THERAPEUTIC COMPOUNDS AND USES THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of CBP/EP300 and methods of treating cancer using such inhibitors.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Nov. 23, 2015, is named 01076.024US3_SL.txt and is 6,794 bytes in size.

BACKGROUND OF THE INVENTION

Chromatin is a complex combination of DNA and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells and is divided between heterochromatin (condensed) and euchromatin (extended) forms. The major components of chromatin are DNA and proteins. Histones are the chief protein components of chromatin, acting as spools around which DNA winds. The functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication. The chromatin structure is controlled by a series of post-translational modifications to histone proteins, notably histones H3 and H4, and most commonly within the “histone tails” which extend beyond the core nucleosome structure. Histone tails tend to be free for protein-protein interaction and are also the portion of the histone most prone to post-translational modification. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, and SUMOylation. These epigenetic marks are written and erased by specific enzymes that place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription.

Of all classes of proteins, histones are amongst the most susceptible to post-translational modification. Histone modifications are dynamic, as they can be added or removed in response to specific stimuli, and these modifications direct both structural changes to chromatin and alterations in gene transcription. Distinct classes of enzymes, namely histone acetyltransferases (HATs) and histone deacetylases (HDACs), acetylate or de-acetylate specific histone lysine residues (Struhl K., Genes Dev., 1989, 12, 5, 599-606).

Bromodomains, which are approximately 110 amino acids long, are found in a large number of chromatin-associated proteins and have been identified in approximately 70 human proteins, often adjacent to other protein motifs (Jeanmougin F., et al., Trends Biochem. Sci., 1997, 22, 5, 151-153; and Tamkun J. W., et al., Cell, 1992, 7, 3, 561-572). Interactions between bromodomains and modified histones may be an important mechanism underlying chromatin structural changes and gene regulation. Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation and viral replication. See, e.g., Prinjha et al., Trends Pharm. Sci., 33(3):146-153 (2012) and Muller et al., Expert Rev., 13(29): 1-20 (September 2011).

Cell-type specificity and proper tissue functionality requires the tight control of distinct transcriptional programs that are intimately influenced by their environment. Alterations to this transcriptional homeostasis are directly associated with numerous disease states, most notably cancer, immuno-inflammation, neurological disorders, and metabolic diseases. Bromodomains reside within key chromatin modifying complexes that serve to control distinctive disease-associated transcriptional pathways. This is highlighted by the observation that mutations in bromodomain-containing proteins are linked to cancer, as well as immune and neurologic dysfunction. Hence, the selective inhibition of bromodomains across a specific family, such as the selective inhibition of a bromodomain of CBP/EP300, creates varied opportunities as novel therapeutic agents in human dysfunction.

There is a need for treatments for cancer, immunological disorders, and other CBP/EP300 bromodomain related diseases.

SUMMARY OF THE INVENTION
Compounds of Formula (I) or Formula (II)

One aspect is a compound of formula (I) or formula (II):

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or a salt thereof, wherein:

R¹of Formula (I) is C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R¹is optionally substituted with one or more groups R^b;

R²of Formula (I) is selected from C₆-C₂₀aryl, C₁-C₂₀heteroaryl, —(C₆-C₂₀aryl)-(C₁-C₂₀heteroaryl), —(C₁-C₂₀heteroaryl)-(C₆-C₂₀aryl), and —(C₁-C₂₀heteroaryl)-(C₁-C₂₀heteroaryl), wherein each C₆-C₂₀aryl, C₁-C₂₀heteroaryl, —(C₆-C₂₀aryl)-(C₁-C₂₀heteroaryl) and —(C₁-C₂₀heteroaryl)-(C₁-C₂₀heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from R^c, oxo, —F, —Cl, —Br, —I, —NO₂, —N(R^a)₂, —CN, —C(O)—N(R^a)₂, —S(O)—N(R^a)₂, —S(O)₂—N(R^a)₂, —O—R^a, —S—R^a, —O—C(O)—R^a, —O—C(O)—O—R^a, —C(O)—R^a, —C(O)—O—R^a, —S(O)—R^a, —S(O)₂—R^a, —O—C(O)—N(R^a)₂, —N(R^a)—C(O)—OR^a, —N(R^a)—C(O)—N(R^a)₂, —N(R^a)—C(O)—R^a, —N(R^a)—S(O)—R^a, —N(R^a)—S(O)₂—R^a, —N(R^a)—S(O)—N(R^a)₂, and —N(R^a)—S(O)₂—N(R^a)₂;

R³of Formula (I) is C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R³is optionally substituted with one or more groups R^e; or

R²and R³of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups R^e;

R⁴of Formula (I) is C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(R^h)₂, —S(O)—N(R^h)₂, —S(O)₂—N(R^h)₂, —C(O)—R^h, —C(O)—O—R^h, —S(O)—R^h, or —S(O)₂—R^h, wherein any C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R^h)₂, —S(O)—N(R^h)₂, —S(O)₂—N(R^h)₂, —O—R^h, —S—R^h, —O—C(O)—R^h, —O—C(O)—O—R^h, —C(O)—R^h, —C(O)—O—R^h, —S(O)—R^h, —S(O)₂—R^h, —O—C(O)—N(R^h)₂, —N(R^h)—C(O)—OR^h, —N(R^h)—C(O)—N(R^h)₂, —N(R^h)—C(O)—R^a, —N(R^h)—S(O)—R^h, —N(R^h)—S(O)₂—R^h, —N(R^h)—S(O)—N(R^h)₂, and —N(R^h)—S(O)₂—N(R^h)₂;

each R^aof Formula (I) is independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-6alkoxy, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^aare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C_1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^bof Formula (I) is independently selected from oxo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO₂, —N(R^c)₂, —CN, —C(O)—N(R^c)₂, —S(O)—N(R^c)₂, —S(O)₂—N(R^c)₂, —O—R^c, —S—R^c, —O—C(O)—R^c, —O—C(O)—O—R^c, —C(O)—R^c, —C(O)—O—R^c, —S(O)—R^c, —S(O)₂—R^c, —O—C(O)—N(R^c)₂, —N(R^c)—C(O)—OR^c, —N(R^c)—C(O)—N(R^c)₂, —N(R^c)—C(O)—R^c, —N(R^c)—S(O)—R^c, —N(R^c)—S(O)₂—R^c, —N(R^c)—S(O)—N(R^c)₂, and —N(R^c)—S(O)₂—N(R^c)₂, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^c)₂, —CN, —C(O)—N(R^c)₂, —S(O)—N(R^c)₂, —S(O)₂—N(R^c)₂, —O—R^c, —S—R^c, —O—C(O)—R^c, —C(O)—R^c, —C(O)—O—R^c, —S(O)—R^c, —S(O)₂—R^c, —C(O)—N(R^c)₂, —N(R^c)—C(O)—R^c, —N(R^c)—S(O)—R^c, —N(R^c)—S(O)₂—R^cand C_1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^cof Formula (I) is independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^d)₂, —CN, —C(O)—N(R^d)₂, —S(O)—N(R^d)₂, —S(O)₂—N(R^d)₂, —O—R^d, —S—R^d, —O—C(O)—R^d, —C(O)—R^d, —C(O)—O—R^d, —S(O)—R^d, —S(O)₂—R^d, —C(O)—N(R^d)₂, —N(R^d)—C(O)—R^d, —N(R^d)—S(O)—R^d, —N(R^d)—S(O)₂—R^d, and C_1-6alkyl, which carbocyclyl and C_1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C_1-6alkyl, cyano, —N(R^d)₂, —O—R^d, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C_1-6alkyl;

each R^dof Formula (I) is independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-6alkoxy, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^dare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C_1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^eof Formula (I) is independently selected from oxo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO₂, —N(R^f)₂, —CN, —C(O)—N(R^f)₂, —S(O)—N(R^f)₂, —S(O)₂—N(R^f)₂, —O—R^f, —S—R^f, —O—C(O)—R^f, —O—C(O)—O—R^f, —C(O)—R^f, —C(O)—O—R^f, —S(O)—R^f, —S(O)₂—R^f, —O—C(O)—N(R^f)₂, —N(R^f)—C(O)—OR^f, —N(R^f)—C(O)—N(R^f)₂, —N(R^f)—C(O)—R^f, —N(R^f)—S(O)—R^f, —N(R^f)—S(O)₂—R^f, —N(R^f)—S(O)—N(R^f)₂, and —N(R^f)—S(O)₂—N(R^f)₂, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^f)₂, —CN, —C(O)—N(R^f)₂, —S(O)—N(R^f)₂, —S(O)₂—N(R^f)₂, —O—R^f, —S—R^f, —O—C(O)—R^f, —C(O)—R^f, —C(O)—O—R^f, —S(O)—R^f, —S(O)₂—R^f, —C(O)—N(R^f)₂, —N(R^f)—C(O)—R^f, —N(R^f)—S(O)—R^f, —N(R^f)—S(O)₂—R^f, carbocycle, and C_1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^fof Formula (I) is independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^g)₂, —CN, —C(O)—N(R^g)₂, —S(O)—N(R^g)₂, —S(O)₂—N(R^g)₂, —O—R^g, —S—R^g, —O—C(O)—R^g, —C(O)—R^g, —C(O)—O—R^g, —S(O)—R^g, —S(O)₂—R^g, —C(O)—N(R^g)₂, —N(R^g)—C(O)—R^g, —N(R^g)—S(O)—R^g, —N(R^g)—S(O)₂—R^g, and C_1-6alkyl, which carbocyclyl and C_1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C_1-6alkyl, cyano, —N(R^g)₂, —O—R^g, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C_1-6alkyl;

each R^gof Formula (I) is independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-6alkoxy, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^gare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C_1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^hof Formula (I) is independently selected from hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, and C_2-5cycloalkyl, wherein each C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, and C_2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-3alkoxy, and C₁-C₃alkyl that is optionally substituted with one or more groups independently selected from halo; and

R¹of Formula (II) is selected from C₆-C₂₀aryl, C₁-C₂₀heteroaryl, —(C₆-C₂₀aryl)-(C₁-C₂₀heteroaryl), and —(C₁-C₂₀heteroaryl)-(C₁-C₂₀heteroaryl), wherein each C₆-C₂₀aryl, C₁-C₂₀heteroaryl, —(C₆-C₂₀aryl)-(C₁-C₂₀heteroaryl) and —(C₁-C₂₀heteroaryl)-(C₁-C₂₀heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from R^c, oxo, —F, —Cl, —Br, —I, —NO₂, —N(R^a)₂, —CN, —C(O)—N(R^a)₂, —S(O)—N(R^a)₂, —S(O)₂—N(R^a)₂, —O—R^a, —S—R^a, —O—C(O)—R^a, —O—C(O)—O—R^a, —C(O)—R^a, —C(O)—O—R^a, —S(O)—R^a, —S(O)₂—R^a, —O—C(O)—N(R^a)₂, —N(R^a)—C(O)—OR^a, —N(R^a)—C(O)—N(R^a)₂, —N(R^a)—C(O)—R^a, —N(R^a)—S(O)—R^a, —N(R^a)—S(O)₂—R^a, —N(R^a)—S(O)—N(R^a)₂, and —N(R^a)—S(O)₂—N(R^a)₂;

R²of Formula (II) is C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R²is optionally substituted with one or more groups R^b;

R³of Formula (II) is C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(R^e)₂, —S(O)—N(R^e)₂, —S(O)₂—N(R^e)₂, —C(O)—R^e, —C(O)—O—R^e, —S(O)—R^e, or —S(O)₂—R^e, wherein any C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R^e)₂, —S(O)—N(R^e)₂, —S(O)₂—N(R^e)₂, —O—R^e, —S—R^e, —O—C(O)—R^e, —O—C(O)—O—R^e, —C(O)—R^e, —C(O)—O—R^e, —S(O)—R^e, —S(O)₂—R^e, —O—C(O)—N(R^e)₂, —N(R^e)—C(O)—OR^e, —N(R^e)—C(O)—N(R^e)₂, —N(R^e)—C(O)—R^e, —N(R^e)—S(O)—R^e, —N(R^e)—S(O)₂—R^e, —N(R^e)—S(O)—N(R^e)₂, and —N(R^e)—S(O)₂—N(R^e)₂;

each R^aof Formula (II) is independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-6alkoxy, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^aare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C_1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^bof Formula (II) is independently selected from oxo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO₂, —N(R^c)₂, —CN, —C(O)—N(R^c)₂, —S(O)—N(R^c)₂, —S(O)₂—N(R^c)₂, —O—R^c, —S—R^c, —O—C(O)—R^c, —O—C(O)—O—R^c, —C(O)—R^c, —C(O)—O—R^c, —S(O)—R^c, —S(O)₂—R^c, —O—C(O)—N(R^c)₂, —N(R^c)—C(O)—OR^c, —N(R^c)—C(O)—N(R^c)₂, —N(R^c)—C(O)—R^c, —N(R^c)—S(O)—R^c, —N(R^c)—S(O)₂—R^c, —N(R^c)—S(O)—N(R^c)₂, and —N(R^c)—S(O)₂—N(R^c)₂, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^c)₂, —CN, —C(O)—N(R^c)₂, —S(O)—N(R^c)₂, —S(O)₂—N(R^c)₂, —O—R^c, —S—R^c, —O—C(O)—R^c, —C(O)—R^c, —C(O)—O—R^c, —S(O)—R^c, —S(O)₂—R^c, —C(O)—N(R^c)₂, —N(R^c)—C(O)—R^c, —N(R^c)—S(O)—R^c, —N(R^c)—S(O)₂—R^cand C_1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^cof Formula (II) is independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^d)₂, —CN, —C(O)—N(R^d)₂, —S(O)—N(R^d)₂, —S(O)₂—N(R^d)₂, —O—R^d, —S—R^d, —O—C(O)—R^d, —C(O)—R^d, —C(O)—O—R^d, —S(O)—R^d, —S(O)₂—R^d, —C(O)—N(R^d)₂, —N(R^d)—C(O)—R^d, —N(R^d)—S(O)—R^d, —N(R^d)—S(O)₂—R^d, and C_1-6alkyl, which carbocyclyl and C_1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C_1-6alkyl, cyano, —N(R^d)₂, —O—R^d, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C_1-6alkyl;

each R^dof Formula (II) is independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-6alkoxy, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^dare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C_1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and

each R^eof Formula (II) is independently selected from hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, and C_2-5cycloalkyl, wherein each C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, and C_2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-3alkoxy, and C₁-C₃alkyl that is optionally substituted with one or more groups independently selected from halo; provided that R¹is not unsubstituted phenyl, when R²is carboxymethyl or 2-carboxyethyl.

Compounds of Formula (I)

Another aspect includes a compound of formula (I):

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or a salt thereof, wherein:

R¹is C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R¹is optionally substituted with one or more groups R^b;

R²is selected from C₆-C₂₀aryl, C₁-C₂₀heteroaryl, —(C₆-C₂₀aryl)-(C₁-C₂₀heteroaryl), —(C₁-C₂₀heteroaryl)-(C₆-C₂₀aryl), and —(C₁-C₂₀heteroaryl)-(C₁-C₂₀heteroaryl), wherein each C₆-C₂₀aryl, C₁-C₂₀heteroaryl, —(C₆-C₂₀aryl)-(C₁-C₂₀heteroaryl) and —(C₁-C₂₀heteroaryl)-(C₁-C₂₀heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from R^c, oxo, —F, —Cl, —Br, —I, —NO₂, —N(R^a)₂, —CN, —C(O)—N(R^a)₂, —S(O)—N(R^a)₂, —S(O)₂—N(R^a)₂, —O—R^a, —S—R^a, —O—C(O)—R^a, —O—C(O)—O—R^a, —C(O)—R^a, —C(O)—O—R^a, —S(O)—R^a, —S(O)₂—R^a, —O—C(O)—N(R^a)₂, —N(R^a)—C(O)—OR^a, —N(R^a)—C(O)—N(R^a)₂, —N(R^a)—C(O)—R^a, —N(R^a)—S(O)—R^a, —N(R^a)—S(O)₂—R^a, —N(R^a)—S(O)—N(R^a)₂, and —N(R^a)—S(O)₂—N(R^a)₂;

R³is C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R³is optionally substituted with one or more groups R^e; or

R²and R³taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups R^e; R⁴is C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(R^h)₂, —S(O)—N(R^h)₂, —S(O)₂—N(R^h)₂, —C(O)—R^h, —C(O)—O—R^h, —S(O)—R^h, or —S(O)₂—R^h, wherein any C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R^h)₂, —S(O)—N(R^h)₂, —S(O)₂—N(R^h)₂, —O—R^h, —S—R^h, —O—C(O)—R^h, —O—C(O)—O—R^h, —C(O)—R^h, —C(O)—O—R^h, —S(O)—R^h, —S(O)₂—R^h, —O—C(O)—N(R^h)₂, —N(R^h)—C(O)—OR^h, —N(R^h)—C(O)—N(R^h)₂, —N(R^h)—C(O)—R^a, —N(R^h)—S(O)—R^h, —N(R^h)—S(O)₂—R^h, —N(R^h)—S(O)—N(R^h)₂, and —N(R^h)—S(O)₂—N(R^h)₂;

each R^ais independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-6alkoxy, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^aare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C_1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^bis independently selected from oxo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO₂, —N(R^c)₂, —CN, —C(O)—N(R^c)₂, —S(O)—N(R^c)₂, —S(O)₂—N(R^c)₂, —O—R^c, —S—R^c, —O—C(O)—R^c, —O—C(O)—O—R^c, —C(O)—R^c, —C(O)—O—R^c, —S(O)—R^c, —S(O)₂—R^c, —O—C(O)—N(R^c)₂, —N(R^c)—C(O)—OR^c, —N(R^c)—C(O)—N(R^c)₂, —N(R^c)—C(O)—R^c, —N(R^c)—S(O)—R^c, —N(R^c)—S(O)₂—R^c, —N(R^c)—S(O)—N(R^c)₂, and —N(R^c)—S(O)₂—N(R^c)₂, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^c)₂, —CN, —C(O)—N(R^c)₂, —S(O)—N(R^c)₂, —S(O)₂—N(R^c)₂, —O—R^c, —S—R^c, —O—C(O)—R^c, —C(O)—R^c, —C(O)—O—R^c, —S(O)—R^c, —S(O)₂—R^c, —C(O)—N(R^c)₂, —N(R^c)—C(O)—R^c, —N(R^c)—S(O)—R^c, —N(R^c)—S(O)₂—R and C_1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^cis independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^d)₂, —CN, —C(O)—N(R^d)₂, —S(O)—N(R^d)₂, —S(O)₂—N(R^d)₂, —O—R^d, —S—R^d, —O—C(O)—R^d, —C(O)—R^d, —C(O)—O—R^d, —S(O)—R^d, —S(O)₂—R^d, —C(O)—N(R^d)₂, —N(R^d)—C(O)—R^d, —N(R^d)—S(O)—R^d, —N(R^d)—S(O)₂—R^d, and C_1-6alkyl, which carbocyclyl and C_1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C_1-6alkyl, cyano, —N(R^d)₂, —O—R^d, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C_1-6alkyl;

each R^dis independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-6alkoxy, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^dare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C_1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^eis independently selected from oxo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO₂, —N(R^f)₂, —CN, —C(O)—N(R^f)₂, —S(O)—N(R^f)₂, —S(O)₂—N(R^f)₂, —O—R^f, —S—R^f, —O—C(O)—R^f—O—C(O)—O—R^f, —C(O)—R^f, —C(O)—O—R^f, —S(O)—R^f, —S(O)₂—R^f, —O—C(O)—N(R^f)₂, —N(R^f)—C(O)—OR^f, —N(R^f)—C(O)—N(R^f)₂, —N(R^f)—C(O)—R^f, —N(R^f)—S(O)—R^f, —N(R^f)—S(O)₂—R^f, —N(R^f)—S(O)—N(R^f)₂, and —N(R^f)—S(O)₂—N(R^f)₂, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^f)₂, —CN, —C(O)—N(R^f)₂, —S(O)—N(R^f)₂, —S(O)₂—N(R^f)₂, —O—R^f, —S—R^f, —O—C(O)—R^f, —C(O)—R^f, —C(O)—O—R^f, —S(O)—R^f, —S(O)₂—R^f, —C(O)—N(R^f)₂, —N(R^f)—C(O)—R^f, —N(R^f)—S(O)—R^f, —N(R^f)—S(O)₂—R^f, carbocycle, and C_1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^fis independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^g)₂, —CN, —C(O)—N(R^g)₂, —S(O)—N(R^g)₂, —S(O)₂—N(R^g)₂, —O—R^g, —S—R^g, —O—C(O)—R^g, —C(O)—R^g, —C(O)—O—R^g, —S(O)—R^g, —S(O)₂—R^g, —C(O)—N(R^g)₂, —N(R^g)—C(O)—R^g, —N(R^g)—S(O)—R^g, —N(R^g)—S(O)₂—R^g, and C_1-6alkyl, which carbocyclyl and C_1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C_1-6alkyl, cyano, —N(R^g)₂, —O—R^g, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C_1-6alkyl;

each R^gis independently selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-6alkoxy, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R^gare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C_1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and

each R^his independently selected from hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, and C_2-5cycloalkyl, wherein each C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, and C_2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-3alkoxy, and C₁-C₃alkyl that is optionally substituted with one or more groups independently selected from halo.

Compounds of Formula (II)

Another aspect includes a compound of formula (II):

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or a salt thereof, wherein:

R¹is selected from C₆-C₂₀aryl, C₁-C₂₀heteroaryl, —(C₆-C₂₀aryl)-(C₁-C₂₀heteroaryl), and —(C₁-C₂₀heteroaryl)-(C₁-C₂₀heteroaryl), wherein each C₆-C₂₀aryl, C₁-C₂₀heteroaryl, —(C₆-C₂₀aryl)-(C₁-C₂₀heteroaryl) and —(C₁-C₂₀heteroaryl)-(C₁-C₂₀heteroaryl) is optionally substituted with one or more substituent groups independently selected from R^c, oxo, —F, —Cl, —Br, —I, —NO₂, —N(R^a)₂, —CN, —C(O)—N(R^a)₂, —S(O)—N(R^a)₂, —S(O)₂—N(R^a)₂, —O—R^a, —S—R^a, —O—C(O)—R^a, —O—C(O)—O—R^a, —C(O)—R^a, —C(O)—O—R^a, —S(O)—R^a, —S(O)₂—R^a, —O—C(O)—N(R^a)₂, —N(R^a)—C(O)—OR^a, —N(R^a)—C(O)—N(R^a)₂, —N(R^a)—C(O)—R^a, —N(R^a)—S(O)—R^a, —N(R^a)—S(O)₂—R^a, —N(R^a)—S(O)—N(R^a)₂, and —N(R^a)—S(O)₂—N(R^a)₂;

R²is C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R²is optionally substituted with one or more groups R^b;

R³is C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(R^e)₂, —S(O)—N(R^e)₂, —S(O)₂—N(R^e)₂, —C(O)—R^e, —C(O)—O—R^e, —S(O)—R^e, or —S(O)₂—R^e, wherein any C_1-4-alkyl, C_2-4alkenyl, C_2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R^e)₂, —S(O)—N(R^e)₂, —S(O)₂—N(R^e)₂, —O—R^e, —S—R^e, —O—C(O)—R^e, —O—C(O)—O—R^e, —C(O)—R^e, —C(O)—O—R^e, —S(O)—R^e, —S(O)₂—R^e, —O—C(O)—N(R^e)₂, —N(R^e)—C(O)−OR^e, —N(R^e)—C(O)—N(R^e)₂, —N(R^e)—C(O)—R^e, —N(R^e)—S(O)—R^e, —N(R^e)—S(O)₂—R^e, —N(R^e)—S(O)—N(R^e)₂, and —N(R^e)—S(O)₂—N(R^e)₂;

each R^bis independently selected from oxo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO₂, —N(R^c)₂, —CN, —C(O)—N(R^c)₂, —S(O)—N(R^c)₂, —S(O)₂—N(R^c)₂, —O—R^c, —S—R^c, —O—C(O)—R^c, —O—C(O)—O—R^c, —C(O)—R^c, —C(O)—O—R^c, —S(O)—R^c, —S(O)₂—R^c, —O—C(O)—N(R^c)₂, —N(R^c)—C(O)—OR^c, —N(R^c)—C(O)—N(R^c)₂, —N(R^c)—C(O)—R^c, —N(R^c)—S(O)—R^c, —N(R^c)—S(O)₂—R^c, —N(R^c)—S(O)—N(R^c)₂, and —N(R^c)—S(O)₂—N(R^c)₂, wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO₂, —N(R^c)₂, —CN, —C(O)—N(R^c)₂, —S(O)—N(R^c)₂, —S(O)₂—N(R^c)₂, —O—R^c, —S—R^c, —O—C(O)—R^c, —C(O)—R^c, —C(O)—O—R^c, —S(O)—R^c, —S(O)₂—R^c, —C(O)—N(R^c)₂, —N(R^c)—C(O)—R^c, —N(R^c)—S(O)—R^c, —N(R^c)—S(O)₂—R^cand C_1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R^eis independently selected from hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, and C_2-5cycloalkyl, wherein each C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, and C_2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-3alkoxy, and C₁-C₃alkyl that is optionally substituted with one or more groups independently selected from halo.

Another aspect includes a composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.

Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal, wherein the disorder is cancer, comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.

Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal, wherein the disorder is a fibrotic disease, comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.

Another aspect includes a method for treating a CBP and/or EP300-mediated disorder in an animal, wherein the disorder is a fibrotic lung disease, comprising administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the animal.

Another aspect includes a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for use in medical therapy.

Another aspect includes a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a CBP and/or EP300-mediated disorder.

Another aspect includes the use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a CBP and/or EP300-mediated disorder in an animal (e.g. a mammal such as a human).

Another aspect includes compounds for the study of CBP and/or EP300.

Another aspect includes synthetic intermediates and synthetic processes disclosed herein that are useful for preparing a compound of formula (I) or formula (II) or a salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Outline of protocol for assaying CBP/p300 SMIs for inhibition of profibrotic gene induction by TGFβ.

FIGS. 2A-E. Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 2A) an inhibitor of TGFβ receptor kinase activity or (FIGS. 2B-E) CBP/p300 inhibitors of Formula (I). Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. CBP/p300 inhibitors reduce TGFβ-driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGFβ signaling is intact.

FIGS. 3A-B. Expression as measured by qPCR of (FIG. 3A) ACTA2 or (FIG. 3B) COL3A1 in primary human fibroblasts treated with TGFβ and CBP/p300 inhibitors of Formula (I). CBP/p300 inhibitors reduce TGFβ-driven ACTA2 and COL3A1 expression in a dose-dependent manner.

FIGS. 4A-E. Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 4A) an inhibitor of TGFβ receptor kinase activity or (FIGS. 4B-E) CBP/p300 inhibitors of Formula (II). Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. CBP/p300 inhibitors reduce TGFβ-driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGFβ signaling is intact.

FIGS. 5A-B. Expression as measured by qPCR of (FIG. 5A) ACTA2 or (FIG. 5B) COL3A1 in primary human fibroblasts treated with TGFβ and CBP/p300 inhibitors of Formula (II). CBP/p300 inhibitors reduce TGFβ-driven ACTA2 and COL3A1 expression in a dose-dependent manner.

FIGS. 6A-E. Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 6A) an inhibitor of TGFβ receptor kinase activity or (FIGS. 6B-E) benzodiazepinone (“BZD”) series CBP/p300 inhibitors. Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. CBP/p300 inhibitors reduce TGFβ-driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGFβ signaling is intact.

FIGS. 7A-B. Expression as measured by qPCR of (FIG. 7A) ACTA2 or (FIG. 7B) COL3A1 in primary human fibroblasts treated with TGFβ and BZD series CBP/p300 inhibitors. CBP/p300 inhibitors reduce TGFβ-driven ACTA2 and COL3A1 expression in a dose-dependent manner.

FIGS. 8A-D. Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 8A) an inhibitor of TGFβ receptor kinase activity or (FIGS. 8B-D) heterocyclic CBP/p300 inhibitors. Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. CBP/p300 inhibitors reduce TGFβ-driven gene expression in a dose-dependent manner. Expression of Serpine1 is unchanged, indicating that TGFβ signaling is intact.

FIGS. 9A-B. Expression as measured by qPCR of (FIG. 9A) ACTA2 or (FIG. 9B) COL3A1 in primary human fibroblasts treated with TGFβ and heterocyclic CBP/p300 inhibitors. CBP/p300 inhibitors reduce TGFβ-driven ACTA2 and COL3A1 expression in a dose-dependent manner.

FIGS. 10A-C. Gene expression as measured by qPCR in primary human fibroblasts treated with TGFβ and (FIG. 10A) an inhibitor of TGFβ receptor kinase activity or (FIGS. 10B-C) modified CBP/p300 inhibitors with decreased activity. Heat maps show TGFβ induction of each gene in the presence of CBP/p300 inhibitor after normalization to induction in the absence of inhibitor. Duplicate treatments are represented as two rows for each inhibitor concentration. After modification of CBP/p300 inhibitors, the effect on TGFβ-driven gene expression is either (B) eliminated or (C) reduced.

FIGS. 11A-B. Expression as measured by qPCR of (FIG. 11A) ACTA2 or (FIG. 11B) COL3A1 in primary human fibroblasts treated with TGFβ and modified CBP/p300 inhibitors with decreased activity. The effect on TGFβ-driven gene expression is reduced or eliminated.

FIGS. 12A-B. (FIG. 12A) Gene expression as measured by qPCR in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or bleomycin plus the indicated dose of CBP/p300 inhibitor G0272 (compound of Formula II). Heat maps show expression of genes assayed, after normalization to GAPDH endogenous control, with each column representing one mouse. G0272 decreased the expression of fibrotic genes in the lung of mice treated with bleomycin to induce pulmonary fibrosis. (FIG. 12B) Collagen synthesis as measured by mass spectrometry of deuterated hydroxyproline in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G0272. G0272 decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis.

FIGS. 13A-B. (FIG. 13A) Gene expression as measured by qPCR in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G5049 (compound of Formula (I)). Heat maps show expression of genes assayed, after normalization to GAPDH endogenous control, with each column representing one mouse. G5049 decreased the expression of fibrotic genes in mice treated with bleomycin to induce pulmonary fibrosis. (FIG. 13B) Collagen synthesis as measured by mass spectrometry of deuterated hydroxyproline in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G5049. G5049 decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis.

FIGS. 14A-B. (FIG. 14A) Gene expression as measured by qPCR in the lung of mice in decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G3486. Heat maps show expression of genes assayed, after normalization to GAPDH endogenous control, with each column representing one mouse. G3486 decreased the expression of fibrotic genes in the lung of mice treated with bleomycin to induce pulmonary fibrosis. (FIG. 14B) Collagen synthesis as measured by mass spectrometry of deuterated hydroxyproline in the lung of mice treated with bleomycin to induce pulmonary fibrosis. Mice were treated with bleomycin plus vehicle or indicated dose of CBP/p300 inhibitor G3486. G3486 decreased collagen synthesis in the lung of mice treated with bleomycin to induce pulmonary fibrosis.

DETAILED DESCRIPTION
Compounds and Definitions

Definitions and terms are described in more detail below. Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^thEd.

Unless otherwise stated, compounds of formula I or formula II include enantiomeric, diastereomeric and geometric (or conformational) isomeric forms of a given structure. For example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are included. Unless otherwise stated, all tautomeric forms of structures depicted herein are included. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of formula I or formula II, wherein the independent replacement or enrichment of one or more hydrogen by deuterium or tritium, carbon by ¹³C— or ¹⁴C carbon, nitrogen by a ¹⁵N nitrogen, sulfur by a ³³S, ³⁴S or ³⁶S sulfur, oxygen by a ¹⁷O or ¹⁸O oxygen, or fluorine by a ¹⁸F are included. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents.

Where a particular enantiomer is described, it may, in certain embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.” “Optically-enriched,” as used herein, means that the mixture of enantiomers is made up of a significantly greater proportion of one enantiomer, and may be described by enantiomeric excess (ee %). In certain embodiments, the mixture of enantiomers is made up of at least about 90% by weight of a given enantiomer (about 90% ee). In other embodiments, the mixture of enantiomers is made up of at least about 95%, 98% or 99% by weight of a given enantiomer (about 95%, 98% or 99% ee). Enantiomers and diastereomers may be isolated from racemic mixtures by any method known to those skilled in the art, including recrystallization from solvents in which one stereoisomer is more soluble than the other, chiral high pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), the formation and crystallization of chiral salts, which are then separated by any of the above methods, or prepared by asymmetric syntheses and optionally further enriched. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

The term “heteroatom” means any atom independently selected from an atom other than carbon or hydrogen, for example, one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; and the quaternized form of any nitrogen).

The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br) and iodine (iodo, —I).

The term “oxo” refers to ═O.

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

The term “carbocyclyl” used alone or as part of a larger moiety, refers to a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms. In one embodiment, carbocyclyl includes 3 to 12 carbon atoms (C₃-C₁₂). In another embodiment, carbocyclyl includes C₃-C₈, C₃-C₁₀or C₅-C₁₀. In other embodiment, carbocyclyl, as a monocycle, includes C₃-C₈, C₃-C₆or C₅-C₆. In another embodiment, carbocyclyl, as a bicycle, includes C₇-C₁₂. In another embodiment, carbocyclyl, as a spiro system, includes C₅-C₁₂. Examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, for example bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane; and spiro carbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocycyl also includes cycloalkyl rings (e.g. saturated or partially unsaturated mono-, bi-, or spiro-carbocycles).

The term “alkyl,” as used herein, refers to a saturated linear or branched-chain hydrocarbon radical. In one embodiment, the alkyl radical is one to eighteen carbon atoms (C₁-C₁₈). In other embodiments, the alkyl radical is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄or C₁-C₃. C₀alkyl refers to a bond. Examples of alkyl groups include methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

The term “alkenyl,” as used herein, denotes a linear or branched-chain hydrocarbon radical with at least one carbon-carbon double bond. An alkenyl includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In one example, the alkenyl radical is two to eighteen carbon atoms (C₂-C₁₈). In other examples, the alkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethenyl or vinyl (—CH═CH₂), prop-1-enyl (—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

The term “alkynyl,” as used herein, refers to a linear or branched hydrocarbon radical with at least one carbon-carbon triple bond. In one example, the alkynyl radical is two to eighteen carbon atoms (C₂-C₁₈). In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethynyl (—C≡CH), prop-1-ynyl (—C≡CCH₃), prop-2-ynyl (propargyl, —CH₂C≡CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.

The term “alkoxy” refers to a linear or branched radical represented by the formula —OR in which R is alkyl, alkenyl, alkynyl or carbocycyl. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and cyclopropoxy.

The term “haloalkyl,” as used herein, refers to an alkyl as defined herein that is substituted with one or more (e.g. 1, 2, 3, or 4) halo groups.

The term “aryl” used alone or as part of a larger moiety as in “arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to a monocyclic, bicyclic or tricyclic, carbon ring system, that includes fused rings, wherein at least one ring in the system is aromatic. The term “aryl” may be used interchangeably with the term “aryl ring”. In one embodiment, aryl includes groups having 6-20 carbon atoms (C₆-C₂₀aryl). In another embodiment, aryl includes groups having 6-10 carbon atoms (C₆-C₁₀aryl). Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like, which may be substituted or independently substituted by one or more substituents described herein. A particular aryl is phenyl. In another embodiment aryl includes an aryl ring fused to one or more carbocyclic rings, such as indanyl, dihydrophenanthryl, or tetrahydronaphthyl, and the like, where the radical or point of attachment is on an aromatic ring.

The term “heteroaryl” used alone or as part of a larger moiety, e.g., “heteroarylalkyl”, or “heteroarylalkoxy”, refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted. In another embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted. In some embodiments, the heteroaryl group is a C₁-C₂₀heteroaryl group, where the heteroaryl ring contains 1-20 carbon atoms and the remaining ring atoms include one or more nitrogen, sulfur, or oxygen atoms. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl, purinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, and pyrazolo[4,3-c]pyridinyl. The terms “heteroaryl” also includes groups in which a heteroaryl is fused to one or more aryl, carbocyclyl, or heterocyclyl rings, where the radical or point of attachment is on the heteroaryl ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-, bi- or tri-cyclic.

As used herein, the term “heterocyclyl” or “heterocycle” refers to a “carbocyclyl” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S). In some embodiments, a heterocyclyl or heterocycle refers to a saturated ring system, such as a 3 to 12 membered saturated heterocyclyl ring system. In some embodiments, a heterocyclyl or heterocycle refers to a heteroaryl ring system, such as a 5 to 14 membered heteroaryl ring system. A heterocyclyl or heterocycle can optionally be substituted with one or more substituents independently selected from those defined herein.

In one example, heterocyclyl or heterocycle includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and one to five ring atoms is a heteroatom selected from nitrogen, sulfur or oxygen, which is independently optionally substituted by one or more groups. In one example, heterocyclyl or heterocycle includes 1 to 4 heteroatoms. In another example, heterocyclyl or heterocycle includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl or heterocycle includes 4- to 6-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl or heterocycle includes 3-membered monocycles. In another example, heterocyclyl or heterocycle includes 4-membered monocycles. In another example, heterocyclyl or heterocycle includes 5-6 membered monocycles. In one example, the heterocyclyl or heterocycle group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g. NO, SO, SO₂), and any nitrogen heteroatom may optionally be quaternized (e.g. [NR₄]⁺Cl⁻, [NR₄]⁺OH⁻). Example heterocyclyls or heterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls or heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ring heterocyclyls or heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocyclyls or heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example 6-membered heterocyclyls or heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are other example heterocyclyl groups.

The term “heterocyclyl” or “heterocycle” also includes groups in which a heterocyclyl is fused to one or more aryl, carbocyclyl, or heterocyclyl rings, where the radical or point of attachment is on the heterocyclyl ring. Nonlimiting examples include tetrahydroquinolinyl and tetrahydroisoquinolinyl.

As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms but the ring moiety is not aromatic.

As used herein, the term “inhibitor” refers to a compound that binds to and inhibits the bromodomain of CBP and/or EP300 with measurable affinity and activity. In certain embodiments, an inhibitor has an IC₅₀or binding constant of less about 20 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as used herein, refer to a measurable reduction in activity (e.g., reduction in recognition of lysine acetyl recognition of chromatin) of the bromodomain of CBP and/or EP300 between: (i) a sample comprising a compound of formula I or formula II or composition thereof and such bromodomain, and (ii) an equivalent sample comprising such bromodomain, in the absence of said compound, or composition thereof.

“Pharmaceutically acceptable salts” include both acid and base addition salts. It is to be understood that when a compound or Example herein is shown as a specific salt, the corresponding free-base, as well as other salts of the corresponding free-base (including pharmaceutically acceptable salts of the corresponding free-base) are contemplated.

“Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water.

“Therapeutically effective amount” refers to an amount of a compound of the present invention that (i) treats the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR). In the case of immunological disorders, the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g. asthma).

“Treatment” (and variations such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include one or more of preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In certain embodiments, a compound of formula I or formula II is used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those individuals in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation or abberent expression of a gene or protein).

“CBP/EP300 bromodomain inhibitor” or “CBP and/or EP300 bromodomain inhibitor” refers to a compound that binds to the CBP bromodomain and/or EP300 bromodomain and inhibits and/or reduces a biological activity of CBP and/or EP300. In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 primarily (e.g., solely) through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain. In some embodiments, CBP/EP300 bromodomain inhibitor binds to the CBP and/or EP300 through contacts and/or interactions with the CBP bromodomain and/or EP300 bromodomain as well as additional CBP and/or EP300 residues and/or domains. In some embodiments, CBP/EP300 bromodomain inhibitor substantially or completely inhibits the biological activity of the CBP and/or EP300. In some embodiments, the biological activity is binding of the bromodomain of CBP and/or EP300 to chromatin (e.g., histones associated with DNA) and/or another acetylated protein. In certain embodiments, the CBP/EP300 bromodomain inhibitor blocks CBP/EP300 activity so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation. In some embodiments, the CBP/EP300 bromodomain inhibitor binds to and inhibits CBP bromodomain. In some embodiments, the CBP/EP300 bromodomain inhibitor binds to and inhibits EP300 bromodomain.

As used herein, “a” or “an” means one or more, unless clearly indicated otherwise. As used herein, “another” means at least a second or more.

Exemplary Values for Compounds of Formula (I)

In certain embodiments of compounds of Formula (I), R¹is C_1-12alkyl or 3-12 membered heterocycle, wherein each C_1-12alkyl and 3-12 membered heterocycle of R¹is optionally substituted with one or more groups R^b.

In certain embodiments of compounds of Formula (I), R¹is methyl or a 4-6 membered heterocycle, wherein each methyl and 4-6 membered heterocycle of R¹is optionally substituted with one or more groups R^b.

In certain embodiments of compounds of Formula (I), R¹is methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R¹is optionally substituted with one or more groups R^b.

In certain embodiments of compounds of Formula (I), R¹is methyl or cyclopropylmethyl.

In certain embodiments of compounds of Formula (I), R¹is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl, and each R^bis independently selected from methyl, acetyl, and oxo.

In certain embodiments of compounds of Formula (I), R¹is cyclohexyl, aryl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, dioxothianyl, piperidyl, pyrrolidinyl, pyridyl, or oxepanyl, and each R^bis independently selected from oxo, C_1-6alkyl, —OR^c, —C(O)—R^c, oxetanyl, —S(O)₂—R^c, and —CH₂CN.

In certain embodiments of compounds of Formula (I), R¹is selected from the group consisting of:

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In certain embodiments of compounds of Formula (I), R¹is:

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In certain embodiments of compounds of Formula (I), R²is C₆-C₂₀aryl optionally substituted with one or more substituent groups independently selected from R^c, and R³is C_1-12alkyl or 3-12 membered carbocycle, wherein each C_1-12alkyl and 3-12 membered carbocycle of R³is optionally substituted with one or more groups R^e.

In certain embodiments of compounds of Formula (I), R²is phenyl optionally substituted with one or more substituent groups independently selected from R^c, and R³is methyl or phenyl, wherein each methyl and phenyl of R³is optionally substituted with one or more groups R^e.

In certain embodiments of compounds of Formula (I), R^cis a 5-membered heterocyclyl optionally substituted with methyl; and R³is benzyl, methyl, cyanomethyl, or phenyl.

In certain embodiments of compounds of Formula (I), R^cis pyrazolyl optionally substituted with methyl; and R³is benzyl, methyl, cyanomethyl, or phenyl.

In certain embodiments of compounds of Formula (I), R²and R³taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups R^e.

In certain embodiments of compounds of Formula (I), R²and R³taken together with the nitrogen to which they are attached form a bicyclic heterocycle that is optionally substituted with one or more groups R^e.

In certain embodiments of compounds of Formula (I), R²and R³taken together with the nitrogen to which they are attached form a 9-12 membered bicyclic heterocycle that is optionally substituted with one or more groups R^e.

In certain embodiments of compounds of Formula (I), R²and R³taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with one or more groups R^e; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring. In certain embodiments the at least one aromatic ring is a benzo ring.

In certain embodiments of compounds of Formula (I), —NR²R³taken together is selected from the group consisting of:

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and wherein each —NR²R³is optionally substituted with one or more groups R^e.

In certain embodiments of compounds of Formula (I), —NR²R³taken together is selected from the group consisting of:

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In certain embodiments of compounds of Formula (I), R³is C_1-12alkyl or 3-12 membered carbocycle, wherein each C_1-12alkyl and 3-12 membered carbocycle of R³is optionally substituted with one or more groups R^e.

In certain embodiments of compounds of Formula (I), R³is methyl or phenyl, wherein each methyl and phenyl of R³is optionally substituted with one or more groups R^e.

In certain embodiments of compounds of Formula (I), R³is benzyl, methyl, cyanomethyl, or phenyl.

In certain embodiments of compounds of Formula (I), R⁴is 3-5 membered heterocycle, —C(O)—N(R^h)₂, —C(O)—R^h, —C(O)—O—R^h, or —S(O)₂—R^h, wherein any 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(R^h)₂, —S(O)—N(R^h)₂, —S(O)₂—N(R^h)₂, —O—R^h, —S—R^h, —O—C(O)—R^h, —O—C(O)—O—R^h, —C(O)—R^h, —C(O)—O—R^h, —S(O)—R^h, —S(O)₂—R^h, —O—C(O)—N(R^h)₂, —N(R^h)—C(O)—OR^h, —N(R^h)—C(O)—N(R^h)₂, —N(R^h)—C(O)—R^a, —N(R^h)—S(O)—R^h, —N(R^h)—S(O)₂—R^h, —N(R^h)—S(O)—N(R^h)₂, and —N(R^h)—S(O)₂—N(R^h)₂.

In certain embodiments of compounds of Formula (I), R^his independently selected from hydrogen, C_1-4alkyl, and C_2-5cycloalkyl, wherein each C_1-4alkyl, and C_2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C_1-3alkoxy, and C₁-C₃alkyl that is optionally substituted with one or more groups independently selected from halo.

In certain embodiments of compounds of Formula (I), R⁴is acetyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, propanoyl, cyclopropylcarbonyl, methylsulfonyl, butanoyl, difluoroacetyl, thiadiazole or isoxazole.

In certain embodiments of compounds of Formula (I), R⁴is substituted or unsubstituted acetyl, propionyl, butyryl, cyclopropylcarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, methylsulfonyl, difluoroacetyl, thiadiazole, methylthiadiazole, oxadiazole, methyloxadiazole, or isoxazole.

In certain embodiments of compounds of Formula (I), R⁴is selected from the group consisting of:

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