Lysine acetyl-transferase inhibitor solid form compositions

Abstract

Solid forms of 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid are provided (Compound 1), including certain salt forms. In some embodiments, crystalline forms of Compound 1 are provided, including crystalline solid forms of the freebase of Compound 1, a phosphate salt of Compound (1), a sulfate salt of Compound (1), an edisylate salt of Compound (1), an oxalate salt of Compound (1), a t-butylamine salt of Compound (1), and a potassium salt of Compound (1).

Description

KRBIO.036WO PATENTLYSINE ACETYL-TRANSFERASE INHIBITOR SOLID FORM COMPOSITIONSTECHNICAL FIELD

[0001] The present disclosure relates to solid forms of compounds useful for preparing pharmaceutical compositions, and their use in the treatment of various diseases, including autoimmune conditions, as well as the preparation of such compositions.BACKGROUND

[0002] Lysine acetylation is a reversible post-translational modification. Lysine acetyltransferases (KATs) catalyze the transfer of an acetyl group from acetyl CoA (AcCoA) to the E-amino group on lysine residues of substrate proteins (Lee, K., Workman, J. Nat Rev Mol Cell Biol 8, 284-295 (2007)). Lysine deacetylases (KDACs) catalyze the removal of the acetyl group. Specific protein domains, including bromodomains, can bind proteins in an acetylation-dependent manner (R. Marmorstein and M.-M. Zhou. Cold Spring Harb Perspect Biol 2014;6:a018762). The presence or absence of the acetyl group can impact protein function, including protein-protein interactions. This is because the acetyl group on the target lysine residue neutralizes the charge of the lysine s-amino group which is known to impact chromatin compaction in the nucleus.

[0003] The p300 protein is encoded by the El A Binding Protein (EP300) gene (Uniprot ID: Q09472) that is located on human chromosome 22pl3.2. The CBP protein is encoded by the CREBBP gene (Uniprot ID: Q92793) that is located on human chromosomel6pl3. p300 is an important cofactor for interferon regulatory factor 4 (IRF4) to enact immune responses across multiple cell types, including those that produce antibodies (B cells) and cytokines (T cells).

[0004] p300 and CBP are multidomain proteins that consist of an enzymatic KAT domain and multiple protein-protein interaction domains, including a bromodomain and KIX domain. The KAT domain catalyzes acetylation of histones and non-histone proteins where acetylated histones are associated with actively transcribed regions of the genome. The proteinprotein interaction domains aid in localizing p300 or CBP to distinct locations in the genome.

[0005] Sjogren’s disease is a chronic autoimmune disease that is characterized by the production of autoantibodies, chronic inflammation and lymphocytic infiltration of the exocrine glands that lead to uncomfortable dryness symptoms, known as sicca. Systemic effects are commonKRBIO.036WO PATENTand impact the lungs, kidneys and nervous system in addition to extensive dryness, profound fatigue and chronic pain. There are no approved treatments that target the underlying cause of Sjogren’s disease.SUMMARY

[0006] Embodiments of the present application provide solid forms of Compound (1):(1).

[0007] Compound (1) is a p300 lysine acetyltransferase (KAT) inhibitor for the potential treatment of Sjogren’s disease. In some embodiments, pharmaceutical compositions comprising Compound (1) provide an orally available therapy for the treatment of Sjogren’s disease.

[0008] In some embodiments, a pharmaceutically acceptable solid form of compound (1), selected from the group consisting of: a freeform solid form of Compound (1), a phosphate salt of Compound (1), a sulfate salt of Compound (1), an edisylate salt of Compound (1), an oxalate salt of Compound (1), a t-butylamine salt of Compound (1), and a potassium salt of Compound (1).

[0009] In some embodiments, polymorphic crystalline or partially crystalline solid forms of compound (1) are provided. In some embodiments, polymorphic (crystalline) forms of compound (1) or salts of compound (1). In some embodiments, the solid form of Compound (1) is crystalline. In some embodiments, the composition comprises two or more solid forms of Compound (1). In some embodiments, the composition comprises two or more crystalline forms of Compound (1). In some embodiments, the composition comprises an amorphous form of Compound (1) and a crystalline form of Compound (1).

[0010] In some embodiments, solid forms of the free base of Compound (1) are provided, including crystalline and partially crystalline solid forms of Compound (1). In some embodiments, the solid form of a free base of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (29 ±0.2) at 7.4 and 14.7. In some embodiments, the solid form of a free base of Compound (1) is characterized by an X-ray powderKRBIO.036WO PATENTdiffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 7.4, 14.7, 17.6, and 19.7. In some embodiments, the solid form of a free base of Compound (1) is characterized by Pattern A (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 1).

[0011] In some embodiments, phosphate salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of a phosphate salt of Compound (1). In some embodiments, solid forms of a phosphate salt of Compound (1) are provided. In some embodiments, a solid form of a phosphate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.2, 8.9, 20.7, and 22.4. hi some embodiments, a solid form of a phosphate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.2, 8.9, 9.2, 10.9, 12.2, 18.0, 18.2, 18.9, 20.7, 21.0, 22.4 and 24.5. In some embodiments, a solid form of a phosphate salt of Compound (1) is characterized by Pattern 9-A (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 2A or Figure 2B).

[0012] In some embodiments, sulfate salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of a sulfate salt of Compound (1). In some embodiments, solid forms of a sulfate salt of Compound (1) are provided. In some embodiments, a solid form of a sulfate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 5.7, 8.7 and 21.3. In some embodiments, a solid form of a sulfate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 5.7, 8.7, 10.2, 10.7, 14.1, 19.7, 20.6, 21.3, 21.6, and 24.0. In some embodiments, a solid form of a sulfate salt of Compound (1) is characterized by Pattern 11-A (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 3A or Figure 3B).

[0013] In some embodiments, edisylate salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of an edisylate salt of Compound (1). In some embodiments, solid forms of an edisylate salt of Compound (1) are provided. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.6 and 13.8. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.6, 13.8, 18.4, 22.5,KRBIO.036WO PATENTand 23.1. Tn some embodiments, a solid form of an edisylate salt of Compound (1 ) is characterized by Pattern 14- A (e.g., characterized by the XRPD spectra with characteristic 26±0.2 peaks as shown in Figure 4A or Figure 4B). In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.1 and 20.0. hi some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.1, 7.3, 9.3, 16.4, 17.7, and 20.0. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by Pattern 14-B (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 5A or Figure 5B). In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2 and 18.5. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2, 17.2, 17.4, 18.5, 20.1, and 20.4. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by Pattern 14-C (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 6A or Figure 6B). In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising an 2-theta peak (20 ±0.2) at 6.5. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.5 and 20.6. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by Pattern 14-D (e.g.. characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 7A or Figure 7B).

[0014] In some embodiments, oxalate salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of an oxalate salt of Compound (1 ). Tn some embodiments, solid forms of an oxalate salt of Compound (1) are provided. In some embodiments, a solid form of an oxalate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.4, 16.9, 18.8 and 19.3. In some embodiments, a solid form of an oxalate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.4, 10.3, 12.5, 16.9, 18.5,18.8, 19.3 and 27.1. In some embodiments, a solid form of an oxalate salt ofKRBIO.036WO PATENTCompound (1) is characterized by Pattern 15-A (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 8 A or Figure 8B).

[0015] In some embodiments, t-butylamine salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of a t-butylamine salt of Compound (1). In some embodiments, solid forms of a t-butylamine salt of Compound (1) are provided. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.1, 16.7, 18.7, 20.3 and 26.8. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.1, 12.2, 13.2, 14.8, 16.7, 18.7, 20.3, 22.3, 24.0, 24.8 and 26.8. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-A (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 9A or Figure 9B). In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.7, 9.1, 17.4, 17.9 and 19.2. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.7, 9.1, 9.6. 11.8. 13.7, 15.3, 15.9, 17.4, 17.9, 19.2, 20.4, 20.6, 21.2. 22.2. 23.3. and 23.7. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-B (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 10A or Figure 10B). In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2 and 18.5. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2, 17.2, 17.4, 18.5. 20.1. and 20.4. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-C (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 11). In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising a 2-theta peak (20 ±0.2) at 6.5. hi some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.5 and 20.6. hi someKRBIO.036WO PATENTembodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-D (e.g., characterized by the XRPD spectra with characteristic 29±0.2 peaks as shown in Figure 12). In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 7.7, 10.7, 12.4, 12.9, 18.8, and 20.1. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 7.7. 10.7, 12.4, 12.9, 13.7, 16.5, 18.8, 19.1, 19.7, 20.1, 20.9, 24.9. and 27.0. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-E (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 13A). In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-C, 16-D or 16-E (e.g., characterized by the XRPD spectra with characteristic 20±O.2 peaks as shown in Figure 13B).

[0016] In some embodiments, potassium salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of a potassium salt of Compound (1). In some embodiments, solid forms of a potassium salt of Compound (1) are provided. In some embodiments, a solid form of a potassium salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.6, 7.0, 20.7. 21.0. and 22.7. In some embodiments, a solid form of a potassium salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.6, 6.0, 7.0, 9.1, 18.0, 20.7, 21.0, and 22.7. In some embodiments, a solid form of a potassium salt of Compound (1) is characterized by Pattern 19-A (e.g., characterized by the XRPD spectra with characteristic 29±0.2 peaks as shown in Figure 14A or Figure 14B).

[0017] In some embodiments, a pharmaceutically acceptable solid form of compound (1) is selected from the group consisting of: a freeform solid form of Compound (1) characterized by XRPD Pattern A, a phosphate salt of Compound (1) characterized by XRPD Pattern 9-A, a sulfate salt of Compound (1) characterized by XPRD Pattern 11-A, an edisylate salt of Compound (1) characterized by Pattern 14-A, an edisylate salt of Compound (1) characterized by Pattern 14-B, an edisylate salt of Compound (1) characterized by Pattern 14-C, an edisylate salt of Compound (1) characterized by Pattern 14-D, an oxalate salt of Compound (1) characterized by Pattern 15- A, a t-butylamine salt of Compound (1) characterized by Pattern 16- A, a t-butylamine salt of Compound (1) characterized by Pattern 16-B, a t-butylamine salt ofKRBIO.036WO PATENTCompound (1) characterized by Pattern 16-C, a t-butylamine salt of Compound (1) characterized by Pattern 16-D, a t-butylamine salt of Compound (1) characterized by Pattern 16-E, and a potassium salt of Compound (1) characterized by Pattern 19-A.

[0018] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is formulated for oral delivery of Compound (1) to a human or veterinary subject. In some embodiments, a process for preparing a pharmaceutical composition, comprising dissolving a solid form provided herein in a solvent. In some embodiments, a method of inhibiting p300 is provided, comprising administering to a subject in need thereof an effective amount of a solid form disclosed herein or a pharmaceutical composition disclosed herein. In some embodiments, a method of treating an autoimmune disorder is provided, comprising administering to a subject in need thereof an effective amount of a solid form or a pharmaceutical composition disclosed herein. In some embodiments, a method of treating Sjogren’s disease is provided, comprising administering to a subject in need thereof an effective amount of a solid form or a pharmaceutical composition disclosed herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIGURE 1 is an XRPD spectrum of Pattern A, obtained from a dry sample of the free form of Compound (1 ).

[0020] FIGURE 2A is an XRPD spectrum of Pattern 9- A, obtained from a sample of a phosphate salt of Compound (1).

[0021] FIGURE 2B is an XRPD spectrum of Pattern 9- A from a sample of a phosphate salt of Compound (1), obtained from salt screening with phosphoric acid (1.1 eq) in ACN: DMSO (95:5 vol) as a wet cake Pattern 9- A (1), as a dry solid Pattern 9-A (2), and as amorphous + 18.1 °20 after overnight exposure to 90%RH at 30 degrees C (3).

[0022] FIGURE 3 A is an XRPD spectrum of Pattern 11-A, obtained from a dry sample of a sulfate salt of Compound (1).

[0023] FIGURE 3B is an XRPD spectrum of Pattern 11-A from a sample of a sulfate salt of Compound (1), obtained from salt screening with sulfuric acid (0.5 eq) in IPA:water (9:1 vol) as a wet cake Pattern 11-A (1), as a dry solid Pattern 11-A (2), and as Pattern 11-A after 3 day exposure to 90%RH at 30 degrees C (3).KRBIO.036WO PATENT

[0024] FIGURE 3C is a TGA / DSC thermogram of a sulfate salt of Compound (1 ) characterized by Pattern 11-A obtained from salt screening with sulfuric acid (1.1 eq) in IPA:water (9:1 vol).

[0025] FIGURE 3D is a DSC thermogram of a sulfate salt of Compound (1) characterized by Pattern 11-A obtained from salt screening with sulfuric acid (1.1 eq) in EtOAc as disclosed herein.

[0026] FIGURE 4A is an XRPD spectrum of Pattern 14- A, obtained from a dry sample of an edisylate salt of Compound (1).

[0027] FIGURE 4B is an XRPD spectrum of Pattern 14-A from a sample of a edisylate salt of Compound (1), obtained from salt screening with ethanedisulfonic acid (0.5 eq) in acetone as a wet cake Pattern 14-A (1), and as a dry solid Pattern 14-A (2).

[0028] FIGURE 4C are TGA / DSC thermograms of a edisylate salt of Compound (1) characterized by Pattern 14-A obtained from salt screening with ethanedisulfonic acid (0.5 eq) in acetone.

[0029] FIGURE 5 A is an XRPD spectrum of Pattern 14-B, obtained from a dry sample of an edisylate salt of Compound (1).

[0030] FIGURE 5B is an XRPD spectrum of Pattern 14-B from a sample of an edisylate salt of Compound (1), obtained from salt screening with ethanedisulfonic acid (1.1 eq) in EtOAc as a wet cake Pattern 14-B (1), and as a dry solid Pattern 14-B (2).

[0031] FIGURE 5C are TGA / DSC thermograms of an edisylate salt of Compound (1) characterized by Pattern 14-B obtained from salt screening with ethanedisulfonic acid (1.1 eq) in EtOAc.

[0032] FIGURE 6A is an XRPD spectrum of Pattern 14-C, obtained from a wet sample of an edisylate salt of Compound (1).

[0033] FIGURE 6B is an XRPD spectrum of Pattern 14-C from a sample of an edisylate salt of Compound (1), obtained from salt screening with ethanedisulfonic acid (1.1 eq) in THF as a wet cake Pattern 14-C (1), and as a dry solid Pattern 14-C (2).

[0034] FIGURE 7A is an XRPD spectrum of Pattern 14-D, obtained from a wet sample of an edisylate salt of Compound (1).KRBIO.036WO PATENT

[0035] FIGURE 7B is an XRPD spectrum of Pattern 14-D from a sample of an edisylate salt of Compound (1), obtained from salt screening with ethanedisulfonic acid (1.1 eq) in ACN as a wet cake Pattern 14-D (1), and as a dry solid Pattern 14-D (2).

[0036] FIGURE 8 A is an XRPD spectrum of Pattern 15-A, obtained from a dry sample of an oxalate salt of Compound (1).

[0037] FIGURE 8B is an XRPD spectrum of Pattern 15-A from a sample of an oxalate salt of Compound (1), obtained from salt screening with oxalic acid (1.1 eq) in ACN as a wet cake Pattern 15-A (1), as a dry solid Pattern 15-A (2), and as Pattern 15-A after 3 day exposure to 90%RH at 30 degrees C (3).

[0038] FIGURE 9 A is an XRPD spectrum of Pattern 16- A, obtained from a dry sample of a t-butylamine salt of Compound (1).

[0039] FIGURE 9B is an XRPD spectrum of Pattern 16-A from a sample of a t-butylamine salt of Compound (1), obtained from salt screening with t-butylamine (1.1 eq) in EtOAc as a wet cake Pattern 16-A (1), and as a dry solid Pattern 16-A (2).

[0040] FIGURE 9C are TGA / DSC thermograms of a t-butylamine salt of Compound (1) characterized by Pattern 16-A obtained from salt screening with t-butylamine (1.1 eq) in EtOAc.

[0041] FIGURE 10A is an XRPD spectrum of Pattern 16-B, obtained from a dry sample of a t-butylamine salt of Compound (1).

[0042] FIGURE 10B is an XRPD spectrum of Pattern 16-B from a sample of a t-butylamine salt of Compound (1), obtained from salt screening with t-butylamine (1.1 eq) in acetone as a wet cake Pattern 16-B (1), and as a dry solid Pattern 16-B (2).

[0043] FIGURE 11 is an XRPD spectrum of Pattern 16-C, obtained from a wet sample of a t-butylamine salt of Compound (1).

[0044] FIGURE 12 is an XRPD spectrum of Pattern 16-D, obtained from a dry sample of a t-butylamine salt of Compound (1).

[0045] FIGURE 13A is an XRPD spectrum of Pattern 16-E, obtained from a humid sample of a t-butylamine salt of Compound (1).

[0046] FIGURE 13B is an XRPD spectrum of Patterns 16-C, 16-D and 16-E from a sample of a t-butylamine salt of Compound (1), obtained from salt screening with t-butylamineKRBIO.036WO PATENT(1.1 eq) in ACN as a wet cake Pattern 15-C (1), as a dry solid Pattern 16-D (2), and as Pattern 15-E after 3 day exposure to 90%RH at 30 degrees C (3).

[0047] FIGURE 14A is an XRPD spectrum of Pattern 19- A, obtained from a dry sample of a potassium salt of Compound (1).

[0048] FIGURE 14B is an XRPD spectrum of Pattern 19- A from a sample of a potassium salt of Compound (1), obtained from salt screening with KOH (1.1 eq) in MIBK as a wet cake Pattern 19-A (1), and as a dry solid Pattern 19-A (2).

[0049] FIGURE 15 A is an XRPD spectrum of two amorphous samples of Compound (1).

[0050] FIGURE 15B shows TGA / DSC thermograms from testing two amorphous samples of Compound (1).

[0051] FIGURE 15C shows a DSC thermogram from testing an amorphous sample of Compound (1).DETAILED DESCRIPTION

[0052] In some embodiments, solid forms of 2-(3-((S)-l-(((S)-phenyl((R)-l, 2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid are provided (Compound 1):(1).

[0053] Compound (1) is a p300 lysine acetyltransferase (KAT) inhibitor for the potential treatment of diseases driven by deregulated transcription, such as Sjogren’s disease. p300 is an important cofactor for interferon regulatory factor 4 (IRF4) to enact immune responses across multiple cell types, including those that produce antibodies (B cells) and cytokines (T cells). Sjogren’s disease is a chronic autoimmune disease that is characterized by the production of autoantibodies, chronic inflammation and lymphocytic infiltration of the exocrine glands that lead to uncomfortable dryness symptoms, known as sicca. Systemic effects are common and impact theKRBIO.036WO PATENTlungs, kidneys and nervous system in addition to extensive dryness, profound fatigue and chronic pain. In some embodiments, pharmaceutical compositions comprising Compound (1) provide an orally available therapy for the treatment of Sjogren’s disease.

[0054] Preclinical data obtained with Compound (1) support the role of p300 in inflammatory indications, including Sjogren’s disease, including: (1) inhibition of the KAT activity of p300, a critical cofactor of proinflammatory transcription factors, resulted in selective downregulation of cytokines such as TNFa, IL-23, IL-17A as well as soluble IgG; (2) selective gene expression changes occurred at doses corresponding to partial inhibition of p300 KAT activity; and (3) p300 KAT inhibition also led to significantly decreased inflammation in the rat CIA model, as measured by joint swelling, clinical score and histopathology. In addition, p300 KAT inhibition in vitro showed a reduction in IL-17 transcript and protein levels in Th17 cells and, in vivo, showed significant decreases in the secondary immune response (i.e. IgG production) in the KLH challenge model.

[0055] Sjogren’s disease is a chronic autoimmune disease characterized by the production of autoantibodies, chronic inflammation and lymphocytic infiltration of the exocrine glands. Systemic effects are common and impact the lungs, kidneys and nervous system in addition to extensive dryness, profound fatigue and chronic pain. Complications can include pneumonia, bronchitis, kidney problems, hepatitis, cirrhosis, peripheral neuropathy and lymphomas, and lead to a 50% increase in all-cause mortality. It is estimated that there are two to four million people in the U. S. living with this disease, making it one of the most prevalent autoimmune diseases. However, given the heterogeneous symptomatology of Sjogren’s disease, it is estimated that only one million patients in the U. S. are diagnosed. The disease is significantly more common in women; most people are older than 40 when they are diagnosed. Currently there are no approved treatments that target the underlying cause of Sjogren’s disease.

[0056] In some embodiments, a pharmaceutically acceptable solid form of compound (1), selected from the group consisting of: a freeform solid form of Compound (1), a phosphate salt of Compound (1), a sulfate salt of Compound (1), an edisylate salt of Compound (1), an oxalate salt of Compound (1), a t-butylamine salt of Compound (1), and a potassium salt of Compound (1). In some embodiments, polymorphic crystalline or partially crystalline solid forms of compound (1) are provided. In some embodiments, polymorphic (crystalline) forms of compound (1) or salts of compound (1). In some embodiments, the solid form of Compound (1) is crystalline. In someKRBIO.036WO PATENTembodiments, the composition comprises two or more solid forms of Compound (1). In some embodiments, the composition comprises two or more crystalline forms of Compound (1). In some embodiments, the composition comprises an amorphous form of Compound (1) and a crystalline form of Compound (1).

[0057] In some embodiments, solid forms of the free base of Compound (1) are provided, including crystalline and partially crystalline solid forms of Compound (1). In some embodiments, the solid form of a free base of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (29 ±0.2) at 7.4 and 14.7. In some embodiments, the solid form of a free base of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (29 ±0.2) at 7.4, 14.7, 17.6, and 19.7. FIGURE 1 is an XRPD spectrum of Pattern A, obtained from a sample of the free form of Compound (1). In some embodiments, the solid form of a free base of Compound (1) is characterized by Pattern A. In some embodiments, the solid form of a free base of Compound (1) is characterized by one, two, three, four, five or more characteristic XRPD peaks and / or d-spacing values in Table 1.Table 1. XRPD Peak List for Compound (1) Freeform Pattern A (with relative intensity at or above 1%)KRBIO.036WO PATENT

[0058] In some embodiments, phosphate salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of a phosphate salt of Compound (1). In some embodiments, solid forms of a phosphate salt of Compound (1 ) are provided. In some embodiments, a solid form of a phosphate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.2, 8.9, 20.7, and 22.4. In some embodiments, a solid form of a phosphate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.2, 8.9. 9.2, 10.9, 12.2, 18.0, 18.2, 18.9, 20.7, 21.0, 22.4 and 24.5.

[0059] In some embodiments, a solid form of a phosphate salt of Compound (1) is characterized by Pattern 9-A. FIGURE 2A is an XRPD spectrum of Pattern 9-A, obtained from a sample of a phosphate salt of Compound (1). FIGURE 2B is an XRPD spectrum of Pattern 9-A from a sample of a phosphate salt of Compound (1), obtained from salt screening with phosphoric acid (1.1 eq) in ACN: DMSO (95:5 vol) as a wet cake Pattern 9-A (1), as a dry solid Pattern 9-A (2), and as amorphous + 18.1 °20 after overnight exposure to 90%RH at 30 degrees C (3).Table 2. XRPD Peak List for Compound (1) Phosphate Pattern 9-A (with relative intensity at or above 1%)KRBIO.036WO PATENT

[0060] In some embodiments, sulfate salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of a sulfate salt of Compound (1). In some embodiments, solid forms of a sulfate salt of Compound (1) are provided. In some embodiments, a solid form of a sulfate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 5.7, 8.7 and 21.3. In some embodiments, a solid form of a sulfate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 5.7, 8.7, 10.2, 10.7, 14.1, 19.7, 20.6, 21.3, 21.6, and 24.0. In some embodiments, a solid form of a sulfate salt of Compound (1) is characterized by Pattern 11-A. FIGURE 3A is an XRPD spectrum of Pattern 11-A, obtained from a sample of a sulfate salt of Compound (1). FIGURE 3B is an XRPD spectrum of Pattern 11-A from a sample of a sulfate salt of Compound (1). obtained from salt screening with sulfuric acid (0.5 eq) in IPA:water (9: 1 vol) as a wet cake Pattern 11-A (1), as a dry solid Pattern 11-A (2), and as Pattern 11-A after 3 day exposure to 90%RH at 30 degrees C (3).Table 3. XRPD Peak List for Compound (1) Sulfate Pattern 11-A (with relative intensity at or above 2%)KRBIO.036WO PATENT

[0061] FIGURE 3C is a TGA / DSC thermogram of a sulfate salt of Compound (1) characterized by Pattern 11-A obtained from salt screening with sulfuric acid (1.1 eq) in IPA:water (9:1 vol). FIGURE 3D is a DSC thermogram of a sulfate salt of Compound (1) characterized by Pattern 11-A obtained from salt screening with sulfuric acid (1.1 eq) in EtOAc as disclosed herein.

[0062] In some embodiments, edisylate salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of an edisylate salt of Compound (1). In some embodiments, solid forms of an edisylate salt of Compound (1 ) are provided. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.6 and 13.8. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.6, 13.8, 18.4, 22.5, and 23.1. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by Pattern 14-A. FIGURE 4A is an XRPD spectrum of Pattern 14- A, obtained fromKRBIO.036WO PATENTa sample of an edisylate salt of Compound (1 ). FIGURE 4B is an XRPD spectrum of Pattern 14-A from a sample of a edisylate salt of Compound (1), obtained from salt screening with ethanedisulfonic acid (0.5 eq) in acetone as a wet cake Pattern 14-A (1), and as a dry solid Pattern 14-A (2).Table 4. XRPD Peak List for Compound (1) Edisylate Pattern 14-A (with relative intensity at or above 1%)

[0063] FIGURE 4C is TGA / DSC thermograms of an edisylate salt of Compound (1) characterized by Pattern 14-A obtained from salt screening with ethanedisulfonic acid (0.5 eq) in acetone.

[0064] In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.1 and 20.0. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.1, 7.3, 9.3. 16.4, 17.7, and 20.0. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by Pattern 14-B. FIGURE 5A is an XRPD spectrum of Pattern 14-B, obtained from a sample of an edisylate salt of Compound (1). FIGURE 5B is an XRPDKRBIO.036WO PATENTspectrum of Pattern 14-B from a sample of an edisylate salt of Compound (1 ), obtained from salt screening with ethanedisulfonic acid (1.1 eq) in EtOAc as a wet cake Pattern 14-B (1), and as a dry solid Pattern 14-B (2).Table 5. XRPD Peak List for Compound (1) Edisylate Pattern 14-B (with relative intensity at or above 1%)

[0065] FIGURE 5C are TGA / DSC thermograms of an edisylate salt of Compound (1) characterized by Pattern 14-B obtained from salt screening with ethanedisulfonic acid (1.1 eq) in EtOAc.

[0066] In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2 and 18.5. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2, 17.2, 17.4, 18.5, 20.1, and 20.4. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by Pattern 14-C. FIGURE 6A is an XRPD spectrum of Pattern 14-C, obtained from a sample of an edisylate salt of Compound (1). FIGURE 6B is an XRPD spectrum of Pattern 14-C from a sample of an edisylate salt of Compound (1), obtainedKRBIO.036WO PATENTfrom salt screening with ethanedisulfonic acid (1.1 eq) in THF as a wet cake Pattern 14-C (1 ), and as a dry solid Pattern 14-C (2).Table 6. XRPD Peak List for Compound (1) Edisylate Pattern 14-C (with relative intensity at or above 1%)

[0067] In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising an 2-theta peak (20 ±0.2) at 6.5. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.5 and 20.6. In some embodiments, a solid form of an edisylate salt of Compound (1) is characterized by Pattern 14-D. FIGURE 7A is an XRPD spectrum of Pattern 14-D, obtained fromKRBIO.036WO PATENTa sample of an edisylate salt of Compound (1 ). FIGURE 7B is an XRPD spectrum of Pattern 14-D from a sample of an edisylate salt of Compound (1), obtained from salt screening with ethanedisulfonic acid (1.1 eq) in ACN as a wet cake Pattern 14-D (1), and as a dry solid Pattern 14-D (2).Table 7. XRPD Peak List for Compound (1) Edisylate Pattern 14-D (with relative intensity at or above 1%)

[0068] In some embodiments, oxalate salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of an oxalate salt of Compound (1). In some embodiments, solid forms of an oxalate salt of Compound (1) are provided. In some embodiments, a solid form of an oxalate salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.4, 16.9, 18.8 and 19.3. In some embodiments, a solid form of an oxalate salt of Compound (1) is characterized byKRBIO.036WO PATENTan X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.4, 10.3, 12.5, 16.9, 18.5,18.8, 19.3 and 27.1. In some embodiments, a solid form of an oxalate salt of Compound (1) is characterized by Pattern 15- A. FIGURE 8 A is an XRPD spectrum of Pattern 15-A, obtained from a sample of an oxalate salt of Compound (1). FIGURE 8B is an XRPD spectrum of Pattern 15-A from a sample of an oxalate salt of Compound (1), obtained from salt screening with oxalic acid (1.1 eq) in ACN as a wet cake Pattern 15-A (1), as a dry solid Pattern 15-A (2), and as Pattern 15-A after 3 day exposure to 90%RH at 30 degrees C (3).Table 8. XRPD Peak List for Compound (1) oxalate Pattern 15-A (with relative intensity at or above 1%)

[0069] In some embodiments, t-butylamine salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of a t-butylamine salt of Compound (1). In some embodiments, solid forms of a t-butylamine salt of Compound (1) are provided. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.1, 16.7, 18.7, 20.3 and 26.8. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.1, 12.2, 13.2, 14.8, 16.7, 18.7, 20.3, 22.3, 24.0, 24.8 and 26.8. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-A. FIGURE 9A is an XRPD spectrum of Pattern 16-A, obtained from a sample of a t-butylamine salt of Compound (1). FIGURE 9B is an XRPD spectrum of Pattern 16-A from a sample of a t-butylamine salt ofKRBIO.036WO PATENTCompound (1), obtained from salt screening with t-butylamine (1.1 eq) in EtOAc as a wet cake Pattern 16-A (1), and as a dry solid Pattern 16-A (2).Table 9. XRPD Peak List for Compound (1) t-butylamine Pattern 16- A (with relative intensity at or above 1%)

[0070] FIGURE 9C are TGA / DSC thermograms of a t-butylamine salt of Compound (1) characterized by Pattern 16-A obtained from salt screening with t-butylamine (1.1 eq) in EtOAc.

[0071] In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.7, 9.1, 17.4, 17.9 and 19.2. In some embodiments, a solid form of a t-butylamine salt ofKRBIO.036WO PATENTCompound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.7, 9.1, 9.6, 11.8, 13.7, 15.3. 15.9, 17.4, 17.9, 19.2, 20.4, 20.6, 21.2, 22.2, 23.3, and 23.7. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-B. FIGURE 10A is an XRPD spectrum of Pattern 16-B, obtained from a sample of a t-butylamine salt of Compound (1). FIGURE 10B is an XRPD spectrum of Pattern 16-B from a sample of a t-butylamine salt of Compound (1 ), obtained from salt screening with t-butylamine (1.1 eq) in acetone as a wet cake Pattern 16-B (1), and as a dry solid Pattern 16-B (2).Table 10. XRPD Peak List for Compound (1) t-butylamine Pattern 16-B (with relative intensity at or above 1%)

[0072] In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2 and 18.5. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2, 17.2, 17.4, 18.5. 20.1. and 20.4. In some embodiments, a solid form of a t-butylamineKRBIO.036WO PATENTsalt of Compound (1) is characterized by Pattern 16-C. FIGURE 11 is an XRPD spectrum of Pattern 16-C, obtained from a sample of a t-butylamine salt of Compound (1).Table 11. XRPD Peak List for Compound (1) t-butylamine Pattern 16-C (with relative intensity at or above 1%)

[0073] In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising a 2-theta peak (20 ±0.2) at 6.5. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.5 and 20.6. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-D. FIGURE 12 is an XRPD spectrum of Pattern 16-D, obtained from a sample of a t-butylamine salt of Compound (1).KRBIO.036WO PATENTTable 12. XRPD Peak List for Compound (1) t-butylamine Pattern 16-D (with relative intensity at or above 1%)

[0074] In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 7.7, 10.7, 12.4, 12.9, 18.8, and 20.1. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 7.7, 10.7, 12.4, 12.9, 13.7, 16.5, 18.8, 19.1, 19.7, 20.1, 20.9, 24.9, and 27.0. In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-E. FIGURE 13A is an XRPD spectrum of Pattern 16-E, obtained from a sample of a t-butylamine salt of Compound (1).Table 13. XRPD Peak List for Compound (1) t-butylamine Pattern 16-E (with relative intensity at or above 1%)KRBIO.036WO PATENT

[0075] In some embodiments, a solid form of a t-butylamine salt of Compound (1) is characterized by Pattern 16-C, 16-D or 16-E. FIGURE 13B is an XRPD spectrum of Patterns 16-C, 16-D and 16-E from a sample of a t-butylamine salt of Compound (1), obtained from salt screening with t-butylamine (1.1 eq) in ACN as a wet cake Pattern 15-C (1), as a dry solid Pattern 15-D (2), and as Pattern 15-E after 3 day exposure to 90%RH at 30 degrees C (3).

[0076] In some embodiments, potassium salts of Compound (1) are provided, including crystalline and partially crystalline solid forms of a potassium salt of Compound (1). In some embodiments, solid forms of a potassium salt of Compound (1) are provided. In some embodiments, a solid form of a potassium salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.6, 7.0, 20.7, 21.0, and 22.7. In some embodiments, a solid form of a potassium salt of Compound (1) is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.6, 6.0, 7.0, 9.1, 18.0, 20.7, 21.0, and 22.7. In some embodiments, a solid form of a potassium salt of Compound (1) is characterized by Pattern 19-A. FIGURE 14A is an XRPD spectrum of Pattern 19-A, obtained from a sample of a potassium salt of Compound (1). FIGURE 14B is an XRPD spectrum of Pattern 19-A from a sample of a potassium salt of Compound (1), obtained from salt screening with KOH (1.1 eq) in MIBK as a wet cake Pattern 19-A (1), and as a dry solid Pattern 19-A (2).Table 14. XRPD Peak List for Compound (1) potassium Pattern 19-A (with relative intensity at or above 2%)KRBIO.036WO PATENT

[0077] In some embodiments, a pharmaceutically acceptable solid form of compound (1) is selected from the group consisting of: a freeform solid form of Compound (1) characterized by XRPD Pattern A, a phosphate salt of Compound (1) characterized by XRPD Pattern 9-A, a sulfate salt of Compound (1) characterized by XPRD Pattern 11-A, an edisylate salt of Compound (1) characterized by Pattern 14-A, an edisylate salt of Compound (1) characterized by Pattern 14-B, an edisylate salt of Compound (1) characterized by Pattern 14-C, an edisylate salt of Compound (1) characterized by Pattern 14-D, an oxalate salt of Compound (1) characterized by Pattern 15- A, a t-butylamine salt of Compound (1) characterized by Pattern 16- A, a t-butylamine salt of Compound (1) characterized by Pattern 16-B, a t-butylamine salt of Compound (1) characterized by Pattern 16-C, a t-butylamine salt of Compound (1)KRBIO.036WO PATENTcharacterized by Pattern 16-D, a t-butylamine salt of Compound (1) characterized by Pattern 16-E, and a potassium salt of Compound (1) characterized by Pattern 19-A.

[0078] FIGURE 15 A is an XRPD spectrum of two amorphous samples of Compound (1). FIGURE 15B shows TGA / DSC thermograms from testing two amorphous samples of Compound (1). FIGURE 15C shows a DSC thermogram from testing an amorphous sample of Compound (1).Administration and Pharmaceutical Compositions

[0079] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is formulated for oral delivery of Compound (1) to a human or veterinary subject. In some embodiments, a process for preparing a pharmaceutical composition, comprising dissolving a solid form provided herein in a solvent. In some embodiments, a method of inhibiting p300 is provided, comprising administering to a subject in need thereof an effective amount of a solid form disclosed herein or a pharmaceutical composition disclosed herein. In some embodiments, a method of treating an autoimmune disorder is provided, comprising administering to a subject in need thereof an effective amount of a solid form or a pharmaceutical composition disclosed herein. In some embodiments, a method of treating Sjogren’s disease is provided, comprising administering to a subject in need thereof an effective amount of a solid form or a pharmaceutical composition disclosed herein.

[0080] The disclosed compounds may be used alone or in combination with other treatments. These compounds, when used in combination with other agents, may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). The compounds may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy with another agent in a treatment program.

[0081] Examples of pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate,KRBIO.036WO PATENTpalmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.

[0082] Compositions containing the active ingredient may be in any form suitable for the intended method of administration. In some embodiments, the compounds of a method and / or composition described herein can be provided via oral administration, rectal administration, transmucosal administration, intestinal administration, enteral administration, topical administration, transdermal administration, intrathecal administration, intraventricular administration, intraperitoneal administration, intranasal administration, intraocular administration and / or parenteral administration.

[0083] When the compounds are administered via oral administration, for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0084] Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient can be mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient can be mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0085] Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain, for example, antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intendedKRBIO.036WO PATENTrecipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0086] In some embodiments unit dosage formulations contain a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.

[0087] The actual dose of the compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. In some embodiments, a daily dose may be from about 0.1 mg / kg to about 100 mg / kg or more of body weight, from about 0.25 mg / kg or less to about 50 mg / kg, from about 0.5 mg / kg or less to about 25 mg / kg, from about 1.0 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 7 mg per day to about 7000 mg per day, from about 35 mg per day or less to about 2000 mg per day or more, from about 70 mg per day to about 1000 mg per day.Methods of Treatment

[0088] Some embodiments of the present disclosure include methods of treating a disease or disorder associated with p300 activity in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutical composition as described herein.

[0089] Some embodiments relate to a method for treating a disease or condition selected from the group consisting of an inflammatory disorder, an allergic disorder, an autoimmune disease, and a cancer in a subject in need thereof, comprising administering aKRBIO.036WO PATENTtherapeutically effective amount of the compound as described herein or a pharmaceutical composition as described herein to the subject.

[0090] In some embodiments, the disease or condition is selected from the group consisting of systemic lupus erythematosus, myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis, Sjoegren’s syndrome, psoriasis, autoimmune hemolytic anemia, asthma, ulcerative colitis, Crohn’s disease, irritable bowel disease, and chronic obstructive pulmonary disease, systemic lupus erythematosus, myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis, Sjoegren’s syndrome, psoriasis, autoimmune hemolytic anemia, asthma, ulcerative colitis, Crohn’s disease, irritable bowel disease, and chronic obstructive pulmonary disease.

[0091] In some embodiments, the disease or condition is selected from the group consisting of asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, and systemic lupus erythematosus.

[0092] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0093] It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.

[0094] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to cany out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference inKRBIO.036WO PATENTtheir entirety) and the like. All the intermediate compounds of the present disclosure were used without further purification unless otherwise specified.

[0095] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and / or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated herein by reference in its entirety.

[0096] The following example schemes are provided for the guidance of the reader, and represent preferred methods for making the compounds exemplified herein. These methods are not limiting, and it will be apparent that other routes may be employed to prepare these compounds. Such methods specifically include solid phase based chemistries, including combinatorial chemistry. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application.Examples

[0097] AbbreviationsKRBIO.036WO PATENT2-Methyltetrahydrofuran 2-MeTHF2-Propanol IPAAcetonitrile ACNDichloromethane DCMDimethyl sulfoxide DMSOEthanol EtOHEthyl acetate EtOAcIsopropyl acetate IPAcMethanol MeOHMethyl acetate MeOAcMethyl isobutyl ketone MIBKMethyl tert-butyl ether MtBETetrahydrofuran THFTrifluoroacetic acid TFATrifluoroethanol TFEX-Ray Powder Diffraction (XRPD)

[0098] XRPD was performed using a Bruker D8 Advance equipped with LYNXEYE detector in reflection mode (i.e. Bragg-Brentano geometry). Samples were prepared on Si zeroreturn wafers. The parameters for XRPD methods used are listed below:Parameter Regular Scan High Resolution ScanX-ray wavelength Cu Kai, 1.540598 A Cu Kai, 1.540598 AX-ray tube setting 40 kV, 40 mA 40 kV, 40 mASlit condition 0.6 mm div. + 2.5 ° soller 0.6 mm div. + 2.5 ° sollerScan mode Step StepScan range (°20) 4-30 4-40Step size (°20) 0.03 0.02Dwell time (s / step) 0.23 0.9Spin Yes (0.5 Hz) Yes (0.5 Hz)Differential Scanning Calorimetry (DSC)

[0099] DSC was performed using a TA Discovery DSC. The sample (1-5 mg) was weighed directly in a 40 pL hermetic aluminum pan with a pinhole and analyzed according to the parameters below:_ Parameters _Method RampSample size 1-5 mgKRBIO.036WO PATENTHeating rate 10.0 °C / minTemperature range 30 to 300°CMethod gas N2 at 50.00 mL / minSimultaneous Thermogravimetric Analysis and Differential Scanning Calorimetry (TGA and DSC)

[0100] TGA and DSC were performed on the same sample simultaneously using a Mettler Toledo TGA / DSC 3+. Protective and purge gas was nitrogen at a flowrate of 20-30 mL / min and 50-100 mL / min, respectively. The desired amount of sample (5-10 mg) was weighed directly in a hermetic aluminum pan with pinhole and analyzed according to the parameters below:ParametersMethod RampSample size 5-10 mgHeating rate 10.0 °C / minTemperature range 30 to 300°CExample 1: Preparation of Compound (1)Step A: tert-butyl N-r -2-[(2-methylpyridin-3-yl) carbamoyl) -l-phenylethyll carbamateKRBIO.036WO PATENT

[0101] To a stirred solution of (35)-3-[(tert-butoxycarbonyl) amino]-3-phenylpropanoic acid (90 g, 339.23 m mol, 1 equiv.) in CH2CI2 (1800 mL) at 0 °C were added TEA (102.79 g, 1017.68 mmol. 3 equiv.) and T4P (aka 1,3,5,2,4,6-Trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide) (366.63 g, 1017.68 mmol, 3 equiv.). The reaction was stirred at 0 °C for 0.5 hour, then was added 2-methylpyridin-3-amine (44.02 g, 407.07 mmol, 1.2 equiv.). The reaction was stirred at 25 °C for 12 hours. Three batches were earned out in parallel (30 g x 3). TLC (Petroleum ether / Ethyl acetate=2 / l, R / = 0.5) indicated reactant was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to get a residue. The mixture was basified to pH=7~8 with saturated aq. NaHCCh solution. Then H2O (2 L) was added to the mixture, and white solid was precipitated in the reaction. The mixture was filtered and the filter cake was washed with 500 mL of H2O, dried in vacuum to give product. Compound tert-butyl N-[(15)-2-[(2-methylpyridin-3-yl) carbamoyl]- 1 -phenylethyl] carbamate (130 g, 329.17 mmol, yield 97.03%) was obtained as white solid.Step B: tert-butyl N-[(l. S')-2-[(2-fomiylpyridin-3-yl) carbamoyll-l-phenylethyll carbamate

[0102] A stirred solution of SeCE (202.93 g, 1828.73 mmol, 5 equiv.) in 1,4-Dioxane (5.2 L) was heated to 80 °C and stirred for 30 mins, then tert-butyl N-[(lS)-2-[(2-methylpyridin-3-yl) carbamoyl] -1 -phenylethyl] carbamate (130 g, 365.75 mmol, 1 equiv.) in 1,4-Dioxane (2.6 L) was slowly added to the above mixture at 80 °C. The reaction was allowed to warm to 110 °C andKRBIO.036WO PATENTstirred at 110 °C for 35.5 hours. Three reactions were carried out in parallel (45 gx2, 40 gxl). LCMS showed the reactant was remained and desired mass was detected. The mixture was allowed to room temperature and filtered. The filtrate was partitioned between EtOAc (2 L X 3) and H2O (2 L). The organic phase was separated, washed with brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep. -HPLC (column: Phenomenex lima C18 250mm*100mm*15um; mobile phase: [H2O (0.2%FA)-ACN]; B%: 35% - 65%, 21 min). Compound tert-butyl N-[(15)-2-[(2-formylpyridin-3-yl) carbamoyl] -1 -phenylethyl] carbamate (40 g, 97.45 mmol, yield 26.64%) was obtained as a yellow solid. LCMS m / z 314.0 [M+H-56]+Step C: tert-butyl ( )-((2-oxo-L2-dihvdro-L5-naDhthyridin-3-yl)(Dhenyl)methyl)carbamate

[0103] To a stirred solution of tert-butyl N-[(lS)-2-[(2-formylpyridin-3-yl) carbamoyl] -1 -phenylethyl] carbamate (40 g, 108.28 mmol, 1 equiv.) in DMF (500 mL) at 0 °C was added CS2CO3 (29.48 g, 216.56 mmol, 2 equiv.). The reaction was stirred at 60 °C for 2 hours. LC-MS showed the reactant was consumed completely and desired mass was detected. Then H2O (1 L) was added to the mixture, and white solid precipitates in the reaction. The mixture was filtered and the filter cake was washed with (100 mL X 3) of H2O, dried in vacuum to give product. Compound tert-butyl (R)-((2-oxo- 1,2-dihydro- 1,5-naphthyridin-3-yl)(phenyl)methyl)carbamate (33 g, 89.21 mmol, yield 82.39%) was obtained as a yellow solid.LCMS m / z 352.1 [M+H]+KRBIO.036WO PATENTStep D: tert-butyl ((lS)-(2-oxo-1,2,3,4-tetrahvdro-l,5-naphthyridin-3-yl)(phenyl)methyl)carbamate

[0104] To a solution of tert-butyl N-[(A)-(2-oxo-lH-l,5-naphthyridin-3-yl) (phenyl )methyl] carbamate (33 g, 93.91 mmol, 1 equiv.) in THF (4 L, 0.02 M, 121.21 Vols) and MeOH (4 L, 0.02 M, 121.21 Vols) were added PtCF (33.05 g, 145.56 mmol, 1.55 equiv.) and NH3. H2O (3.3 mL, 93.91 mmol, 1 equiv.). The suspension was degassed and purged with H2 for 3 times. The mixture was stirred at 80 °C for 12 h under H2 (50 Psi). (Seven reactions were carried out in parallel (5 gx6, 3 gxl)). LC-MS showed the reactant was consumed completely and desired mass was detected (some of the batches showed that there is a small amount of starting material remaining (about 10-20%)). The mixture was allowed to room temperature and filtered. The filter cake was washed with 1 L of MeOH. The filtrate was concentrated under reduced pressure to get residue. Compound tert-butyl ((15)-(2-oxo-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)(phenyl)methyl)carbamate (32 g, 72.44 mmol, yield 77.13%) was obtained as a yellow solid. LCMS m / z 354.1 [M+H]+Step E: tert-butyl ((, S,)-phenyl((. S,)-l.2.3.4-tetrahydro-1.5-naphthyridin-3-yl)methyl)carbamate tert-butyl ((S)-phenyl((7?)-l,2,3,4-tetrahydro-L5-naphthyridin-3-yl)methyl)carbamate

[0105] To a solution of tert-butyl N-[(5)-(2-oxo-3. 4-dihydro-lH-l,5-naphthyridin-3-yl) (phenyl)methyl] carbamate (24 g, 67.91 mmol, 1 equiv.) in THF (500 mL, 0.14 M, 20.83 Vols) at 0 °C was dropwise added 2M LiBH4 in THF (169.77 mL, 2 M, 39.54 mmol, 5 equiv.) under N2.KRBIO.036WO PATENTThe mixture was stirred at 35 °C for 12 h under N2. LC-MS showed the reactant was remained and desired mass was detected. TLC (CH2C12 / THF=3 / 1, R / =0.25 and 0.2) indicated reactant was remained and two new spots formed. The reaction mixture was quenched by addition Saturated NH4CI aqueous solution (500 mL) at 0 °C. Then the mixture was acidified to pH~6 with aqueous solution of hydrochloric acid (1 mol / L) (slowly added). The mixture was stirred at 70 °C for 12 h. The reaction mixture was partitioned between EtOAc (100 mL 3) and H2O (100 mL). The organic phase was separated, washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 220 g SepaFlash@ Silica Flash Column, Eluent of 9-10% THF / DCM @ 80 mL / min). Compound tert-butyl ((S)-phenyl ((5)- 1,2, 3, 4-tetrahydro- 1.5-naphthyridin-3-yl)methyl)carbamate (5 g, 13.257 mmol, yield 19.52%) was obtained as white solid. (TLC (DCM / THF=3 / 1), Ry=0.25)Compound tert-butyl ((S)-phenyl ((7?)-l,2,3,4-tetrahydro-1.5-naphthyridin-3-yl)methyl)carbamate (5.9 g, 13.905 mmol, yield 20.47%) was obtained as white solid.(TLC (DCM / THF=3 / 1), Ry=0.2). LCMS m / z 340.2 [M+H]+Step F. -l-phenyl-l-r(37?)-l,2,3,4-tetrahvdro-l,5-naDhthyridin-3-yl1 methanamine

[0106] To a solution of tert-butyl N-[(S)-phenyl ((37?)- 1,2,3, 4-tetrahydro- 1,5-naphthyridin-3-yl) methyl]carbamate (5 g, 14.73 mmol. 1 equiv.) in HC1 (4 M in EtOAc) (100 mL, 14.73 mmol, 1 equiv.). The mixture was stirred at 25 °C for 12 h. LCMS showed the reactant was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to get a residue. The residue was diluted with saturated Na2COs aqueous solution (250 mL) and extracted with EtOAc / THF (1:1, 200 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to giveKRBIO.036WO PATENTa residue. Compound (lS)-l-phenyl-1-[(3 / ?)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl] methanamine (3.5 g, 13.99 mmol, yield 95.01%) was obtained as a yellow solid. LCMS m / z 240.2 [M+H]+Step G. (S)-2-(3-(isoxazol-4-yl) phenyl)-N-((S)-phenyl((R)- 1,2,3, 4-tetrahydro-l, 5-naphthyridin-3-yl)methyl)propanamide

[0107] To a solution of (2S)-2-[3-(l,2-oxazol-4-yl) phenyl] propanoic acid (synthesized via Suzuki Coupling of commercially available (S)-2-(3-bromophenyl)propanoic acid (CAS [1146411-14-4]) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (CAS [928664-98-6])) (3.18 g, 14.63 mmol, 1 equiv.) and (lS)-l-phenyl-1-[(3 / ?)-l,2,3,4-tetrahydro-1,5-naphthyridin-3-yl] methanamine (3.5 g, 14.63 mmol, 1 equiv.) in CH2CI2 (70 mL, 0.04 M, 110.17 Vols) at 0 °C was added TEA (7.40 g, 73.12 mmol, 5 equiv.). Then to the above mixture was added T4P (21.08 g, 29.25 mmol, 2 equiv.) slowly to the solution at 0 °C under N2. The mixture was stirred at 25 °C for 2 h under N2. LC-MS showed the reactant was consumed completely and desired mass was detected. The reaction mixture was quenched by addition H2O (30 mL) at 0 °C. Then the residue was diluted with H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 80 g SepaFlash@ Silica Flash Column, Eluent of 25-30% THF / CH2Q2 @ 80 mL / min). The product fraction was combined and evaporated under reduced pressure to give (5)-2-(3-(isoxazol-4-yl) phenyl)-N-((S)-phenyl(( / ?)-1,2, 3, 4-tetrahydro-l,5-naphthyridin-3-yl)methyl)propanamide (6.4 g, 14.59 mmol, purity: 87%, yield 86%) as a yellow solid.LCMS m / z 439.3 [M+H]+KRBIO.036WO PATENTStep H. (S)-2-(3-(isoxazol-4-yl) phenyl)-N-((S)-phenyl(( / ?)-l ^. S^-tetrahvdro-LS-naphthyridin- O-vDmethvDpropan-l-amine

[0108] To a solution of ( )-2-(3-(isoxazol-4-yl)phenyl)-N-((S)-phenyl((7?)-l, 2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)propanamide (6.4 g, 14.59 mmol, 1 equiv.) in diglyme (64 mL, 0.46 M, 10 Vols) at 0 °C were added BF3. Et2O (24.86 g, 175.13 mmol, 12 equiv.) and NaBEE (3.05 g, 80.62 mmol, 5.5 equiv.). The mixture was stirred at 40 °C for 12 h under N2. Two reactions were carried out in parallel (3.2 g x 2). LC-MS showed the reactant was consumed completely and desired mass was detected. The reaction mixture was quenched by addition MeOH (50 mL) at 0 °C. The mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure to get a residue. The reaction mixture was quenched by addition Na2COs (100 mL), and then diluted with EtOAc (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated NaCl solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 80 g SepaFlash@ Silica Flash Column, Eluent of 60-70% THF / DCM @ 80 mL / min). Compound (5)-2-(3-(isoxazol-4-yl)phenyl)-N-((5)-phenyl((7?)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)propan-l-amine (4.1 g, 8.40 mmol) was obtained as yellow solid. LCMS m / z 425.2 [M+H]+Step I. 2-(3-((S)-l-(((S)-phenyl((R)-L2,3,4-tetrahvdro-l,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acidCompound (1)

[0109] To a solution of (S)-2-(3-(isoxazol-4-yl)phenyl)-N-((S)-phenyl((7?)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)propan-l-amine (4 g, 9.42 mmol, 1 equiv.) in EtOH (32 mL, 0.29 M, 8 Vols) was cooled to 0 °C, then NaOH (3768.431 mg, 94.218 mmol, 10 equiv.) inKRBIO.036WO PATENTH2O (16 mL, 0.589 M, 4 Vols) was dropwise added to the above mixture under N2, the mixture was stirred at 80 °C for 12 h under dark and N2. LC-MS showed the reactant was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove EtOH. The mixture was acidified to pH 9 with aqueous solution of hydrochloric acid (12 mol / L). The reaction mixture was partitioned between EtOAc (100 mL X 3) and H2O (100 mL). The organic phase was separated, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was loaded to Biotage® using an Agela flash silica gel column (eluted with 0% to 10% DCM in MeOH). The product fraction was combined and evaporated under reduced pressure to yield crude product (~ 2 g). The crude product was purified by Prep.-HPLC (neutral condition: column: Waters Xbridge BEH C18 250*50mm*10um; mobile phase: [A: H2O (lOmM NH4HCO3); B: ACN]; B%: 10.00%-45.00%,10.00min) to give product 1 (batch 1, 800 mg, purity: 98.9%) and product 2 (batch 2, 500 mg, crude). Product 2 (batch 2) was purified by / Vc.-HPLC (column: Waters Xbridge BEH C18 250*50mm*10um; mobile phase: [A: H2O (lOmM NH4HCO3); B: ACN]; B%: 15.00%-40.00%,10.00min) to give product 2 (-400 mg) as a white solid. Then product 1 and product 2 were dissolved in MeCN (20 mL) and H2O (100 mL) and lyophilized to give Compound (1) 2-(3-((S)-l-(((S)-phenyl((R)-l,2,3,4-tetrahydro-l,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid (1160.7 mg, 2.77 mmol, yield 29.42%) as a white solid. LCMS m / z 416.2 [M+H]+. 'H NMR (400 MHz, DMSO-rfc) d ppm 7.53 (dd, J= 1.4, 4.5 Hz, 1H), 7.33 - 7.27 (m, 2H), 7.26 - 7.17 (m, 4H), 7.06 (d, J= 7.6 Hz, 1H), 7.02 - 6.98 (m, 2H), 6.81 (dd, J = 4.6, 8.0 Hz, 1H), 6.72 (dd, J = 1.3, 8.1 Hz, 1H), 5.80 (br s, 1H), 3.54 - 3.50 (m, 3H), 3.33 - 3.33 (m, 1H), 2.91 - 2.85 (m, 1H), 2.79 - 2.71 (m, 1H), 2.44 (dd, J= 7.3, 11.6 Hz, 1H), 2.36 -2.26 (m, 2H), 2.24 - 2.16 (m, 1H), 2.04 - 1.92 (m, 1H), 1.14 (d, 7= 6.8 Hz, 3H).An amorphous solid form of Compound (1) was characterized with the following results:KRBIO.036WO PATENTExample 2: Short-Term Slurries

[0110] Short-term slurries were carried out at RT in two solvents during the initial screening along with the gravimetric solubility assessment. Approximately 20 mg solid (L1MA83001-3-1) was added to a 2 mL vial, followed by 0.75 mL solvent. Slurries were stirred at a constant temperature overnight. After stirring overnight, solids were allowed to settle and were then recovered for X-ray powder diffraction (XRPD) analysis. Unique XRPD patterns were dried at 50 °C under vacuum (-29 inHg) for 3 h and reanalyzed by XRPD. The results are summarized in Table 3 and shown in Figure 11 and Figure 12.

[0111] One new crystalline freeform, Pattern A, was obtained in water. Pattern A was unstable ondrying at both RT and 50 °C for 3 h, converting into Pattern A + B and amorphous, respectively.Table 3- Summary of short-term slurry experiments of L1MA83001-3-1.Example 3: Salt Screening

[0112] Experiments were set up for the salt screening process in 2 mL vials containing 6.3 mm stir bars. A stock solution of L1MA83001-3-1 was prepared in trifluoroethanol (TFE) with a concentration of 58.8 mg / mL. Stock solutions of counter ions were prepared in ethanol (EtOH) with the exception of KOH and NaOH, which were prepared in EtOH:water (1:1 vol.). Calcium oxide was weighed directly as solid. The counter ions, their IDs, and corresponding pKas are listed in Table 5. The equivalent of 20 mg freeform solution was added to each vial, followed by the appropriate counter ion stock solution. The vials were left to stir at 45 °C for 1 h before cooling to RT, after which solvents were evaporated using a SpeedVac at RT. The vials were then placed under active vacuum (~-29 inHg) at 50 °C overnight to dry thoroughly.KRBIO.036WO PATENT

[0113] Approximately 10 vol. (200 pL) of screening solvent (EtOAc, acetone, or 2-propanol[IPA]:water [9:1 vol.]) was added to each vial, and the samples were heated to 45 °C with stirring (400 rpm). Vials that demonstrated significant precipitation or gumming were vortexed and sonicated often to ensure thorough mixing. After 2 h, the temperature was reduced to RT and the samples were left to stir for three days. XRPD analysis was done in three stages. First, XRPD analysis of the wet cake was completed for all samples where solids were observed. Unique solids were then left on XRPD plates and dried under vacuum (~-29 inHg) at 50 °C for 3 h before they were analyzed by XRPD. Finally, solids were exposed to > 95 % RH overnight and XRPD on the resulting solids was carried out.

[0114] All XRPD patterns were compared to counter ion XRPD patterns and known freeform patterns. Any crystalline patterns observed will be denoted with the counter ion number followed by a letter in alphabetical order. For example, the first crystalline pattern observed for HC1 would be denoted 1-A.

[0115] If a clear solution was obtained from the first round of screening, it was cooled to 5 °C andstirred for three days. If gum formed, the sample was sonicated for approximately 2 h and stirred at RT for three days. If no crystalline salts formed, the solvents were evaporated using a SpeedVac at RT, followed by drying under active vacuum (~-29 inHg) at 50 °C overnight. After drying, the second round of solvent was added (EtOH, tetrahydrofuran [THF], and acetonitrile [ACN]). If no crystalline salts formed from the second round, the solvents were evaporated using a SpeedVac at RT, followed by drying under active vacuum (~-29 inHg) at 50 °C overnight. After drying, the third round of solvent was added (methyl isobutyl ketone [MIBK], 1,4-dioxane, and toluene:IPA [8:2 vol.]). The experiments were ceased at the request of the client at this stage. The XRPD data from the salt screening is shown in Table 6 and Figure 14 through Figure 29.

[0116] After screening experiments with 21 counter ions using 9 different solvents / solvent systems, 13 unique crystalline salt patterns were observed with phosphoric acid, sulfuric acid.KRBIO.036WO PATENTethanedisulfonic acid, oxalic acid, t-butylamine, and potassium hydroxide. Pattern 11-A (sulfate) and 15- A (oxalate) were stable upon both drying and humidification among all new crystalline salts.Table 4. Summary of Salt Screening ResultsKRBIO.036WO PATENTKRBIO.036WO PATENTKRBIO.036WO PATENTKRBIO.036WO PATENTKRBIO.036WO PATENTNote. Am., amorphous; CI, counter ion; del., deliquesced; L. C, low-crystalline; N / A means freeform was used. aSample was sonicated for 2 h then stirred at RT for three days.bAntisolvent addition using 10-15 vol. MtBE was done on the sample.cSolid was dissolved after adding 5 vol. % of DMSO as the cosolvent.dAntisolvent addition using 30 vol. IPA was done on tire sample.eSolid converted to gum after adding 5 vol. % of DMSO as tire cosolvent.fAntisolvent addition using 30 vol. water was done on the sample.gAntisolvenl addition using 1 vol. heptane was done on the sample.h5 vol. % of DMSO added to the solid as the cosolvent.iSolution was cooled to 5 °C and stirred overnight.jAntisolvent addition using 4 vol. heptane was done on the sample.* Pattern 16-E L. C. was obtained under humid conditionsTable 5. Summary of Crystalline Salts observed during salt screeningKRBIO.036WO PATENTNote. Am., amorphous; CI, counter ion; del., deliquesced; L. C., low-crystalline. Hyphen indicates no data were collected.a Indicates that analysis done on solid sample (1.1 eq. in IPAiwater (9:1 vol.))

[0117] After screening experiments with 21 counter ions using 9 different solvents / solvent systems, 13 unique crystalline salt patterns were observed with phosphoric acid, sulfuric acid, ethanedisulfonic acid, oxalic acid, t-butylamine, and potassium hydroxide. Pattern 11-A (sulfate) and 15- A (oxalate) were stable upon both drying and humidification among all new crystalline salts.Example 4: p300 TR-FRET Competition Assay

[0118] Compound (1) was tested for its potency of binding to p300 protein on a competition TR-FRET assay. The competition TR-FRET assay was run in dose-response format on a 384-well microplate. All reagents were diluted in reaction buffer (50 mM HEPES, pH = 7.5; 200 mM NaCl; 0.1% BSA; 1 mM TCEP.0.01% Triton X-100). Compound (1) dissolved in DMSO was deposited on a plate using Echo 650 acoustic liquid handler (Beckman Coulter). The final DMSO concentration in the assay was 2%. Biotinylated p300 protein (a construct covering amino acids 1287-1652, with the following mutations: (i) 1523-1554 deletion, (ii) K.1637R, and (iii) M1652G; with N-terminal methionine residue and a C-terminal peptide of the following sequence: CMLVELHTQSQDRFGGSG{Lys(biotin)} was preincubated with ten 3.16-fold serial dilutions of Compound (1) starting at 30 pM, 10 pM, 1 pM, or 100 nM, in duplicates, for 30 min at room temperature. Next, donor fluorophore Eu-W1024 chelate-labeled streptavidin (PerkinElmer) and l-(6-((2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-lH-pyrazol-l-yl)ethyl)amino)-6-oxohexyl)-2-((lE,3E,5E)-5-(3,3-dimethyl-5-sulfonato-l-(3-sulfonatopropyl)indolin-2-ylidene)penta-l,3-dien-l-yl)-3-methyl-3-(4-sulfonatobutyl)-3H-indol-l-ium-5 -sulfonate (the acceptor fluorophore-labeled p300 ligand) were added at final assay concentrations of 1 nM and 40 nM, respectively. The final p300 protein concentration in the assay was 2 nM. The mixture was allowed to equilibrate for 30 min at room temperature. The TR-FRET signal was measured using EnVision 2105 multimode plate reader (PerkinElmer) equipped with 337 nm TRF light unit, TRF laser LANCE D407 / D630 dual mirror, and two emission filters: APC 665 (665 nm) filter and LANCE laser attenuated Europium (615 nm) filter. The signal was calculated as a ratio of fluorescent intensities at 665 nm and 615 nm. The signal was normalizedKRBIO.036WO PATENTto no-protein control (100% response) and vehicle control (0% response) and fitted using the four-parameter logistic regression model. The IC50 value (defined as a concentration, at which the assay response equaled 50%) was used as a measure of binding affinity of Compound (1). As a result of these experiments, Compound (1) exhibited an IC50 of <100 nM.

[0119] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are encompassed by the following claims.

Claims

KRBIO.036WO PATENTCLAIMSWe claim:

1. A composition comprising a solid form of Compound (1), or a pharmaceutically acceptable salt thereof:(1).

2. The composition of claim 1, wherein the solid form is a free base of Compound (1).

3. The composition of claim 2, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 7.4 and 14.7.

4. The composition of claim 2, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 7.4, 14.7, 17.6, and 19.7.

5. The composition of claim 2, wherein the solid form is the freeform solid form of Compound (1) characterized by Pattern A.

6. The composition of claim 1, wherein the solid form is a phosphate salt of Compound (1).

7. The composition of claim 6, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.2, 8.9, 20.7, and 22.4.

8. The composition of claim 6, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.2, 8.9, 9.2, 10.9, 12.2, 18.0, 18.2, 18.9, 20.7, 21.0, 22.4 and 24.5.

9. The composition of claim 6, wherein the solid form is the phosphate salt of Compound (1) characterized by Pattern 9- A.

10. The composition of claim 1, wherein the solid form is a sulfate salt of Compound (1).KRBIO.036WO PATENT11. The composition of claim 10, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 5.7, 8.7 and 21.3.

12. The composition of claim 10, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 5.7, 8.7, 10.2, 10.7, 14.1, 19.7, 20.6, 21.

3. 21.

6. and 24.0.

13. The composition of claim 10, wherein the solid form is the sulfate salt of Compound (1) characterized by Pattern 11-A.

14. The composition of claim 1, wherein the solid form is an edisylate salt of Compound (1).

15. The composition of claim 14, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.6 and 13.8.

16. The composition of claim 14, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.

6. 13.8, 18.4, 22.5, and 23.1.

17. The composition of claim 14, wherein the solid form is the edisylate salt of Compound (1) characterized by Pattern 14- A.

18. The composition of claim 14, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.1 and 20.0.

19. The composition of claim 14, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.1, 7.3, 9.3, 16.4, 17.7, and 20.0.

20. The composition of claim 14, wherein the solid form is the edisylate salt of Compound (1) characterized by Pattern 14-B.

21. The composition of claim 14, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2 and 18.5.

22. The composition of claim 14, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.4, 9.2, 17.2, 17.4, 18.5, 20.1, and 20.4.

23. The composition of claim 14, wherein the solid form is the edisylate salt of Compound (1) characterized by Pattern 14-C.

24. The composition of claim 14, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peak (20 ±0.2) at 6.5.KRBIO.036WO PATENT25. The composition of claim 14, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.5 and 20.6.

26. The composition of claim 14, wherein the solid form is the edisylate salt of Compound (1) characterized by Pattern 14-D.

27. The composition of claim 1, wherein the solid form is an oxalate salt of Compound (1).

28. The composition of claim 27, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.4, 16.9, 18.8 and 19.3.

29. The composition of claim 27, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.4, 10.3, 12.5, 16.9, 18.5,18.8, 19.3 and 27.1.

30. The composition of claim 27, wherein the solid form is the oxalate salt of Compound (1) characterized by Pattern 15-A.

31. The composition of claim 1, wherein the solid form is a t-butylamine salt of Compound (1).

32. The composition of claim 31, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.1, 16.7, 18.7, 20.3 and 26.8.

33. The composition of claim 31, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.

1. 12.2, 13.2, 14.8, 16.7, 18.7, 20.3, 22.3, 24.0, 24.8 and 26.8.

34. The composition of claim 31, wherein the solid form is the t-butylamine salt of Compound (1) characterized by Pattern 16- A.

35. The composition of claim 31, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.

7. 9.1, 17.4, 17.9 and 19.2.

36. The composition of claim 31, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 8.7, 9.1, 9.6, 11.8, 13.7, 15.3, 15.9, 17.4, 17.9, 19.2, 20.4, 20.6, 21.2, 22.2, 23.3, and 23.7.

37. The composition of claim 27. wherein the solid form is the t-butylamine salt of Compound (1) characterized by Pattern 16-B.KRBIO.036WO PATENT38. The composition of claim 31, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 10.8, 12.1, 12.3, 12.6, 17.9, 18.7, and 20.5.

39. The composition of claim 31, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 6.2, 7.1, 10.8, 12.1, 12.3, 12.6, 14.2, 17.9, 18.7, 20.5, 21.9, and 23.9.

40. The composition of claim 31, wherein the solid form is the t-butylamine salt of Compound (1) characterized by Pattern 16-C.

41. The composition of claim 31, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 13.1, 20.2, 20.4 and 21.9.

42. The composition of claim 31, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 12.5, 13.1, 13.9, 20.2, 20.4 and 21.9.

43. The composition of claim 31. wherein the solid form is the t-butylamine salt of Compound (1) characterized by Pattern 16-D.

44. The composition of claim 31, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 7.7, 10.7, 12.4, 12.9, 18.8, and 20.1.

45. The composition of claim 31. wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 7.7, 10.7, 12.4, 12.9, 13.7, 16.5, 18.8, 19.1, 19.

7. 20.

1. 20.

9. 24.9, and 27.0.

46. The composition of claim 31, wherein the solid form is the t-butylamine salt of Compound (1) characterized by Pattern 16-E.

47. The composition of claim 1, wherein the solid form is a potassium salt of Compound (1).

48. The composition of claim 47, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.

6. 7.0, 20.7, 21.0, and 22.7,49. The composition of claim 47, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern comprising 2-theta peaks (20 ±0.2) at 4.

6. 6.0, 7.

0. 9.1, 18.0, 20.7, 21.0, and 22.7.KRBIO.036WO PATENT50. The composition of claim 31, wherein the solid form is the potassium salt of Compound (1) characterized by Pattern 19- A.

51. A pharmaceutically acceptable solid form of Compound (1),(1),selected from the group consisting of:a freeform solid form of Compound (1),a phosphate salt of Compound (1),a sulfate salt of Compound (1),an edisylate salt of Compound (1),an oxalate salt of Compound (1),a t-butylamine salt of Compound (1), anda potassium salt of Compound (1).

52. A pharmaceutically acceptable solid form of Compound (1),(1),selected from the group consisting of:a freeform solid form of Compound (1) characterized by XRPD Pattern A, a phosphate salt of Compound (1) characterized by XRPD Pattern 9-A, a sulfate salt of Compound (1) characterized by XPRD Pattern 11-A, an edisylate salt of Compound (1) characterized by Pattern 14-A,KRBIO.036WO PATENTan edisylate salt of Compound (1) characterized by Pattern 14-B, an edisylate salt of Compound (1) characterized by Pattern 14-C, an edisylate salt of Compound (1) characterized by Pattern 14-D, an oxalate salt of Compound (1) characterized by Pattern 15-A,a t-butylamine salt of Compound (1) characterized by Pattern 16- A, a t-butylamine salt of Compound (1) characterized by Pattern 16-B, a t-butylamine salt of Compound (1) characterized by Pattern 16-C, a t-butylamine salt of Compound (1) characterized by Pattern 16-D, a t-butylamine salt of Compound (1) characterized by Pattern 16-E, and a potassium salt of Compound (1) characterized by Pattern 19-A.

53. The composition of any one of claims 1-52, wherein the solid form of Compound (1) is crystalline.

54. The composition of any one of claims 1-53, comprising two or more solid forms of Compound (1).

55. The composition of claim 54, wherein the composition comprises two or more crystalline forms of Compound (1).

56. The composition of claim 54, wherein the composition comprises an amorphous form of Compound (1) and a crystalline form of Compound (1).

57. The composition of any one of claims 1-56, wherein the composition is a pharmaceutical composition.

58. The composition of claim 57, wherein the composition is formulated for oral delivery of Compound (1) to a human or veterinary subject.

59. A process for preparing a pharmaceutical composition, comprising dissolving in a solvent a solid form any one of claims 1-56.

60. A method of inhibiting p300. comprising administering to a subject in need thereof an effective amount of a solid form according to any one of claims 1-56 or a pharmaceutical composition of claim 57.

61. A method of treating an autoimmune disorder, comprising administering to a subject in need thereof an effective amount of a solid form according to any one of claims 1-56 or a pharmaceutical composition of claim 57.KRBIO.036WO PATENT62. A method of treating Sjogren’s disease, comprising administering to a subject in need thereof an effective amount of a solid form according to any one of claims 1-56 or a pharmaceutical composition of claim 57.

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