961-969 (2004).

[0139] The phrase "therapeutically effective" is intended to limit the amount of active ingredient used in the treatment of a disease or disorder, or in achieving a clinical endpoint.

[0140] The term "therapeutably acceptable" refers to a compound (or salt, prodrug, tautomer, zwitterionic form, etc.) that is suitable for use in contact with a patient's tissue without excessive toxicity, irritation, or allergic reaction, is balanced by a reasonable benefit / risk ratio, and is effective for its intended use.

[0141] As used herein, references to patient “treatment” are intended to include prevention. Treatment may be preemptive in nature, that is, it may include prevention of disease. Prevention of disease may include complete protection from disease, such as in the case of prevention of infection by a pathogen, or it may include prevention of disease progression. For example, prevention of disease may not mean the complete elimination of any effects associated with disease at any level, but rather may mean preventing the symptoms of disease from reaching a clinically significant or detectable level. Prevention of disease may also mean preventing the disease from progressing to a later stage.

[0142] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, as well as companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is human.

[0143] The term "prodrug" refers to a compound that is more activated in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in "Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology" (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Furthermore, prodrugs may be converted to compounds by chemical or biochemical methods in an ex vivo environment. For example, a prodrug may be slowly converted to a compound when placed in a transdermal patch reservoir with appropriate enzymes or chemical reagents. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound or parent drug. For example, a prodrug may be bioavailable by oral administration, even though the parent drug is not. Furthermore, prodrugs may exhibit improved solubility in pharmaceutical compositions compared to their parent drugs. Various types of prodrug derivatives are known in the art, including those that depend on hydrolytic cleavage or oxidative activation of the prodrug. An example (but not limited to) of a prodrug may be a compound that is administered as an ester ("prodrug") but is subsequently metabolically hydrolyzed to a carboxylic acid, which is the active substance. Additional examples include peptidyl derivatives of compounds.

[0144] The compounds disclosed herein may exist as therapeutically acceptable salts. This disclosure includes the above compounds in the form of salts, including acid addition salts. Suitable salts include those formed by both organic and inorganic acids. Such acid addition salts are usually pharmaceutically acceptable. However, salts of pharmaceutically unacceptable salts may be useful in the preparation and purification of the compounds in question. Base addition salts can also be formed and may be pharmaceutically acceptable. For a more complete discussion of salt preparation and selection, see "Pharmaceutical Salts: Properties, Selection, and Use" (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0145] As used herein, the term “therapeutably acceptable salt” refers to a salt or amphoteric form of a compound disclosed herein that is water-soluble, oil-soluble, or dispersible and therapeutically acceptable as defined herein. Salts may be prepared during the final isolation and purification of the compound, or separately, by reacting a suitable compound in the form of a free base with a suitable acid. Typical acid addition salts include acetate, adipine, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisinate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionic acid), lactate, maleate, malonate, and DL-mandextrin. This includes oxalates, mesitylene sulfonates, methanesulfonates, naphthylene sulfonates, nicotinates, 2-naphthalene sulfonates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphonates, picrinates, pivalates, propions, pyroglutamates, succinates, sulfonates, tartrates, L-tartrates, trichloroacetates, 2,2,2-trifluoroacetates, phosphates, glutamates, bicarbonates, p-toluenesulfonates (p-tosylates), and undecanoates. The basic groups in the compounds disclosed herein can be quaternized by chlorides, bromides, and methyl, ethyl, propyl, and butyl iodides; dimethyl sulfate, diethyl, dibutyl, and diamyl sulfate; chlorides, bromides, and decyl iodides, lauryl, myristyl, and steryl; as well as benzyl bromide and phenethyl. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination between a compound and an alkali metal or alkaline earth metal ion.Accordingly, this disclosure intends to include sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein.

[0146] Base addition salts can be prepared during the final isolation and purification of a compound by reacting the carboxyl group with a suitable base such as a metal cation hydroxide, carbonate, or bicarbonate, or with ammonia or an organic primary, secondary, or tertiary amine. Cationic cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0147] Pharmaceutical composition While the compounds disclosed herein may be administered as chemical substances in their raw form, they may also be provided as pharmaceutical formulations. Accordingly, pharmaceutical formulations are provided herein that include one or more of the specific compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic components. The carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to its recipient. The appropriate formulation is determined by the chosen route of administration. Any appropriate and well-known techniques, carriers, and excipients understood in the art may be used. The pharmaceutical compositions disclosed herein may be produced by any method known in the art, for example, by conventional mixing, dissolution, granulation, sugar-coating, levigating, emulsification, encapsulation, encapsulation, or compression processes.

[0148] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most appropriate route may depend, for example, on the recipient's condition and impairment. Formulations can conveniently be provided in unit dosage forms and can be prepared by any method well known in the pharmaceutical art. Typically, these methods involve associating a compound of the subject disclosure or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate thereof ("active ingredient") with a carrier constituting one or more auxiliary components. Generally, formulations are prepared by homogeneously and closely associating the active ingredient with a liquid carrier or a pulverized solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0149] Oral administration The compounds of this disclosure may be administered orally (including by swallowing), thereby entering the gastrointestinal tract or being absorbed directly into the bloodstream from the oral cavity (including sublingual or buccal administration).

[0150] Compositions suitable for oral administration include solid formulations such as tablets, pills, cachets, lozenges, and hard or soft capsules, which may include solutions or turbidities in liquids, gels, powders or granules, aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions. The active ingredient may be presented as a bolus, lick, or paste.

[0151] In a tablet or capsule dosage form, the amount of drug present may be about 0.05% to about 95% by weight of the dosage form, more typically about 2% to about 50% by weight.

[0152] In addition, tablets or capsules may contain a tablet disintegrant, comprising approximately 0.5% to 35% by weight, more typically 2% to 25%, of the dosage form. Examples of tablet disintegrants include methylcellulose, sodium carboxymethylcellulose or calcium, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropylcellulose, and starch.

[0153] Suitable binders for use in tablets include gelatin, polyethylene glycol, sugar, gum, starch, and hydroxypropyl cellulose. Suitable diluents for use in tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, and starch.

[0154] Suitable surfactants and flow enhancers used in tablets or capsules may be present in amounts of about 0.1% to about 3% by weight and include polysorbate 80, sodium dodecyl sulfate, talc, and silicon dioxide.

[0155] A suitable lubricant used in the tablet or capsule may be present in an amount of about 0.1% to about 5% by weight and may include calcium, zinc, or magnesium stearate, sodium stearyl fumarate, etc.

[0156] Tablets may be manufactured by compression or molding, with any one or more adjuncts. Compressed tablets may be prepared by compressing a freely flowing active ingredient, such as a powder or granules, in a suitable machine, optionally mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersant. Molded tablets may be manufactured by molding a mixture of powdered compounds moistened with a liquid diluent in a suitable machine. Dyes or pigments may be added to the tablets for identification or to characterize various combinations of active compound dosages.

[0157] Liquid formulations may include emulsions, liquids, syrups, elixirs, and suspending agents, which may be used in soft or hard capsules. Such formulations may contain pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulations may also contain one or more emulsifiers and / or suspending agents.

[0158] Compositions for oral administration may optionally have an enteric coating and may be formulated as immediate-release or controlled-release, including delayed-release or sustained-release.

[0159] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0160] Pharmaceutical preparations for oral use include tablets, gelatin-based press-fit capsules, and sealed soft capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Tablets may be manufactured by compression or molding, with optionally one or more auxiliary components. Compressed tablets may be manufactured by compressing a freely flowing active ingredient, such as a powder or granule, in appropriate machinery, optionally mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersant. Molded tablets may be manufactured by molding a mixture of powder compounds moistened with an inert liquid diluent in appropriate machinery. Tablets may optionally be coated or scored, and may also be formulated to provide sustained or controlled release of the active ingredient therein. All formulations for oral administration must be in dosages suitable for such administration. Press-fit capsules may contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Furthermore, stabilizers may be added. A suitable coating is provided for the sugar-coated tablet core. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for identification or to characterize various combinations of active compound dosages.

[0161] Parenteral administration The compounds of this disclosure may be administered directly to the bloodstream, muscle, or viscera by injection, for example, by bolus injection or continuous infusion. Suitable means of parenteral administration include intravenous, intramuscular, subcutaneous arterial, intraperitoneal, subarachnoid, and intracranial administration. Apparatus suitable for parenteral administration includes syringes (with and without needles) and methods of administration. The formulations may be contained in single-dose or multi-dose containers, such as sealed ampoules and vials.

[0162] Most parenteral preparations are aqueous solutions containing salts, buffers, suspending agents, stabilizers and / or dispersants, antioxidants, bacteriostatic agents, preservatives, and excipients including solutes that make the preparation isotonic with the recipient's blood, and carbohydrates.

[0163] Parenteral formulations may also be prepared in a dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with a suitable vehicle, such as sterile water. Solubility enhancers may also be used in parenteral solution preparations. Compositions for parenteral administration may be formulated as immediate or controlled release, including delayed-release or sustained-release formulations. Compounds may also be formulated as depot formulations. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Accordingly, for example, compounds may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion-exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0164] The compound may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage forms with added preservatives, such as ampoules or multi-dose containers. Compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. Formulations may be provided in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or freeze-dried state, requiring only the addition of a sterile liquid carrier, such as physiological saline or sterile pyrogen-free water, immediately before use. Immediate injection solutions and suspensions may be prepared from the above-described sterile powders, granules, and tablets.

[0165] Preparations for parenteral administration include aqueous and non-aqueous (oil-based) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the preparation isotonic with the recipient's blood, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickeners. Suitable lipophilic solvents or media include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, enabling the preparation of highly concentrated solutions.

[0166] In addition to the formulations described above, the compound may be formulated as a depot formulation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Accordingly, for example, the compound may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0167] Local administration The compounds of this disclosure may be administered topically (e.g., to the skin, mucous membranes, ears, nose, or eyes) or transdermally. Formulations for topical administration include, but are not limited to, lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, and patches. Pharmaceutically acceptable carriers for topical formulations include water, alcohol, mineral oil, glycerin, and polyethylene glycol. Topical administration may also be performed by means of electroporation, ion electrophoresis, phonophoresis, etc.

[0168] Typically, the active ingredient for topical administration may constitute 0.001% to 10% w / w (by weight) of the formulation. In specific embodiments, the active ingredient may constitute 10% w / w; less than 5% w / w; 2% w / w to 5% w / w; or 0.1% to 1% w / w of the formulation.

[0169] Compositions for topical administration may be formulated as immediate or controlled release, including delayed-release or sustained-release.

[0170] Certain compounds disclosed herein may be administered topically, i.e., non-systemically. This includes external application of the compounds disclosed herein to the epithelium or buccal oral cavity, as well as in drops of such compounds into the ears, eyes, and nose, so as to minimize their entry into the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0171] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration into the inflamed area through the skin, such as gels, liniments, lotions, creams, ointments, or pastes, as well as intravenous preparations suitable for administration to the eyes, ears, or nose. The active ingredient for topical administration may be present in, for example, 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may be present in 10% w / w. In other embodiments, it may be present in less than 5% w / w. In certain embodiments, the active ingredient may be present in 2% w / w to 5% w / w. In other embodiments, it may be present in 0.1% to 1% w / w of the formulation.

[0172] Rectal, buccal, and sublingual administration Suppositories for rectal administration of the compounds of this disclosure may be prepared by mixing the active agent with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides, fatty acids, or polyethylene glycol, which are solid at room temperature but liquid at rectal temperature and thus melt in the rectum to release the drug.

[0173] For buccal or sublingual administration, the composition may take the form of tablets, lozenges, troches, or gels as conventionally prescribed. Such compositions may contain the active ingredient in a sucrose and a flavored base such as acacia or tragacanth.

[0174] The compound may be formulated in rectal compositions such as suppositories or retained enemas, which include, for example, conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0175] Administration by inhalation In the case of administration by inhalation, the compound may be conveniently delivered from an injector, a nebulizer-pressurized pack, or other means convenient for delivering an aerosol spray. The pressurized pack may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a measured amount. Alternatively, in the case of administration by inhalation or infusion, the compound according to this disclosure may take the form of a dry powder composition, for example, a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition may be provided in unit dosage forms, for example, capsules, cartridges, gelatin, or blister packs, and the powder may be administered from the unit dosage form using an inhaler or injector.

[0176] Other carrier materials and administration modes known in the pharmaceutical field may also be used. The pharmaceutical compositions of this disclosure may be prepared by any well-known pharmaceutical technique, such as effective formulations and administration procedures. Preferred unit dosage forms contain an effective dose or a suitable fraction thereof of the active ingredient, as described below herein.

[0177] In particular, it should be understood that, in addition to the ingredients listed above, the above-mentioned formulations may contain other agents that are customary in the art, taking into account the type of formulation in question. For example, those suitable for oral administration may contain flavoring agents.

[0178] The compound may be administered orally or by injection at doses of 0.1 to 500 mg / kg per day. The dose range for adults is generally 5 mg to 2 g / day. Tablets or other presenting forms provided in individual units can conveniently contain one or more compounds in amounts effective in such doses or multiple doses; for example, a unit may contain 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0179] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration.

[0180] Compounds can be administered in various modes, for example, orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attending physician. Specific dose levels for any particular patient will depend on various factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, time of administration, route of administration, excretion rate, combination drugs, specific complications during treatment, and the severity of signs or conditions during treatment. In addition, the route of administration may vary depending on the condition and its severity. The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks.

[0181] A preferred unit dosage form contains an effective dose or a suitable fraction thereof of the active ingredient, as described below in this specification.

[0182] In particular, it should be understood that, in addition to the ingredients listed above, the above-mentioned formulations may contain other agents that are customary in the art, taking into account the type of formulation in question. For example, those suitable for oral administration may contain flavoring agents.

[0183] The compound may be administered orally or by injection at doses of 0.1 to 500 mg / kg per day. The dose range for adults is generally 5 mg to 2 g / day. Tablets or other presenting forms provided in individual units can conveniently contain one or more compounds in amounts effective for such dosages or multiple doses thereof; for example, a unit may contain 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0184] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration.

[0185] Compounds can be administered in various modes, for example, orally, topically, or by injection. The precise amount of compound administered to a patient may be the responsibility of the attending physician. A specific dose level for any particular patient may depend on various factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, time of administration, route of administration, elimination rate, combination drugs, exact impairment during treatment, and the severity of signs or conditions during treatment. The route of administration may also vary depending on the condition and its severity.

[0186] Combination and combination therapies In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of just one example, if one of the side effects a patient experiences when receiving one of the compounds herein is hypertension, it may be appropriate to administer an antihypertensive agent in combination with the first therapeutic agent. Alternatively, by way of just one example, the therapeutic efficacy of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., the adjuvant may have minimal therapeutic benefit on its own, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of just one example, the benefit a patient experiences may be increased by administering one of the compounds described herein together with another therapeutic agent (including a therapeutic regimen) that also has a therapeutic benefit. By way of just one example, in the treatment of diabetes involving the administration of one of the compounds described herein, an increase in therapeutic benefit may occur by also providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit the patient experiences may simply be the additive benefit of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0187] Certain non-limiting examples of possible combination therapies include the use of a particular compound of the invention with an anti-cancer agent (chemotherapeutic agent). Classes of anti-cancer agents include, but are not limited to: alkylating agents, antimetabolites, mitotic inhibitors, checkpoint inhibitors, plant alkaloids and terpenoids, topoisomerase inhibitors, cytotoxic antibiotics, aromatase inhibitors, angiogenesis inhibitors, anti-steroids and anti-androgens, mTOR inhibitors, tyrosine kinase inhibitors, and others.

[0188] For use in cancer and neoplastic diseases, the CBP / EP300 inhibitor can be optimally used with one or more of the following non-limiting examples of anti-cancer agents: (1) Alkylating agents including, but not limited to, carmustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, and cyclophosphamide (ENDOXAN); (2) Antimetabolites including, but not limited to, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX), and larotrexed; (3) Mitotic inhibitors which are often plant alkaloids and terpenoids, or derivatives thereof, including, but not limited to, taxanes such as docetaxel (TAXITERE) and paclitaxel (ABRAXANE, TAXOL); vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, and vinorelbine (NAVELBINE); (4) Checkpoint inhibitors such as anti-PD-1 or PD-L1 antibodies pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, and MPDL3280A; anti-CTLA-4 antibody ipilimumab (YERVOY); and those targeting LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3 (T cell immunoglobulin and mucin-domain containing-3), and OX40 (tumor necrosis factor receptor superfamily member 4); (5) Topoisomerase inhibitors, including but not limited to camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), and etoposide (EPOSIN); (6) Cytotoxic antibiotics including, but not limited to, actinomycin D (dactinomycin, cosmegene), bleomycin (blenoxane), doxorubicin (adriamycin), daunorubicin (cerubidine), epirubicin (ellence), fludarabine (fludarabine), idarubicin, mitomycin (mitosol), mitoxantrone (novantronone), and plicamycin; (7) Aromatase inhibitors, including but not limited to aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), borozol (RIVIZOR), and exemestane (AROMASIN); (8) Angiogenesis inhibitors, including but not limited to genistein, sunitinib (SUTENT), and bevacizumab (AVASTIN); (9) Antisteroids and antiandrogens such as aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), and nilutamide (NILANDRON); (10) Tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); (11) mTOR inhibitors such as everolimus, temsirolimus (TORISEL), and sirolimus; (12) Monoclonal antibodies such as trastuzumab (HERCEPTIN) and rituximab (RITUXAN); (13) Amsacrin; Calmette-Guéran bacillus (BCG) vaccine; Buserelin (ETILAMIDE); Chloroquine (ARALEN); Clodronate, Pamidronate, and other bisphosphonates; Colchicine; Demethoxypyridine; Dichloroacetic acid; Estramustine; Filgrastim (NEUPOGEN); Fludrocortisone (FLORINEF); Goserelin (ZOLADEX); Interferon; Leucovorin; Leuprolide (LUPRON); Lebamisol; Ronidamin; Mesna; Metformin; Mitotan (o,p'-D DD, LYSODREN); Nocodazole; Octreotide (SANDOSTATIN); Perifosine; Porfimers (especially in combination with phototherapy and radiotherapy); Suramin; Tamoxifen; Titanocene dichloride; Tretinoin; Anabolic steroids such as fluoxymesterone (HALOTESTIN); Estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; Progestins such as medroxyprogesterone acetate (MPA) and megestrol; and other drugs such as testosterone.

[0189] If the subject has or is at risk of developing an inflammatory condition, the CBP / EP300 inhibitor compounds described herein may be used optionally in any combination with one or more drugs or methods for treating the inflammatory condition. Therapeutic / treatments for treating autoimmune and / or inflammatory conditions include, but are not limited to, any of the following examples: (1) Corticosteroids, including but not limited to cortisone, dexamethasone, and methylprednisolone; (2) Nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON), flurbiprofen (ANSAID), ketoprofen, oxaprofen (DAYPRO), diclofenac sodium (VOLTAREN), diclofenac potassium (CATAFLAM), etodolac (LODINE), indomethacin (INDOCIN), ketorolac (TORADOL), sulindac (CLINORIL), tolmetin (TOLECTIN), meclofenamete (MECLOMEN), mefenamic acid (PONSTEL), nabumetone (RELAFEN), and piroxicam (FELDENE); (3) Immunosuppressants including, but not limited to, methotrexate (RHEUMATREX), leflunomide (ARAVA), azathioprine (IMURAN), cyclosporine (NEORAL, SANDIMMUNE), tacrolimus, and cyclophosphamide (Citoxane); (4) CD20 blockers, including but not limited to rituximab (RITUXAN); (5) Tumor necrosis factor (TNF) blockers, including but not limited to etanercept (ENBREL), infliximab (REMICADE), and adalimumab (HUMIRA); (6) Interleukin-1 receptor antagonists, including but not limited to anakinra (KINERET); (7) Interleukin-6 inhibitors, including but not limited to tocilizumab (ACTEMRA); (8) Interleukin-17 inhibitors, including but not limited to AIN457; (9) Janus kinase inhibitors, including but not limited to tasocitinib; and (10) SYK inhibitors, including but not limited to hostamatinib.

[0190] In any case, multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided in a single combined form or in multiple forms (for example, as a single pill or two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given in multiple doses. If not administered simultaneously, the timing between doses may be any period ranging from a few minutes to four weeks.

[0191] Accordingly, in another embodiment, a particular embodiment provides a method for treating a CBP-mediated disorder in a human or animal subject requiring treatment, the method comprising administering to the subject an amount of a compound disclosed herein that is effective in reducing or preventing the disorder in the subject, in combination with at least one additional agent known in the art for treating the disorder. In a related embodiment, a particular embodiment provides a therapeutic composition comprising at least one compound disclosed herein in combination with one or more additional agents for treating a CBP-mediated disorder.

[0192] Accordingly, in another embodiment, a particular embodiment provides a method for treating a P300-mediated injury in a human or animal subject requiring treatment, the method comprising administering to the subject an amount of a compound disclosed herein that is effective in reducing or preventing the injury in the subject, in combination with at least one additional agent known in the art for treating the injury. In a related embodiment, a particular embodiment provides a therapeutic composition comprising at least one compound disclosed herein in combination with one or more additional agents for treating a P300-mediated injury.

[0193] The compounds, compositions, and methods disclosed herein are useful for treating diseases. In certain embodiments, the disease is one of the dysregulated cell proliferations, including cancer. Cancer may be hormone-dependent or hormone-resistant, as in the case of breast cancer. In certain embodiments, cancer is a solid tumor. In other embodiments, cancer is lymphoma or leukemia. In certain embodiments, cancer is a drug-resistant phenotype of cancer, as disclosed herein or known in the art. Tumor invasion, tumor growth, tumor metastasis, and angiogenesis can also be treated using the compositions and methods disclosed herein. Precancerous tumors are also treated using the compositions and methods disclosed herein.

[0194] Cancers treated by the methods disclosed herein include colon cancer, breast cancer, ovarian cancer, lung cancer, and prostate cancer; oral cavity and pharynx (lips, tongue, oral cavity, larynx, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, liver, and bile duct; cancers of the pancreas, bone, connective tissue, skin, cervix, uterus, corpus endometrium, testes, bladder, kidney, and other non-urinary tract tissues (including renal cell carcinoma (RCC)); the eye, brain, spinal cord, and other components of the central and peripheral nervous system, as well as related structures such as the meninges; and cancers of the thyroid and other endocrine glands. The term "cancer" includes Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, and hematopoietic malignancies, including leukemia (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML)), as well as lymphomas, including lymphoid, granulocytic, and monocytic types, and cancers that do not necessarily form solid tumors. Further types of cancer that can be treated with the compounds and methods of the present invention include adenocarcinoma, angiosarcoma, astrocytoma, otolaryngeal neuroma, undifferentiated astrocytoma, basal cell carcinoma, blastoglioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonic carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary cancer, glioblastoma multiforme, head and neck cancer, angioblastoma, hepatocellular carcinoma, hepatocellular carcinoma, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemia, liposarcoma, lymphoid carcinoma, This includes, but is not limited to, lymphoma, lymphangiosarcoma, lymphangioendotheliosarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma, mesothelioma, myeloma, myxosarcoma, neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteosarcoma, epithelial ovarian carcinoma, papillary carcinoma, papillary adenocarcinoma, paraganglioma, parathyroid tumor, pheochromocytoma, pineal glandoma, plasmacytoma, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminomas, skin cancer, melanoma, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, sweat gland carcinoma, synoviomas, thyroid cancer, uveal melanoma, and Wilms' tumor.

[0195] In certain embodiments, the compositions and methods disclosed herein are useful for preventing or reducing tumor invasion and tumor metastasis.

[0196] In addition to their usefulness in human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals, and livestock (including mammals, rodents, etc.). More preferred animals include horses, dogs, and cats.

[0197] Compound synthesis The compounds of this disclosure can be prepared using the methods described in the general synthesis schemes and experimental procedures detailed below. These general synthesis schemes and experimental procedures are provided for illustrative purposes only and are not intended to limit the scope of the disclosure. The starting materials used to prepare the compounds of this disclosure are commercially available or can be prepared using routine methods known in the art.

[0198] List of abbreviations Ac2O = Acetic anhydride; AcCl = Acetyl chloride; AcOH = Acetic acid; AIBN = Azobisisobutyronitrile; aq. = Aqueous solution; BPin2 = Bis(pinacorato)diborone = 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Brettphos = 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl; Bu3SnH = Tributyltin hydride; CBz = Carboxybenzyl = PhCH2OC(=O)-; CBzCl = Benzyl chloroformate = PhCH2OC(=O)Cl; CD3OD = Deuterated methanol; CDCl3 = Deuterated chloroform; CDI = 1,1'-Carbonyl diimidazo DAST = Diethylaminosulfur trifluoride; DBU = 1,8-Diazabicyclo[5.4.0]unde-7-ene; DCE = 1,2-Dichloroethane; DCM = Dichloromethane; DEAD = Diethyl azodicarboxylic acid; DIBAL-H = Diisobutylaluminum hydride; DIEA = DIPEA = N,N-Diisopropylethylamine; DMAP = 4-Dimethylaminopyridine; DMF = N,N-Dimethylformamide; DMSO-d6 = Deuterated dimethyl sulfoxide; DMSO = Dimethyl sulfoxide; DPPA = Diphenylphosphoryl azide; dppe = 1,2-Bis(diphenylphosphino)ethane; dppf = 1,1'-Bis(diphenylphosphino)ferrocene; EDC.HCl = EDCI.HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = diethyl ether; SiO = ethyl acetate; EtOH = ethanol; h = hour; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methaneaminium; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; iPr = i-Pr = isopropyl = (CH3)2CH-; i-PrOH = Isopropanol = (CH3)2CH-OH; LAH = LiAlH4 = Lithium aluminum hydride; LiHMDS = LiN(TMS)2 = Lithium bis(trimethylsilyl)amide; MeCN = Acetonitrile; MeOH = Methanol; MP-Carbonate resin = Macroporous triethylammonium methyl polystyrene carbonate resin; MsCl = Methyl chloride; MTBE = Methyl tertiary butyl ether; MW = Microwave irradiation; n-BuLi = n-butyllithium; NaHMDS = Sodium bimethyl ether Su(trimethylsilyl)amide; NaOMe = sodium methoxide; NaOtBu = sodium tert-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NIS = N-iodosuccinimide; NMP = N-methyl-2-pyrrolidone; PdCl2(dppf) = Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride; Pd(Ph3)4 = tetrakis(triphenylphosphine)palladium(O); P d2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; prep-HPLC = preparative high-performance liquid chromatography; PyBop = (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphin-2',6'-diisopropoxybiphenyl; sat.=Saturation; ss = Saturated solution; tBu = t-Bu = tert-Butyl = (CH3)3C-; t-BuOH = tert-Butanol = (CH3)3C-OH; T3P = Propylphosphonic anhydride; TBS = TBDMS = tert-Butyldimethylsilyl; TBSCl = TBDMSCl = tert-Butyldimethylchlorosilane; TEA = Et3N = Triethylamine; TFA = Trifluoroacetic acid; TFAA = Trifluoroacetic anhydride; THF = Tetrahydrofuran; Tol = Toluene; TsCl = Tosyl chloride; XPhos = 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl; Xphos Pd G2 = Chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II).

[0199] General synthetic methods for preparing compounds The present disclosure can be implemented using the following scheme. Scheme I [Chemical formula] Examples can be synthesized using the general synthetic procedures shown in Scheme I. The synthesis of imidazole I-02 starts from ethylenediamine I-01 having a suitable protecting group represented by the symbol (P), for example a carbamate protecting group. Compound I-01 is reacted with glyoxal and aldehyde R 1 -CHO. The monoiodo compound I-03 is formed by a two-step procedure consisting of the synthesis of a 4,5-diiodoimidazole compound (not shown), followed by selective halogen / metal exchange, and quenching of the resulting organometallic with H + The protecting group is removed (for example, the Boc group is removed with HCl), and a bicyclic structure is obtained by condensation with formaldehyde. The amino group can be functionalized with acetyl chloride (or an equivalent such as acetic anhydride) to obtain amide I-06. The synthesis is completed by Pd(II)-mediated coupling of I-06 with an arylboronic acid or ester to obtain I-07.

[0200] Scheme II [ka] Other examples can be synthesized using the general synthesis procedure shown in Scheme II. The reaction of I-06 with NBS provides a bromo-iodine intermediate II-01, which can be selectively reacted twice under Suzuki coupling conditions to first provide II-02 and then II-03.

[0201] Scheme III [ka] Other examples can be synthesized using the general synthetic procedure shown in Scheme III. Coupling of acid III-01 with pyrazine-2-ylmethaneamine provides amide III-02, which is cyclized to provide imidazopyrazine III-03. Imidazopyrazine III-03 is reduced to imidazopiperazine III-04 by hydrogenation. Imidazopyrazine III-04 reacts with acetyl chloride (or an equivalent such as acetic anhydride) and then with iodine to provide amide III-05. The synthesis is completed by Pd(II)-mediated coupling of III-05 with an arylboronic acid ester or arylboronic acid to obtain III-06.

[0202] This disclosure is further illustrated by the following embodiments. [Examples]

[0203] Intermediate "A" 1-(3-cyclopropyl-1-iodo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethane-1-one [ka] tert-butyl(2-(2-cyclopropyl-1H-imidazole-1-yl)ethyl)carbamate To a solution of cyclopropanecarbaldehyde (0.70 g, 10 mmol) in MeOH (50 mL) at RT, tert-butyl(2-aminoethyl)carbamate (1.60 g, 10 mmol) was added, followed by NH4OAc (0.771 g, 10.0 mmol) and a 40% aqueous glyoxal solution (1.451 g, 10.00 mmol). This mixture was stirred at RT for 16 hours and then concentrated under reduced pressure. Saturated aqueous NaHCO3 (50 mL) was added, the aqueous phase was extracted with SiO2 (3 × 20 mL), the combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title crude compound as a yellow foamy solid (2.51 g), which was used in the next step without further purification. MS(ES) + )C 13 H 21 N3O2 theoretical value: 251, measured value: 252 [M+H] + .

[0204] [ka] tert-butyl(2-(2-cyclopropyl-4,5-diiodo-1H-imidazole-1-yl)ethyl)carbamate To a solution of the crude product (2.51 g, 10.0 mmol) prepared in the previous step in DMF (30 mL), NIS (6.75 g, 30.0 mmol) was added, and the resulting mixture was stirred at 80°C for 2 hours, then cooled to RT. H2O (100 mL) and saturated aq. Na2S2O3 (5 mL) were added. The aqueous phase was extracted with RINKAN (3 × 50 mL), and the combined organic layers were washed with saturated aq. NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (0%~50%, RINKAN in hexane) to obtain the title compound as a pale yellow foamy solid (2.41 g, 48%). MS(ES) + )C 13 H 19 I2N3O2 theoretical value: 503, measured value: 504 [M+H] +.

[0205] [ka] tert-butyl(2-(2-cyclopropyl-4-iodo-1H-imidazole-1-yl)ethyl)carbamate To a solution of the product from the previous step (2.40 g, 4.77 mmol) in THF (20 mL) at -78 °C, 2.0 M iPrMgCl (3.58 mL, 7.16 mmol) in THF was added, and the resulting mixture was stirred at -78 °C for 0.5 hours. Saturated aq.NH4Cl (50 mL) was added, and the layers were separated. The aqueous phase was extracted with RINKAN (3 × 30 mL), and the combined organic layers were washed with saturated aq.NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (0%~60%, RINKAN in hexane) to obtain the title compound as an off-white solid (1.45 g, 81%). MS(ES) + )C 13 H 20 IN3O2 theoretical value: 377, measured value: 378 [M+H] + .

[0206] [ka] 1-(3-cyclopropyl-1-iodo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethane-1-one A solution of HCl in MeOH (prepared by dropwise adding AcCl (2 mL) to MeOH (10 mL)) was added to the product from the previous step (700 mg, 1.86 mmol), and the resulting mixture was stirred under reduced pressure for 1 hour. This mixture was concentrated under reduced pressure, and the residue was dissolved in EtOH (10 mL). 50% aq. HCHO (2.045 mL, 37.1 mmol) was added to the resulting mixture, and the mixture was stirred at 100 °C for 3 hours, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL), and the resulting mixture was cooled to 0 °C and treated with iPr2NEt (0.972 mL, 5.57 mmol) and acetyl chloride (0.198 mL, 2.78 mmol). This mixture was stirred under reduced pressure for 1 hour, then concentrated under reduced pressure. The residue was treated with H2O (20 mL), extracted with à (3 × 10 mL), and the combined organic layer was washed with saturated aq. NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (0%~5%, MeOH in CH2Cl2) to obtain the title compound as an off-white solid (355 mg, 58%). MS(ES) + )C 11 H 14 IN3O Theoretical value: 331, Measured value: 332 [M+H] + .

[0207] Intermediate “B” 1-(1-iodo-3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethanone [ka] tert-butyl 2-(2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole-1-yl)ethylcarbamate. A mixture of tetrahydro-2H-pyran-4-carbaldehyde (2.80 g, 25 mmol) and 40% aq. glyoxal (5.0 g, 34 mmol) in MeOH (100 mL) at 0 °C was treated with NH4OAc (3.8 g, 49 mmol), and then tert-butyl 2-aminoethylcarbamate (3.94 g, 24.6 mmol) was added dropwise. The mixture was stirred overnight at RT and then concentrated under reduced pressure. The residue was diluted with MeOH / CH2Cl2 (1 / 10, 400 mL), the mixture was washed with saturated aq. NH4Cl (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title crude compound as a red oil (7.0 g, 96%). MS (ES + ) C 15 H 25 N3O3 Calcd: 295, Found: 296 [M+H] + .

[0208]

Chem.

[0209]

Chem.

[0210]

Chem.

[0211]

Chem.

[0212] Intermediate “C” N-methyl-5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-3-yl)picolinamide [ka] 5-(8-chloroisoquinoline-3-yl)-N-methylpicolinamide A mixture of 8-chloroisoquinoline-3-yltrifluoromethanesulfonate (11.9 g, 38.2 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (10.0 g, 38.2 mmol), Pd(dppf)Cl2 (2.80 g, 3.82 mmol), and K2CO3 (13.8 g, 100 mmol) in THF (250 mL) and H2O (50 mL) was stirred at 80°C for 3 hours. This mixture was poured into water (400 mL) and extracted with RINKAN (400 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (70%-90% petroleum ether in RINKAN) to obtain the title compound as a yellow solid (330 mg, 73%). MS(ES) + )C 16 H 12 ClN3O Theoretical value: 297, Measured value: 298 [M+H] + . [ka]

[0213] N-methyl-5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-3-yl)picolinamide. A suspension of the product from the previous step (3.5 g, 11.8 mmol), Pd2(dba)3 (1.08 g, 1.18 mmol), Cy3P (1.32 g, 4.72 mmol), AcOK (3.43 g, 35.0 mmol), and B2Pin2 (4.58 g, 18.0 mmol) in dioxane (200 mL) was stirred overnight at 120 °C. This mixture was poured into water (400 mL) and extracted with phenylethylamine (400 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (70%-100% phenylethylamine in petroleum ether) to obtain the title compound as a yellow solid (4.1 g, 89%). MS(ES) + )C 22 H 24 BN3O3 theoretical value: 389, measured value: 390 [M+H]+ .

[0214] Intermediate “D” 8-Chloro-7-fluoroisoquinoline-3-yltrifluoromethanesulfonate [ka] N-(2-chloro-3-fluorobenzyl)-2,2-diethoxyacetamide. A mixture of (2-chloro-3-fluorophenyl)methaneamine (12 g, 75 mmol) and ethyl 2,2-diethoxyacetate (19.93 g, 113.2 mmol) in MeOH (120 mL) was mixed with Et3N (22.87 g, 226.4 mmol). The mixture was stirred overnight at 80°C and then concentrated under reduced pressure. The residual oil was poured into water (150 mL), and the mixture was extracted with Et2O (150 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (40%-60%, SiO2 in petroleum ether) to obtain the title compound as a yellow solid (17.3 g, 79%). MS(ES) + )C 13 H 17 ClFNO3 theoretical value: 289, measured value: 290 [M+H] + . [ka] 8-Chloro-7-fluoroisoquinoline-3-ol The product from the previous step (17.3 g, 59.9 mmol) was dissolved in concentrated aq. H2SO4 (200 mL), and the mixture was stirred overnight under RT. This mixture was poured into ice water (400 mL) to adjust the pH to 7, and the mixture was extracted with Et2O (400 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as a yellow solid (15.8 g).

[0215] [ka] 8-Chloro-7-fluoroisoquinoline-3-yl-trifluoromethanesulfonate The mixture of the product from the previous step (15.8 g, 80.2 mmol), 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (34.36 g, 96.24 mmol), and Et3N (24.3 g, 241 mmol) in CH2Cl2 (500 mL) was stirred at RT for 3 hours, then poured into water (500 mL) and extracted with CH2Cl2 (500 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (3%-5%, siRNA in petroleum ether) to obtain the title compound as a yellow solid (14.7 g, 75%). MS(ES) + )C 10 H4ClF4NO3S Theoretical value: 329, Measured value: 330 [M+H] + .

[0216] Example 1 1-(1-(3-(2-methylthiazole-5-yl)isoquinoline-8-yl)-3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethane-1-one [ka] 5-(8-bromoisoquinoline-3-yl)-2-methylthiazole A mixture of 8-bromoisoquinoline-3-yltrifluoromethanesulfonate (0.90 g, 2.5 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (0.57 g, 2.5 mmol), NaHCO3 (0.63 g, 7.5 mmol), and Pd(PPh3)4 (280 mg, 0.25 mmol) in THF / H2O (20 mL / 4 mL) was degassed, purged with N2, and stirred overnight at 50°C. This mixture was concentrated under reduced pressure, and the residue was purified by SiO2 gel chromatography (0%~50%, Â in petroleum ether) to obtain the title compound as a yellow solid (450 mg, 60%). MS(ES) + ):C 13 H9BrN2S Theoretical value: 304, Measured value: 305 [M+H] + .

[0217] [ka] 2-Methyl-5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-3-yl)thiazole PdCl2 (dppf) (120 mg, 0.15 mmol) was added to a mixture of the product from the previous step (450 mg, 1.48 mmol), B2Pin2 (450 mg, 1.78 mmol), and KOAc (435 mg, 4.44 mmol) in dioxane (20 mL). The resulting mixture was purged with N2 for 5 minutes, then sealed and stirred overnight at 100°C. This mixture was concentrated under reduced pressure, and the residue was purified by SiO2 gel chromatography (0%~100%, SiO2 in petroleum ether) to obtain the title compound as a yellow solid (400 mg, 76%). MS(ES) + ):C 19 H 21 BN2O2S Theoretical value: 352, Measured value: 353 [M+H] + .

[0218] [ka] 1-(1-(3-(2-methylthiazole-5-yl)isoquinoline-8-yl)-3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethanone To a suspension of intermediate "B" (30 g, 80 mmol) in DMF (400 ml), the product from the previous step (28.2 g, 80.0 mmol), PdCl2(dppf)-CH2Cl2 (3.26 g, 4.00 mmol), and 2.0 M aq. K2CO3 (80 ml, 160 mmol) were added. The mixture was degassed by bubbling with N2 for 5 minutes, and the resulting mixture was then stirred under N2 at 100°C for 2 hours. After cooling the reaction to RT, it was treated with saturated aq. NaCl (200 mL), and the solid was removed by filtration. This mixture was extracted with siRNA (3 × 300 mL), and the combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with siRNA, and the precipitate was isolated to obtain the desired product. The filtrate was concentrated under reduced pressure, and the residue was purified by SiO2 gel chromatography (0% to 15% MeOH in CH2Cl2) to obtain the desired product. This product was then combined with the precipitate product described above to obtain the title compound as an off-white solid (13.5 g, 36%). MS!ES + )C 26 H 27 N5O2S Theoretical value: 473, Measured value: 474 [M+H] + . 1 H NMR (400MHz, DMSO-d6) (approximately 2:1 mixture of rotamers) δ 9.97(s,1H),8.38-8.37(m,2H),7.96-7.74(m,2H),7.56-7.47(m,1H),4.87(s,0.7H),4.79(d,1.3H),4.30-4.04(m,2H), 4.00-3.92(m,4H),3.59-3.38(m,2H),3.12(quintet,J=7.4Hz,1H),2.71(s,3H),2.11(s,2H),2.04(s,1H),1.94-1.71(m,4H).

[0219] Example 2 5-(8-(7-acetyl-3-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-yl)isoquinoline-3-yl)-N-methylpicolinamide [ka] To a degassed solution of intermediate "A" (83 mg, 0.25 mmol) in 4:1 dioxane / water (3 mL), intermediate "C" (100 mg, 0.25 mmol), K2CO3 (69 mg, 0.50 mmol), and Pd(dppf)Cl2 (20 mg, 0.025 mmol) were added, and the resulting mixture was stirred at 100°C for 2 hours. This mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC (mobile phase: A = 0.1% NH4HCO3 / H2O, B = MeCN; gradient: B = 35% to 75% over 14 minutes; column: C18) to obtain the title compound as a white solid (28 mg, 24%). MS!ES + ):C 27 H 26 N6O2 theoretical value: 466, measured value: 467 [M+H] + . 1 H NMR (500MHz, CDCl3) (approximately 2:1 mixture of rotamers) δ 9.83-9.82(m,1H),9.41-9.22(m,1H),8.68-8.43(m,1H),8.35-8.32(m,1H),8.17-8.11(m,2H),7.93-7.57(m,2H),7.57-7.43(m,1H),4 .87(s,0.7H),4.75(s,1.3H),4.37-3.83(m,4H),3.08(d,J=5.0Hz,3H),2.24(s,1H),2.12(s,2H),1.95-1.81(m,1H),1.18-1.04(m,4H).

[0220] Example 3 5-(8-(7-acetyl-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-yl)isoquinoline-3-yl)-N-methylpicolinamide [ka] A suspension of intermediate "C" (7.00 g, 18.0 mmol), intermediate "B" (6.75 g, 18.0 mmol), Pd(dppf)Cl2 (1.32 g, 1.80 mmol), and K2CO3 (7.5 g, 54 mmol) in THF (200 mL) and water (40 mL) was degassed by purging with N2, and the mixture was stirred under N2 at 80°C for 3 hours. This mixture was poured into water (400 mL) and extracted with SiO2 (400 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (0%-10% MeOH in SiO2) to obtain the title compound as a yellow solid (4.6 g, 50%). MS!ES + )C 29 H 30 N6O3 theoretical value: 510, measured value: 511 [M+H] + . 1 ¹H NMR (500MHz, CD3OD) (approximately a 2:1 mixture of rotational isomers) δ 9.70 (s, 0.3H), 9.69 (s, 0.7H), 9.40 (br s, 1H), 8.68-8.67 (m, 1H), 8.49 (s, 0.3H), 8.48 (s, 0.7H), 8.23 ​​(obvious d, J=8.2Hz, 1H), 8.09-8.06 (m, 1H), 7.91-7.87 (m, 1H), 7.71-7.66 (m, 1H), 4.86 (s, 0.7H), 4.82 (s, 1.3H), 4.33 (t, J=5.5Hz,1.3H),4.23(t,J=5.4Hz,0.7H),4.15-4.01(m,4H),3.65(t,J=11.8Hz,2H),3.26- 3.21(m,1H),3.03(s,3H),2.24(s,2H),2.12(s,1H),2.12-2.02(m,2H),1.98-1.83(m,2H).

[0221] Example 4 5-(8-(7-acetyl-3-(2-oxabicyclo[2.2.2]octan-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-yl)isoquinoline-3-yl)-N-methylpicolinamide [ka] 2-Oxabicyclo[2.2.2]octane-4-carboxylic acid A mixture of 2-oxabicyclo[2.2.2]octan-4-ylmethanol (3.00 g, 21.1 mmol) in acetone (50 mL) at 0°C was mixed with Jones' reagent (18.6 mL, 49.7 mmol). The mixture was stirred at RT for 1 hour, then diluted with water (50 mL) and extracted with RINKAN (50 mL x 3). The combined organic layer was washed with saturated aq. NaCl (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (0%-10% MeOH in CH2Cl2) to obtain the title compound as a white solid (2.73 g, 83%). MS(ES) - ):C8H 12 O3 theoretical value: 156, measured value: 155 [MH] - .

[0222] [ka] N-(pyrazine-2-ylmethyl)-2-oxabicyclo[2.2.2]octane-4-carboxamide HATU (7.31 g, 19.2 mmol) was added to a mixture of the product from the previous step (2.73 g, 17.5 mmol), pyrazine-2-ylmethaneamine (2.10 g, 19.2 mmol), and DIEA (8.67 mL, 2.44 mmol) in DMF (45 mL). This mixture was stirred at RT for 1 hour and then concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (0%-5% MeOH in CH2Cl2) to obtain the title compound as a yellow solid (3.30 g, 76%). MS (ES) + ):C 13 H17 N3O2 theoretical value: 247, measured value: 248 [M+H] + .

[0223] [ka] 3-(2-oxabicyclo[2.2.2]octan-4-yl)imidazo[1,5-a]pyrazine To a solution of the product from the previous step (2.00 g, 8.09 mmol) and N,N-dimethylaniline (206.33 μl, 1.62 mmol) in dioxane (160 mL), phosphorus oxychloride (3.77 mL, 40.4 mmol) and Et3N (3.37 mL, 24.3 mmol) were added. The resulting mixture was stirred at 90°C for 4 hours and then partially concentrated under reduced pressure. The residue was treated with saturated aq. NaHCO3 (50 mL) with ice, and the layers were separated. The aqueous phase was extracted with siRNA (3 × 100 mL), and the combined organic layers were washed with saturated aq. NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (0%~10% MeOH in CH2Cl2) to obtain the title compound as a yellow solid (819.00 mg, 44%). MS(ES) + ):C 13 H 15 N3O Theoretical value: 229, Measured value: 230 [M+H] + .

[0224] [ka] 3-(2-oxabicyclo[2.2.2]octan-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine To a mixture of the product from the previous step (1.51 g, 6.59 mmol) in EtOH (90 mL), 10% Pd / C (1.00 g, 940 μmol) was added. The mixture was stirred under H2 (balloon) at RT for 5 hours, then filtered and concentrated under reduced pressure to obtain the title compound as a yellow solid (1.55 g, quantitative analysis). MS(ES) + ):C 13 H19 N3O Theoretical value: 233, Measured value: 234 [M+H] + .

[0225] [ka] 1-(3-(2-oxabicyclo[2.2.2]octan-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethanone To a solution of the product from the previous step (1.55 g, 6.64 mmol) in CH2Cl2 (75 ml) at 0°C, Et3N (2.77 mL, 19.9 mmol) and acetic anhydride (935.92 μl, 9.90 mmol) were added. The resulting mixture was stirred for 1 hour, then treated with saturated aq. NaHCO3 and extracted with CH2Cl2 (75 mL × 3). The combined organic layer was washed with saturated aq. NaCl (45 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound as yellow oil (1.40 g, 77%). MS(ES) + ):C 15 H 21 N3O2 theoretical value: 275, measured value: 276 [M+H] + .

[0226] [ka] 1-(3-(2-oxabicyclo[2.2.2]octan-4-yl)-1-bromo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethanone. NBS (904.95 mg, 5.08 mmol) was added to a mixture of the product from the previous step (1.50 g, 5.08 mmol) in THF (60 mL). The mixture was stirred at RT for 15 minutes, then poured into ice water and extracted with CH2Cl2 (75 mL x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (0%-10% MeOH in CH2Cl2) to obtain the title compound as a white solid (1.16 g, 64%). MS(ES) + ):C15 H 20 BrN3O2 theoretical value: 353, measured value: 354 [M+H] + .

[0227] [ka] 5-(8-(7-acetyl-3-(2-oxabicyclo[2.2.2]octan-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-yl)isoquinoline-3-yl)-N-methylpicolinamide The mixture of intermediate "C" (1.65 g, 4.25 mmol), the product from the previous step (1.16 g, 3.27 mmol), and Pd(dppf)Cl2 (272.40 mg, 326.89 μmol) in THF (75 mL) was degassed by purging with N2, and then treated with 2.0 M aq. K2CO3 (4.9 mL, 9.8 mM) injected by syringe. The mixture was purged three times with N2 and stirred overnight at 90°C under N2. The mixture was concentrated, and the residue was purified by SiO2 gel chromatography (0% to 75% in CH2Cl2 (10% MeOH in SiO)) to obtain the title compound as a pale yellow solid (1.29 g, 73%). MS!ES + ):C 31 H 32 N6O3 theoretical value: 536, measured value: 537 [M+H] + . 1¹H NMR (400 MHz, CDCl3) (approximately 1:1 mixture of rotational isomers) δ 9.85 (obvious d, J=10.7 Hz, 1H), 9.28 (obvious d, J=5.4 Hz, 1H), 8.57 (obvious d, J=8.1 Hz, 1H), 8.32 (obvious d, J=8.1 Hz, 1H), 8.15 (obvious d, J=9.2 Hz, 1H), 8.14-8.10 (m, 1H), 7.89-7.84 (m, 1H), 7.77-7.73 (m,1H),7.51-7.47(m,1H),4.84(s,1H),4.75(s,1H),4.43-4.21(m,4H),4.09-3.83(m,3H) ,3.08(d,J=5.1Hz,3H),2.33-2.20(m,6H),2.20(s,1.5H),2.09(s,1.5H)1.89-1.72(m,2H).

[0228] Example 5 5-(8-(7-acetyl-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-yl)-7-fluoroisoquinoline-3-yl)-N-methylpicolinamide [ka] 5-(8-chloro-7-fluoroisoquinoline-3-yl)-N-methylpicolinamide To a degassed solution of intermediate "D" (1.00 g, 3.04 mmol) in 4:1 THF / water (50 mL), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (0.797 g, 3.04 mmol), K2CO3 (839 mg, 6.08 mmol), and Pd(dppf)Cl2 (244 mg, 0.333 mmol) were added. The resulting mixture was stirred at 100°C for 6 hours and then concentrated under reduced pressure. The residue was made into a slurry in water (20 mL), and the solid was isolated by filtration to obtain the title compound as a gray solid (0.7 g, 73%). MS(ES) + )C 16 H 11 ClFN3O Theoretical value: 315, Measured value: 316 [M+H] + .

[0229] [ka] 5-(7-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-3-yl)-N-methylpicolinamide To a degassed solution of the product from the previous step (60 mg, 0.19 mmol) in dioxane (3 mL), B2Pin2 (720 mg, 0.285 mmol), KOAc (37 mg, 0.38 mmol), tricyclohexylphosphine (5.3 mg, 0.019 mmol), and Pd2(dba)3 (17 mg, 0.019 mmol) were added. The resulting mixture was stirred under argon at 110°C for 16 hours in a sealed tube, then concentrated under reduced pressure to obtain the crude compound of the title, which was used directly in the next step. MS(ES) + )C 22 H 23 BFN3O3 theoretical value: 407, measured value: 408 [M+H] + .

[0230] [ka] tert-butyl5-(8-(7-acetyl-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-yl)-7-fluoroisoquinoline-3-yl)-N-methylpicolinamide To a degassed solution of intermediate "B" (considered to be 0.19 mmol) in 4:1 dioxane / water (10 mL), the product from the previous step (76 mg, 0.19 mmol), K2CO3 (50 mg, 0.36 mmol), and Pd(dppf)Cl2 (14 mg, 0.018 mmol) were added. The resulting mixture was stirred at 100°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (mobile phase: A=0.1% NH4HCO3 / H2O, B=MeCN; gradient: B=25%~65% over 12 mins; column: C18) to obtain the title compound as a white solid (7.5 mg, 7%). MS!ES+ )C 29 H 29 FN6O3 theoretical value: 528, measured value: 529 [M+H] + . 1 ¹H NMR (500 MHz, CD3OD) (approximately a 2:1 mixture of rotational isomers): δ 9.82 (s, 0.7H), 9.75 (s, 0.3H), 9.30-9.28 (m, 1H), 8.66 (obvious d, J=8.1 Hz, 1H), 8.50 (obvious d, J=8.2 Hz, 1H), 8.23-8.15 (m, 2H), 7.79-7.73 (m, 1H), 4.76 (s, 0.7H), 4.71 (s, 1.3H) ,4.34(t,J=6.0Hz,1.3H),4.25(t,J=5.5Hz,0.7H),4.10-4.06(m,4H),3.65(t,J=12.0 Hz,2H),3.27-3.23(m,1H),3.02(s,3H),2.25(s,2H),2.14(s,1H),2.09-1.96(m,4H).

[0231] Example 6 1-(1-(7-fluoro-3-(2-methylthiazole-5-yl)isoquinoline-8-yl)-3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethane-1-one [ka] 5-(8-chloro-7-fluoroisoquinoline-3-yl)-2-methylthiazole. A mixture of dioxane (15 mL) and intermediate "D" (500 mg, 1.52 mmol) in H2O (3 mL), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (412 mg, 1.83 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), and K2CO3 (630 mg, 4.56 mmol) was stirred at 80°C for 2 hours. This mixture was poured into water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 gel chromatography (70%-100% ethyl acetate in petroleum ether) to obtain the title compound as a gray solid (460 mg, 100%). MS(ES) + )C 13 H8ClFN2S Theoretical value: 278, Measured value: 279 [M+H] + .

[0232] [ka] 5-(7-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-3-yl)-2-methylthiazole. The product from the previous step (70 mg, 0.25 mmol) in dioxane (3 mL) was mixed with Pd2(dba)3 (28 mg, 0.03 mmol), Cy3P (23 mg, 0.08 mmol), KOAc (106 mg, 1.08 mmol), and B2Pin2 (97 mg, 0.38 mmol) and stirred overnight at 120°C. This mixture was cooled to RT, filtered, and the filtrate was concentrated to obtain the crude compound of the title (63 mg, 68%), which was used without further purification. MS(ES) + )C 19 H 20 BFN2O2S Theoretical value: 370, Measured value: 371 [M+H] + .

[0233] [ka] 1-(1-(7-fluoro-3-(2-methylthiazole-5-yl)isoquinoline-8-yl)-3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)ethanone To a degassed solution of intermediate "B" (70 mg, 0.18 mmol) in 4:1 dioxane / water (10 mL), 5-(7-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-3-yl)-2-methylthiazole (68.8 mg, 0.186 mmol), K2CO3 (50 mg, 0.37 mmol), and Pd(dppf)Cl2 (14 mg, 0.018 mmol) were added. The resulting mixture was stirred at 100°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (mobile phase: A=0.1% NH4HCO3 / H2O, B=MeCN; gradient: B=30%~85% over 11 min; column: C18) to obtain the title compound as a white solid (13.5 mg, 15%). MS!ES + )C 26 H 26 FN5O2S Theoretical value: 491, Measured value: 492 [M+H] + . 1 H NMR (500MHz, CDCl3) (approximately 2:1 mixture of rotamers) δ 9.62(s,0.7H),9.56(s,0.3H),8.18(s,1H),7.92-7.91(m,1H),7.84-7.81(m,1H),7.52(explicit t,J=9.4Hz,1H),4.74(s,0.7H),4. 65(s,1.3H),4.33-3.96(m,6H),3.56(t,J=11.7Hz,2H),3.02-2.83(m,1H),2.77(s,3H),2.27-2.01(m,5H),1.90-1.88(m,2H).

[0234] The activity of the compounds in Examples 1-6 as inhibitors of CBP and BRD4 will be described in the following assays. Other compounds listed above (which have not yet been prepared and / or tested) are also expected to exhibit activity in these assays.

[0235] Bioactivity assay The specific binding of CBP or BRD4 bromodomains to acetylated peptides derived from H4 histone substrates (tetraacetylated H4(1-21)Ac-K5 / 8 / 12 / 16) was measured in the absence or presence of inhibitors. GST-tagged bromodomains of CBP (1081-1197) and BRD4 (49-170) were obtained from BPS Bioscience, and their binding to biotinylated H4(1-21)Ac-K5 / 8 / 12 / 16 (AnaSpec.64989) was evaluated using AlphaScreen technology (Perkin Elmer).

[0236] CBP AlphaScreen assay: 5 nM GST-CBP (1081-1197) and 20 nM biotin-H4 (1-21)Ac-K5 / 8 / 12 / 16 (AnaSpec.64989) were incubated with various concentrations of CBP inhibitors in 15 μL of buffer containing 50 mM HEPES 7.5, 100 nM NaCl, 1 mM TCEP, and 0.003% Tween-20. After incubation at room temperature for 30 minutes, 15 μL of detection buffer (BPS Bio.33006) containing 7 μg / mL glutathione AlphaLisa acceptor beads (Perkin Elmer AL109) and 14 μg / mL streptavidin donor beads (Perkin Elmer 676002) was added to the previous mixture. The reaction mixture was incubated at room temperature for a further 2 hours, and the AlphaScreen signal was quantified using an Envision Multilabel plate reader. As a negative control, GST-CBP(1081-1197) was incubated with non-acetylated biotin-H4(1-21) peptide (AnaSpec.62555) in the presence of a final DMSO concentration of 0.25%.

[0237] BRD4 AlphaScreen assay: The binding of 2.5 nM BRD4(49-170) to 10 nM biotin-H4(1-21)Ac-K5 / 8 / 12 / 16 (AnaSpec.64989) was evaluated using the same procedure as described for the CBP assay. Standard dose-response curves were fitted using a variable gradient model with Geneda Screener software. Signal = Signal 陰性対照 +(signal) DMSO対照 -signal 陰性対照 ) / (1+(IC 50 / dose)^Hill slope).

[0238] In this equation, only the signal and dose were treated as known values.

[0239] The results are shown in Table 1 below. The table shows that the compounds described herein inhibit CBP and are more selective than BRD4. Structural analogs 7 and 8 were previously disclosed in U.S. Patent Application Publication 2019 / 0298729 (U.S. Patent Application No. 16 / 370,404), which is incorporated herein by reference in whole.

[0240] [Table 1]

[0241] [Table 2]

[0242] DOHH2 proliferation assay: On day 1, 1000 DOHH2 cells were inoculated into 384-well TC plates (PerkinElmer #6007680) in 40 μL RPMI1640 medium. CBP inhibitors were added to all wells except for column 13, which contained 3.3 μM staurosporine as a negative control. DMSO was added at 0.1% in all wells. Cells were lysed, and viability was counted on day 7 using 40 μL CellTiter-Glo (Promega #G9243). Luminescence signals were quantified using an Envision Multilabel plate reader, and standard dose-response curves were fitted using a variable gradient model with Geneda Screener software: signal = signal 陰性対照 +(signal) DMSO対照 -signal 陰性対照 ) / (1+(IC 50 / dose)^Hill slope).

[0243] In this equation, only the signal and dose were treated as known values.

[0244] The assay results are shown below.

[0245] [Table 3]

[0246] [Table 4]

[0247] The compounds described herein exhibit unexpected improvements in in vivo pharmacokinetics, particularly clearance and half-life, in mice, which serve as an in vivo model used to screen pharmacokinetic behavior that is not predicted by in vitro microsomal stability data and is not due to obvious structural reasons. Relevant comparative data are shown in Tables 3 and 4. Table 3 shows that the in vitro microsomal stability of compounds 1 and 3 is similar to or lower than that of previously disclosed structural analogues. However, as shown in Table 4, the mouse in vivo clearance of compounds 1 and 3 is dramatically reduced and the half-life is increased compared to previously disclosed structural analogues.

[0248] [Table 5]

[0249] [Table 6]

[0250] Compound 1 was further characterized in vivo pharmacokinetically in rats, monkeys, and dogs. Table 5 shows the microsomal stability of Compound 1 in species not yet shown in Table 3. Table 6 shows the pharmacokinetic parameters in rats, monkeys, and dogs after single intravenous (IV) and oral (PO) administration.

[0251] [Table 7]

[0252] [Table 8]

[0253] Microsomal Stability. Microsomal stability assays were performed using a Beckmann Biomek FXp laboratory automation system. The hepatic microsome incubation mixture consisted of hepatic microsomes (0.5 mg microsomal protein / mL), compound (1 μm), MgCl2 (3 mM), and EDTA (1 mM) in potassium phosphate buffer (100 mM, pH 7.4). Midazolam and ketanserin were used as assay control substrates. The reaction was initiated by adding NADPH regeneration solution (1.3 mM NADPH) and maintained at 37°C with shaking. At five time points ranging from 0 to 45 minutes, a fixed volume (50 μL) was taken and quenched with acetonitrile (100 μL) containing an internal standard (imipramine). After vortexing and centrifugation, the samples were analyzed by LC-MS / MS. In vitro half-life and clearance calculations followed literature guidelines.

[0254] In vivo pharmacokinetics The IV (intravenous) dose was prepared in 20% DMSO + 60% PEG400 + 20% water. The PO (oral) dose was prepared in 0.5% methylcellulose in water.

[0255] Mice: Female mice weighing 20-30g (CD1 strain, purchased from Shanghai JH Laboratory Animal Co., LTD) were used in the study. All animals had free access to feed and water. The test product was administered via tail vein (IV dose) or forced oral administration (PO dose). Blood samples were collected from all animals before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration in tubes containing the anticoagulant K2EDTA (3 animals per time point, 3 time points per animal). Plasma was separated from blood by centrifugation at 4°C and stored at -70°C until analysis. The concentration of the test product in plasma was quantified using liquid chromatography and tandem mass spectrometry (LC-MS / MS).

[0256] Rats: Male rats weighing 200-300g (SD strain, purchased from Shanghai JH Laboratory Animal Co., Ltd.) were used in the study. The animals were fasted overnight and fed for 4 hours after administration. All animals had free access to water. The test product was administered via dorsal foot vein (IV dose) or forced oral administration (PO dose). Blood samples were collected from all animals via the tail vein in tubes containing the anticoagulant K2EDTA before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Plasma was separated from blood by centrifugation at 4°C and stored at -70°C until analysis. The concentration of the test product in plasma was quantified using liquid chromatography and tandem mass spectrometry (LC-MS / MS).

[0257] Dogs: Male Beagle dogs weighing 7-10 kg (purchased from Beijing Marshall Biotechnology Co., Ltd.) were used in the study. The animals were fasted overnight and fed for 4 hours after administration. The test product was administered to the dogs via cephalic vein (IV dose) or forced oral administration (PO dose). Blood samples were collected from all animals via saphenous vein or cephalic vein into tubes containing the anticoagulant K2EDTA before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Plasma was separated from blood by centrifugation at 4°C and stored at -70°C until analysis. The concentration of the test product in plasma was quantified using liquid chromatography and tandem mass spectrometry (LC-MS / MS).

[0258] Monkeys: Male cynomolgus macaques weighing 3-5 kg ​​(purchased from Hainan Jingang Biotech.Co.,Ltd) were used in the study. The animals were fasted overnight and fed for 4 hours after administration. The test product was administered to the monkeys via cephalic vein (IV dose) or forced intranasal administration (PO dose). Blood samples were collected from all animals via saphenous vein or cephalic vein into tubes containing the anticoagulant K2EDTA before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Plasma was separated from blood by centrifugation at 4°C and stored at -70°C until analysis. The concentration of the test product in plasma was quantified using liquid chromatography and tandem mass spectrometry (LC-MS / MS).

[0259] DOHH2 xenotransplantation study: 4-6 week old CB17 / scid female mice (Jackson Labs) were transplanted with DOHH2 cells (1 × 10⁶ dilution in Matrigel). 6 Cells (in a mouse) are injected subcutaneously into the right flank and transplanted, then monitored by caliper measurement at a depth of 200-300 mm. 3 The tumors were allowed to grow to an average volume. The animals were then randomized into groups of eight. All animals were free-fed LabDiet5053 solid feed. The animals were orally administered Example 1, formulated in a vehicle of 0.5% methylcellulose in sterile water (50 mg / kg, BID schedule of 5 days with administration / 2 days without). Tumor volume was measured twice weekly by caliper and calculated using the following formula: V=l 2 *L / 2 (l = length; L = width). Weight was monitored throughout the study period. GraphPad Prism was used to generate the graphs, and the data are expressed as mean ± standard error of the mean.

[0260] All references, patents, or patent applications (in the United States or abroad) cited herein are incorporated herein by reference as if they were contained in their entirety. In the event of any conflict, the material literally disclosed herein shall prevail.

[0261] From the foregoing description, those skilled in the art will readily recognize the essential features of this disclosure and can make various modifications and alterations to adapt it to various uses and conditions without departing from its intent and scope. This specification includes the following disclosures: <Note 1> Compounds having the following structural formula I: [ka] or its salt (In the formula, X 1 N is X 2 CH is; R 1 The R is selected from cyclopropyl, tetrahydro-2H-pyran-4-yl, and 2-oxabicyclo[2.2.2]octan-4-yl, any one of which may contain one or two R 5 Substituted by the group; R 2 It is methyl; R 3 The R is selected from pyridine-3-yl and thiazole-5-yl, and optionally contains one or two R 7 Substituted by the group; R 4 is selected from H and fluoro; Each R 5 The elements are independently selected from alkyl, alkoxy, cyano, carboxy, halo, haloalkyl, haloalkoxyl, hydroxy, and oxo; R 7 Each occurrence is -C(O)NR 8 R 9 and selected independently from alkyl, and R 8 and R 9 (The element is independently selected from hydrogen and alkyl). <Note 2> R 1 This refers to a compound selected from cyclopropyl and tetrahydro-2H-pyran-4-yl, or a salt thereof, as described in Appendix 1. <Note 3> R 3 This refers to a compound or salt thereof, selected from 6-(methylcarbamoyl)pyridine-3-yl and 2-methylthiazole-5-yl, as described in Appendix 1 or 2. <Note 4> The compound described in Appendix 1, having the following structural formula I:

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Claims

1. The compound represented by the following structural formula: 【Chemistry 1】 , or its salt.

2. A pharmaceutical composition comprising the compound or salt thereof described in claim 1 together with a pharmaceutically acceptable carrier.

3. A method for inhibiting CBP, comprising contacting CBP with the compound or salt thereof described in claim 1 (except when the method is performed in the human body).

4. A method for inhibiting P300, comprising contacting P300 with the compound or salt thereof described in claim 1 (except when the method is performed in the human body).

5. A pharmaceutical agent for the treatment of diseases mediated by CBP or P300, comprising the compound or a salt thereof described in claim 1.

6. The pharmaceutical product according to claim 5, wherein the disease is selected from proliferative disorders, inflammatory disorders, autoimmune diseases, and fibrosis.

7. The pharmaceutical product according to claim 6, wherein the disease is a proliferative disorder.

8. The pharmaceutical product according to claim 7, wherein the disease is cancer.

9. The aforementioned cancers include: neuroma of the inner ear, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic lung cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, and diffuse large B-cell leukemia. Lymphoma, proliferative abnormalities, embryonic carcinoma, endometrial cancer, endometrial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glial cell tumor, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, white blood cell carcinoma Hematological cancers, liposarcomas, lung cancers, intralymphatic sarcomas, lymphangiosarcomas, lymphocytic leukemias, lymphomas, lymphoid neoplasms of T-cell or B-cell origin, medullary carcinomas, medulloblastomas, melanomas, meningiomas, mesotheliomas, multiple myelomas, myeloid leukemias, myelomas, myxosarcomas, neuroblastomas, NUT midline carcinoma (NMC), non-small cell lung cancers, oligodendrogliomas, oral cancers, osteosarcomas, ovarian cancers, pancreatic cancers, papillary carcinomas, papillary carcinomas The pharmaceutical product according to claim 8, selected from pineal gland tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminomas, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synoviomas, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumor, uterine cancer, and Wilms' tumor.

10. The pharmaceutical product according to claim 9, wherein the cancer is selected from lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and melanoma.

11. A pharmaceutical product according to any one of claims 8 to 10, for use in combination with a cytotoxic agent.

12. The pharmacopoeia according to claim 11, wherein the cytotoxic agent is selected from microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signaling pathway inhibitors, nonreceptor tyrosine kinase angiogenesis inhibitors, immunotherapy agents, apoptosis promoters, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and cancer metabolism inhibitors.

13. A pharmaceutical product according to any one of claims 8 to 12, for use in conjunction with non-chemical methods for treating cancer.

14. The non-chemical method of cancer treatment is selected from surgery, radiotherapy, cauterization, focused ultrasound therapy, and cryotherapy, according to claim 13.

15. The pharmaceutical product according to claim 6, wherein the disease is an autoimmune disease.

16. The aforementioned autoimmune diseases include Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behçet's disease, bullous skin diseases, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, and organ transplant rejection. The pharmaceutical product according to claim 15, selected from osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, interstitial pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock syndrome, thyroiditis, type 1 diabetes mellitus, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

17. The pharmaceutical product according to claim 6, wherein the disease is fibrosis.

18. The pharmacopoeia according to claim 17, wherein the fibrosis is selected from pulmonary fibrosis, silicosis, cystic fibrosis, renal fibrosis, hepatic fibrosis, cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, endocardial myocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive large fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloid, myocardial infarction, systemic sclerosis, or articular fibrosis.

19. The pharmacopoeia according to claim 18, wherein the fibrosis is pulmonary fibrosis.

20. The pharmacopoeia according to claim 19, wherein the pulmonary fibrosis is selected from idiopathic pulmonary fibrosis, fibrous interstitial lung disease, interstitial pneumonia, fibrotic variant of nonspecific interstitial pneumonia, cystic fibrosis, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), or pulmonary arterial hypertension.

21. A pharmaceutical product for use in a method for treating a CBP-mediated disease, comprising the compound or salt thereof described in claim 1, wherein the method is (a) A therapeutically effective amount of the compound or a salt thereof, (b) Second therapeutic agent and A pharmaceutical product, including the administration of [a specific substance].

22. A pharmaceutical product for use in a method for treating a P300-mediated disease, comprising the compound or salt thereof described in claim 1, wherein the method is (a) A therapeutically effective amount of the compound or a salt thereof, (b) Second therapeutic agent and A pharmaceutical product, including the administration of [a specific substance].

23. A pharmaceutical product comprising the compound or a salt thereof described in claim 1, for achieving an effect in a patient, wherein the effect is a reduction in inflammation.

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