BR122023016197B1 - CRYSTALLINE SALT OF 2-(TERT-BUTYLAMINO)-4-((1R,3R,4R)-3-HYDROXY-4-METHYLCYCLOHEXYLAMINO)-PYRIMIDINE-5-CARBOXAMIDE, PHARMACEUTICAL COMPOSITION THE UNDERSTOOD AND USE THEREOF - Google Patents

Abstract

Pharmaceutical compositions and dosage forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, or a stereoisomer, tautomer are provided. , solid form, polymorph, pharmaceutically acceptable salt, hydrate, clathrate or solvate thereof. Also provided are methods of treating, controlling or preventing various disorders, such as diseases or disorders treatable or preventable by inhibiting a JNK pathway in mammals using such pharmaceutical compositions or dosage forms. 2-(tert-Butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide salts and methods of preparing such salts are additionally provided.h

Description

PHARMACEUTICS UNDERSTANDING AND USE THEREOF Split from BR 11 2017 012795 4, filed on 12/15/2015

[001] This application claims the benefit of US Provisional Application No. 62/196,044, filed on July 23, 2015; and US Provisional Application No. 62/092,537, filed on December 16, 2014, the contents of which are incorporated herein by reference in their entirety.

1. FIELD

[002] Pharmaceutical compositions, dosage forms and salts of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5 are provided herein. -carboxamide. Methods for using the pharmaceutical compositions, dosage forms and salts are also provided.

2. FUNDAMENTALS

[003] The connection between abnormal protein phosphorylation and the cause or consequence of diseases has been known for more than 20 years. Consequently, protein kinases have become a very important group of drug targets. (See Cohen, Nature, 1:309-315 (2002), Gaestel et al. Curr.Med.Chem.14: 2214 to 223 (2007); Grimminger et al. Nat. Rev. Drug Disc. 9(12): 956 to 970 (2010)). Various protein kinase inhibitors have been used clinically in the treatment of a wide variety of diseases, such as cancer and chronic inflammatory diseases, including rheumatoid arthritis and psoriasis. (See Cohen, Eur. J. Biochem., 268:5001 to 5010 (2001); Protein Kinase Inhibitors for the Treatment of Disease: The Promise and the Problems, Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167 (2005)).

[004] JNK is a ubiquitously expressed serine/threonine kinase that belongs, together with ERK (extracellular regulated kinase) and p38, to the family of mitogen-activated protein kinases (MAPKs). (Kyriakis JM, Sci. STKE (48):pe1 (2000); Whitmarsh AJ, et al. Sci. STKE (1):pe1 (1999); Schramek H, News Physiol. Sci.17:62-67 (2002) ; Ichijo H, Oncogene 18(45):6087-6093 (1999)). MAPKs are important mediators of signal transduction from the cell surface to the nuclei, using phosphorylation cascades to generate a coordinated response by a cell to an external stimulus by phosphorylation of selected intracellular proteins, including transcription factors. Additionally, JNK also phosphorylates non-nuclear proteins, for example, family members IRS-1 and Bcl-2. (Davis RJ, Trends Biochem. Sci. 9(11):470-473 (1994); Seger R et al., FASEB J.; 9(9):726-735 (1995); Fanger GR et al., Curr .

[005] The elucidation of the complexity of protein kinase pathways and the complexity of the relationship and interaction within and between the various protein kinases and kinase pathways highlights the importance of developing pharmaceutical agents capable of acting as modulators, regulators or protein kinase inhibitors have beneficial activity on multiple kinases or multiple kinase pathways.

[006] The compound chemically called 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (alternatively called 2-[(1 ,1-dimethylethyl)amino]-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]-5-pyrimidinecarboxamide) and tautomers thereof are disclosed in the U.S. Patent Application Publication No. 2013/0029987, published on January 31, 2013, and in International Publication No. WO2012/145569, the entirety of which is incorporated into this document by reference.

[007] The identification and selection of a formulation of a pharmaceutical compound is complex, given that a change in the formulation can affect a variety of physical and chemical properties, which can provide benefits or disadvantages in safety, processing, stability, solubility and bioavailability, among other important pharmaceutical characteristics.

[008] Notably, the various excipients employed in a formulation of a pharmaceutical compound can have a profound effect on the manufacturing process, whereby characteristics such as fluidity (e.g., blend flow), hardness, compressibility, stickiness, film application and Coverage may be affected by the identity and quantity of excipients used.

[009] The citation or identification of any reference in Section 2 of this application should not be interpreted as an admission that it represents prior art to the present application.

3. SUMMARY

[010] Pharmaceutical compositions and dosage forms comprising: which has the name 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (alternatively called 2-[(1,1- dimethylethyl)amino]-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]-5-pyrimidinecarboxamide) (Compound 1), or a pharmaceutically acceptable salt, stereoisomer, tautomer, form solid, polymorph, hydrate, clathrate or solvate thereof (collectively referred to herein as “Compound A”).

[011] Additionally provided herein are pharmaceutically acceptable salts of Compound 1, including salts of hydrochloride, sulfate, phosphate, L-tartrate, L-malate, L-lactate, succinate, p-toluenesulfonate (tosylate), methanesulfonate (mesylate) , benzenesulfonate (besylate), fumarate and citrate.

[012] Additionally provided herein are methods for using the pharmaceutical compositions, and dosage forms of Compound A to treat or prevent diseases or disorders treatable or preventable by inhibiting a JNK pathway, as described herein. Also provided herein is a pharmaceutical composition of Compound A for use in a method of treating diseases or disorders treatable or preventable by inhibiting a JNK pathway as described herein. Also provided herein is a dosage form of Compound A for use in a method of treating diseases or disorders treatable or preventable by inhibiting a JNK pathway as described herein. Also provided herein is a pharmaceutical composition of Compound A for use in a method of preventing diseases or disorders treatable or preventable by inhibiting a JNK pathway as described herein. Also provided herein is a dosage form of Compound A for use in a method of preventing diseases or disorders treatable or preventable by inhibiting a JNK pathway as described herein. In some embodiments, the diseases or disorders include, without limitation, interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection, or lupus. In other embodiments, the diseases or disorders include, without limitation, fibrotic liver disorders, or diabetes and/or metabolic syndrome leading to fibrotic liver disorders, as described herein. In one embodiment, the disease or disorder is a fibrotic liver disorder. In another embodiment, the disease or disorder is diabetes. In another embodiment, the disease or disorder is a metabolic syndrome leading to fibrotic disorders of the liver.

[013] Methods for preparing, isolating and characterizing salts are also provided.

[014] The present embodiments can be more fully understood by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.

4. BRIEF DESCRIPTION OF THE DRAWINGS

[015] Figure 1 represents the process and equipment for wet granulation processes of Compound 1 compositions.

[016] Figure 2 represents dissolution profiles of Compound 1 tablets in HCl at 0.1 N.

[017] Figure 3 represents dissolution profiles of Compound 1 tablets in HCl at 0.01 N.

[018] Figure 4 represents dissolution profiles of Compound 1 tablets in an aqueous solution at pH 4.5.

[019] Figure 5 represents pharmacokinetic (PK) data of Compound 1 capsules and tablets in a dog.

[020] Figure 6 represents an overlay of X-ray powder diffractogram (XRPD) patterns of Compound 1 (free base) isolated from ACN (previously called Form C), EtOH/IPA (previously called Form C), EtOAc ( formerly called Form G) or acetone (formerly called Form B), Form A (starting material) and HCl salt forms 1 to 4 of Compound 1 isolated from ACN, EtOH/IPA, EtOAc or acetone (from top to bottom). Freebase Forms A (starting material labeled in Figures 6 to 13, 16 to 29), Form B, Form C and Form G were previously described in US Provisional Patent Application No. 61/933,636, filed in 30 January 2014, and in US Provisional Patent Application No. 62/025,161, filed on July 16, 2014.

[021] Figure 7 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and HCl salt forms 1 to 4 of Compound 1 isolated from ACN, EtOH/IPA, EtOAc or acetone (from top to bottom).

[022] Figure 8 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and H2SO4 salt forms 1 and 2 of Compound 1 isolated from ACN, IPA, EtOAc or acetone (from top to bottom).

[023] Figure 9 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and H2SO4 salt forms 1 to 2 of Compound 1 isolated from ACN, IPA, EtOAc or acetone (from top to bottom).

[024] Figure 10 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and the H3PO4 salt of Compound 1 isolated from ACN, EtOH, EtOAc or acetone (from top to bottom).

[025] Figure 11 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and the H3PO4 salt of Compound 1 isolated from ACN, EtOH, EtOAc or acetone (from top to bottom).

[026] Figure 12 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and the L-tartrate salt of Compound 1 isolated from ACN, EtOH, EtOAc or acetone (from top to bottom).

[027] Figure 13 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and the L-tartrate salt of Compound 1 isolated from ACN, EtOH, EtOAc or acetone (from top to bottom).

[028] Figure 14 represents a 1H NMR spectrum of the L-tartrate salt of Compound 1 prepared from acetone.

[029] Figure 15 represents a TGA/DSC thermogram of the L-tartrate salt of Compound 1 prepared from acetone.

[030] Figure 16 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and L-lactate salt forms 1 and 2 of Compound 1 isolated from ACN, hexane, EtOAc, or acetone (from top to bottom).

[031] Figure 17 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and L-lactate salt forms 1 and 2 of Compound 1 isolated from ACN, hexane, EtOAc, or acetone (from top to bottom).

[032] Figure 18 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and L-malate salt forms 1 to 4 of Compound 1 isolated from ACN, MeNO2, EtOAc or IPA (from top to bottom).

[033] Figure 19 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and L-malate salt forms 1 to 4 of Compound 1 isolated from ACN, MeNO2, EtOAc or IPA (from top to bottom).

[034] Figure 20 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and the L-malate salt of Compound 1 isolated from MTBE, MeNO2, hexane or MeOAc (from top to bottom).

[035] Figure 21 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and the L-malate salt of Compound 1 isolated from MTBE, MeNO2, hexane or MeOAc (from top to bottom).

[036] Figure 22 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and succinate salt forms 1 and 2 and their mixture of Compound 1 isolated from ACN, EtOH, EtOAc or acetone (from top to bottom).

[037] Figure 23 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and succinate salt forms 1 and 2 and their mixture of Compound 1 isolated from ACN, EtOH, EtOAc or acetone (from top to bottom).

[038] Figure 24 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and tosylate salt forms 1 to 3 of Compound 1 isolated from ACN, MeNO2, EtOAc or acetone (from top to bottom).

[039] Figure 25 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and tosylate salt forms 1 to 3 of Compound 1 isolated from ACN, MeNO2, EtOAc or acetone (from top to bottom).

[040] Figure 26 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and mesylate salt forms 1 and 2 of Compound 1 isolated from ACN/IPA, EtOH/IPA, EtOAc or acetone (from top to bottom).

[041] Figure 27 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and mesylate salt forms 1 and 2 of Compound 1 isolated from ACN/IPA, EtOH/IPA, EtOAc or acetone (from top to bottom).

[042] Figure 28 represents an overlay of XRPD patterns of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material) and the fumarate salt isolated from ACN and the salt of besylate isolated from MeNO2 (from top to bottom).

[043] Figure 29 represents an overlay of Raman spectra of Compound 1 (free base) isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (starting material), the fumarate salt isolated from ACN and the salt from besylate isolated from MeNO2 (from top to bottom).

[044] Figure 30 represents an overlay of 1H NMR spectra of L-lactate salt, L-malate salt, L-tartrate salt, H3PO4 salt, H2SO4 salt, HCl salt and Compound 1 ( free base) (from top to bottom).

[045] Figure 31 represents photomicrographs of the HCl salt, H2SO4 salt, H3PO4 salt, L-tartrate salt, L-malate salt, L-lactate salt and Compound 1 (free base) (from left to right, and from top to bottom).

[046] Figure 32 represents an overlay of Raman spectra of Compound 1 (free base), HCl salt, H2SO4 salt, H3PO4 salt, L-tartrate salt, L-malate salt and L salt -lactate (from top to bottom).

[047] Figure 33 represents an overlay of XRPD patterns of Compound 1 (free base), HCl salt, H2SO4 salt, H3PO4 salt, L-tartrate salt, L-malate salt and L salt -lactate (from top to bottom).

[048] Figure 34 represents a TGA/DSC thermogram of form 2 of the HCl salt of Compound 1.

[049] Figure 35 represents a TGA/DSC thermogram of the H2SO4 salt of Compound 1.

[050] Figure 36 represents a TGA/DSC thermogram of the H3PO4 salt of Compound 1.

[051] Figure 37 represents a TGA/DSC thermogram of the L-tartrate salt of Compound 1.

[052] Figure 38 represents a TGA/DSC thermogram of the L-malate salt of Compound 1.

[053] Figure 39 represents a TGA/DSC thermogram of the L-lactate salt of Compound 1.

[054] Figure 40 represents an overlay of 1H NMR spectra of the L-lactate salt before and after heating (from top to bottom).

[055] Figure 41 represents a DVS thermogram of the HCl salt of Compound 1.

[056] Figure 42 represents an overlay of XRPD patterns of the HCl salt, the HCl salt after DVS, the HCl salt in water and the HCl salt in Simulated Gastric Fluid (SGF) (from top to bottom).

[057] Figure 43 represents a DVS thermogram of the H2SO4 salt of Compound 1.

[058] Figure 44 represents an overlay of XRPD patterns of the H2SO4 salt, the H2SO4 salt after DVS, the H2SO4 salt in water and the H2SO4 salt in SGF (from top to bottom).

[059] Figure 45 represents a DVS thermogram of the H3PO4 salt of Compound 1.

[060] Figure 46 represents an overlay of XRPD patterns of the H3PO4 salt, the H3PO4 salt after DVS, the H3PO4 salt in water and the H3PO4 salt in SGF (from top to bottom).

[061] Figure 47 represents a DVS thermogram of the L-tartrate salt of Compound 1.

[062] Figure 48 represents a DVS thermogram of the L-tartrate salt of Compound 1 after preheating at 50 ° C for 3 hours. (from top to bottom).

[063] Figure 49 represents an overlay of XRPD patterns of the L-tartrate salt, the L-tartrate salt after DVS, the L-tartrate salt after DVS after preheating at 50 ° C for 3 hours, the L-tartrate in water and the L-tartrate salt in SGF (from top to bottom).

[064] Figure 50 represents a DVS thermogram of the L-malate salt of Compound 1.

[065] Figure 51 represents an overlay of XRPD patterns of the L-malate salt, the L-malate salt after DVS, the L-malate salt in water and the L-malate salt in SGF (from top to low).

[066] Figure 52 represents a DVS thermogram of the L-lactate salt of Compound 1.

[067] Figure 53 represents an overlay of XRPD patterns of the L-lactate salt, the L-lactate salt after DVS, the L-lactate salt in water and the L-lactate salt in SGF (from top to low).

[068] Figure 54 represents an overlay of XRPD patterns of the L-H2SO4 salt in SGF, the L-malate salt in SGF, the L-tartrate salt in SGF, the H3PO4 salt, the L- lactate in SGF, Compound 1 (free base) in SGF, HCl salt in SGF, HCl salt and HCl salt in water (from top to bottom).

[069] Figure 55 represents an overlay of XRPD patterns of the HCl salt, the HCl salt stored at 80 ° C for 2 weeks and the HCl salt stored at 80 ° C under 75% relative humidity for two weeks ( from top to bottom).

[070] Figure 56 represents an overlay of Raman spectra of form 4, form 3, form 5, form 6, form 1 and form 2 of the HCl salt (from top to bottom).

[071] Figure 57 represents an overlay of XRPD patterns of form 7, form 6, form 5, form 4, form 3, form 2 and form 1 of the HCl salt (from top to bottom) .

[072] Figure 58 represents a TGA/DSC thermogram of HCl salt stored at 40°C/75% relative humidity for two weeks.

[073] Figure 59 represents a TGA/DSC thermogram of form 6 of the HCl salt.

[074] Figure 60 represents a DSC thermogram of form 1 of the HCl salt.

[075] Figure 61 represents an overlay of XRPD patterns of the H2SO4 salt, the H2SO4 salt stored at 80 ° C for 2 weeks and the H2SO4 salt stored at 80 ° C under 75% relative humidity for two weeks ( from top to bottom).

[076] Figure 62 represents an overlay of XRPD patterns of the H3PO4 salt, the H3PO4 salt stored at 80 ° C for two weeks and the H3PO4 salt stored at 80 ° C under 75% relative humidity for two weeks ( from top to bottom).

[077] Figure 63 represents an overlay of XRPD patterns of the L-tartrate salt, the L-tartrate salt stored at 80 ° C for two weeks and the L-tartrate salt stored at 80 ° C under 75% relative humidity for two weeks (from top to bottom).

[078] Figure 64 represents an overlay of XRPD-DSC patterns of the L-tartrate salt.

[079] Figure 65 represents an overlay of XRPD patterns of the L-tartrate salt before and after heated to 130°C.

[080] Figure 66 represents an overlay of XRPD patterns of the L-malate salt, the L-malate salt stored at 80 ° C for two weeks and the L-malate salt stored at 80 ° C under 75% relative humidity for two weeks (from top to bottom).

[081] Figure 67 represents an overlay of XRPD patterns of the L-lactate salt, the L-lactate salt stored at 80 ° C for two weeks and the L-lactate salt stored at 80 ° C under 75% relative humidity for two weeks (from top to bottom).

[082] Figure 68 represents an overlay of HPLC chromatograms of Compound 1 (free base) stored at 80 ° C for two weeks, Compound 1 (free base) and Compound 1 (free base) stored at 80 ° C under 75% relative humidity for two weeks (top to bottom).

[083] Figure 69 represents an overlay of HPLC chromatograms of the HCl salt stored at 80 ° C under 75% relative humidity for two weeks, the HCl salt stored at 80 ° C for two weeks and the HCl salt ( from top to bottom).

[084] Figure 70 represents an overlay of HPLC chromatograms of the H2SO4 salt stored at 80°C under 75% relative humidity for two weeks, the H2SO4 salt stored at 80°C for two weeks and the H2SO4 salt ( from top to bottom).

[085] Figure 71 represents an overlay of HPLC chromatograms of the HsPO4 salt stored at 80 ° C under 75% relative humidity for two weeks, the H3PO4 salt stored at 80 ° C for two weeks and the H3PO4 salt (from top to bottom).

[086] Figure 72 represents an overlay of HPLC chromatograms of the L-tartrate salt stored at 80 ° C under 75% relative humidity for two weeks, the L-tartrate salt stored at 80 ° C for two weeks and the L-tartrate salt (from top to bottom).

[087] Figure 73 represents an overlay of HPLC chromatograms of the L-malate salt stored at 80 ° C under 75% relative humidity for two weeks, the L-malate salt stored at 80 ° C for two weeks and the L-malate salt (from top to bottom).

[088] Figure 74 represents an overlay of HPLC chromatograms of the L-lactate salt stored at 80 ° C under 75% relative humidity for two weeks, the L-lactate salt stored at 80 ° C for two weeks and the L-lactate salt (from top to bottom).

[089] Figure 75 represents an XRPD pattern of HCl 1 salt form.

[090] Figure 76 represents an XRPD pattern of HCl 2 salt form.

[091] Figure 77 represents an XRPD pattern of HCl 3 salt form.

[092] Figure 78 represents an XRPD pattern of HCl 4 salt form.

[093] Figure 79 represents an XRPD pattern of HCl 5 salt form.

[094] Figure 80 represents an XRPD pattern of HCl 6 salt form.

[095] Figure 81 represents an XRPD pattern of HCl 7 salt form.

[096] Figure 82 represents an XRPD pattern of H2SO41 salt form.

[097] Figure 83 represents an XRPD pattern of H2SO42 salt form.

[098] Figure 84 represents an XRPD pattern of H2SO4 salt form 3, obtained from H2SO4 salt form 1 when stored under 80°C/75% RH conditions for two weeks.

[099] Figure 85 represents an XRPD pattern of the H3PO4 salt.

[0100] Figure 86 represents an XRPD pattern of L-lactate salt form 1.

[0101] Figure 87 represents an XRPD pattern of L-lactate 2 salt form.

[0102] Figure 88 represents an XRPD pattern of L-tartrate salt form 1.

[0103] Figure 89 represents an XRPD pattern of L-tartrate 2 salt form.

[0104] Figure 90 represents an XRPD pattern of L-malate 1 salt form.

[0105] Figure 91 represents an XRPD pattern of L-malate 2 salt form.

[0106] Figure 92 represents an XRPD pattern of L-malate 3 salt form.

[0107] Figure 93 represents an XRPD pattern of L-malate 4 salt form.

[0108] Figure 94 represents an XRPD pattern of succinate salt form 1.

[0109] Figure 95 represents an XRPD pattern of succinate salt form 2.

[0110] Figure 96 represents an XRPD pattern of tosylate salt form 1.

[0111] Figure 97 represents an XRPD pattern of tosylate salt form 2.

[0112] Figure 98 represents an XRPD pattern of tosylate salt form 3.

[0113] Figure 99 represents an XRPD pattern of mesylate salt form 1.

[0114] Figure 100 represents an XRPD pattern of mesylate salt form 2.

[0115] Figure 101 represents an XRPD pattern of the besylate salt.

[0116] Figure 102 represents an XRPD pattern of the fumarate salt.

[0117] Figure 103 represents arithmetic mean (± SD) plasma concentrations of Compound 1 in healthy subjects after multiple doses (qd x 6 days) of Compound 1 (Part 1).

[0118] Figure 104 represents arithmetic mean (±SD) plasma concentrations of Compound 1 in healthy subjects following a single dose of Compound 1 under fasted and fed conditions in a study of Compound 1 (Part 2).

[0119] Figure 105 represents arithmetic mean (± SD) plasma concentrations of Compound 1 in healthy subjects after a single dose of compound 1 under fasting conditions (Part 2).

[0120] Figure 106 depicts plasma concentrations versus whole blood concentrations of Compound 1 in healthy subjects following a single 200 mg dose of Compound 1 (Part 2, Treatment D).

[0121] Figure 107 represents individual percentages of baseline phospho c-Jun integrated optical density scores.

[0122] Figure 108 depicts changes from baseline in individual phospho c-Jun immunohistochemistry histology scores.

5. DETAILED DESCRIPTION 5.1. DEFINITIONS

[0123] As used herein, the term “pharmaceutically acceptable salt (or salts)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts include, without limitation, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine , ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, without limitation, inorganic and organic acids such as acetic, alginic, anthranilic, L-asparate, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic acid, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric and p-toluenesulfonic acids. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acid. Examples of specific salts therefore include hydrochloride and mesylate salts. Others are well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton PA (1995).

[0124] As used herein and unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means a stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a sterically pure compound that has a chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. Compounds may have chiral centers and may occur as individual racemates, enantiomers, or diastereomers, and mixtures thereof. All of these isomeric forms are included in the embodiments disclosed herein, including mixtures thereof. The use of stereomerically pure forms of such compounds, as well as the use of mixtures of these forms are covered by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound can be used in methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2,725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions, page 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0125] It should also be noted that the compounds may include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, compounds are isolated as either a cis isomer or a trans isomer. In other embodiments, compounds are a mixture of cis and trans isomers.

[0126] As used herein, and in the specification and attached claims, the indefinite articles “a” and “an” and the definite article “the” include plural or singular references, unless the context evidently indicate otherwise.

[0127] As used herein, and except where otherwise specified, the terms “about” and “approximately”, when used in connection with doses, amounts or percentage by weight of ingredients of a composition or a dosage form, mean a dose, amount or weight percentage that is recognized by one skilled in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount or weight percentage. In certain embodiments, the terms “about” and “approximately”, when used in this context, contemplate a dose, amount or percentage by weight within 30%, within 20%, within 15%, within 10% or within 5% of the specified dose, quantity or percentage by weight.

[0128] As used herein, and except where otherwise specified, a crystalline solid that is “pure”, that is, substantially free of other crystalline or amorphous solids, contains less than about 10% by weight of one or more other crystalline or amorphous solids, less than about 5% by weight of one or more other amorphous or crystalline solids, less than about 3% by weight of one or more other crystalline or amorphous solids, or less than about 1% by weight weight of one or more other crystalline or amorphous solids.

[0129] As used herein, and except where otherwise specified, a solid form that is “substantially and physically pure” is substantially free from other solid forms. In certain embodiments, a crystal form that is substantially and physically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% , 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% of one or more other solid forms on a weight basis. Detection of other solid forms may be accomplished by any method apparent to a person skilled in the art, including, without limitation, diffraction analysis, thermal analysis, elemental combustion analysis and/or spectroscopic analysis.

[0130] As used herein, and except where otherwise specified, a solid form that is “substantially and chemically pure” is substantially free of other chemical compounds (i.e., chemical impurities). In certain embodiments, a solid form that is substantially and chemically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% of one or more other chemical compounds on a weight basis. Detection of other chemical compounds may be accomplished by any method apparent to a person skilled in the art, including, without limitation, chemical analysis methods, such as, for example, mass spectroscopy analysis, spectroscopic analysis, thermal analysis, combustion analysis. elemental and/or chromatographic analysis.

[0131] As used herein, and unless otherwise indicated, a chemical compound, solid form or composition that is “substantially free” from another chemical compound, solid form or composition means that the compound, solid form or composition contains , in certain embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0 .3%, 0.2%, 0.1%, 0.05% or 0.01% by weight of the other compound, solid form or composition.

[0132] Unless otherwise specified, the terms “solvate” and “solvated”, as used herein, refer to a solid form of a solvent-containing substance. The terms “hydrate” and “hydrate” refer to a solvate, where the solvent is water. “Solvate polymorphs” refer to the existence of more than one solid form for a particular solvate composition. Similarly, “hydrate polymorphs” refer to the existence of more than one solid form for a particular hydrate composition. The term “desolvated solvate,” as used herein, refers to a solid form of a substance that can be manufactured by removing the solvent from a solvate. The terms “solvate” and “solvated”, as used herein, may also refer to a solvate of a salt, cocrystal or molecular complex. The terms “hydrate” and “hydrate”, as used herein, may also refer to a hydrate of a salt, cocrystal or molecular complex.

[0133] “Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is found and may be different depending, for example, on whether the compound is a solid or is an organic or aqueous solution. For example, in aqueous solution, pyrazoles can exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0134] As readily understood by those skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism and all tautomers of Compound 1 are within the scope of the present invention.

[0135] It should also be noted that Compound 1 may contain unnatural proportions of atomic isotopes in one or more of the atoms. For example, Compound 1 may be radiolabeled with radioactive isotopes, such as, for example, tritium (3H) or carbon-14 (14C), or it may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition different from that atom's natural isotopic composition. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of Compound 1 and/or Compound A, whether radioactive or not, are intended to fall within the scope of the embodiments provided herein. In some embodiments, isotopologues of Compound 1 are provided, for example, the isotopologues are Compound 1 and/or Compound A enriched in deuterium, carbon-13, or nitrogen-15.

[0136] Unless otherwise specified, the term “composition” as used herein is intended to encompass a product comprising the specified ingredient (or ingredients) (and in the specified quantity (or quantities), if indicated), as well as any product that results, directly or indirectly, from the combination of the specified ingredient (or ingredients) in the specified quantity (or quantities). By “pharmaceutically acceptable”, it is meant that a diluent, excipient or carrier in a formulation must be compatible with the other ingredient (or ingredients) in the formulation and not harmful to the recipient thereof.

[0137] “JNK” means a protein or an isoform thereof expressed by a JNK1, JNK2 or JNK3 gene (Gupta, S., Barrett, T., Whitmarsh, A.J., Cavanagh, J., Sluss, H.K., Derijard, B . and Davis, R. J. The EMBO J. 15:2760-2770 (1996)).

[0138] “Treat” as used herein means alleviating, in whole or in part, a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease or condition, or lessening or stopping the further progress or worsening of these symptoms, or alleviating or eradicating the cause (or causes) of the disorder, disease or condition itself. In one embodiment, the disorder is a condition that is treatable or preventable by inhibiting a JNK pathway, as described herein. In another embodiment, the disorder is selected from interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection, or lupus. In yet another embodiment, the disorder is a fibrotic liver disorder, or diabetes and/or metabolic syndrome leading to fibrotic liver disorders, as described herein. In some embodiments, the disorder is a fibrotic liver disorder, such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosis cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, or coincident liver fibrosis. with chronic or repeated alcohol intake (alcoholic hepatitis), with infection (e.g., viral infection such as HCV), with liver transplantation, or with drug-induced liver damage (e.g., acetaminophen toxicity). In some embodiments, "treat" means alleviation, in whole or in part, of a disorder, disease or condition, or symptoms associated with diabetes or metabolic syndrome leading to fibrotic disorders of the liver, such as non-alcoholic steatohepatitis, steatosis ( i.e., fatty liver), hepatitis, or cirrhosis, or a decrease in, or cessation of, further progress or worsening of these symptoms. In one embodiment, the symptom is jaundice.

[0139] “Prevent” as used herein means a method of delaying and/or preventing the onset, recurrence or dispersion, in whole or in part, of a disorder, disease or condition; prevent an individual from having a disorder, disease or condition; or reduce the individual's risk of acquiring a disorder, disease or condition. In one embodiment, the disorder is a condition that is treatable or preventable by inhibiting a JNK pathway, as described herein. In another embodiment, the disorder is selected from interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection, or lupus. In one embodiment, the disorder is a fibrotic liver disorder, or diabetes or metabolic syndrome leading to fibrotic liver disorders as described herein, or symptoms thereof. In another embodiment, the disorder is selected from interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection, or lupus. In yet another embodiment, the disorder is a fibrotic liver disorder, or diabetes and/or metabolic syndrome leading to fibrotic liver disorders, as described herein. In some embodiments, the disorder is a fibrotic liver disorder, such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosis cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, or coincident liver fibrosis. with chronic or repeated alcohol intake (alcoholic hepatitis), with infection (e.g., viral infection such as HCV), with liver transplantation, or with drug-induced liver damage (e.g., acetaminophen toxicity).

[0140] The term “effective amount” in connection with Compound 1 or Compound A means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.

[0141] “Patient” or “individual” is defined herein as including animals, such as mammals, including, without limitation, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats , mice, monkeys, chickens, turkeys, quails or guinea pigs and the like, in one embodiment, a mammal, in another embodiment, a human being. In one embodiment, an individual is a human having or at risk of having interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection, or lupus. In another, an individual is a human being having or at risk of having fibrotic liver disorders or diabetes or metabolic syndrome leading to fibrotic liver disorders, or a condition, treatable or preventable by inhibition of a JNK pathway, or a symptom of same. In one embodiment, an individual is fasting. In another embodiment, the individual is fed.

5.2. COMPOUND 1

[0142] The compositions and methods of use provided in this document refer to Compound 1: having the alternative names 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide or 2-[(1,1-dimethylethyl) amino]-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]-5-pyrimidinecarboxamide, or a stereoisomer, tautomer, solid form, polymorph, salt, hydrate, clathrate or solvate pharmaceutically acceptable thereof (collectively called Compound A).

[0143] Compound A and Compound 1 can be prepared using reagents and methods provided herein or known in the art, including the methods provided in US Patent Application Publication No. 2013/0029987, published January 31, 2013 , in US Provisional Patent Application No. 61/933,636, filed on January 30, 2014, in US Provisional Patent Application No. 62/025,161, filed on July 16, 2014, and in International Publication No. WO2012/145569 , the contents of which are incorporated into this document by reference.

[0144] Free base forms (Forms A, B, C, D, E, F, G, H and I) were previously described in US Provisional Patent Application No. 61/933,636, filed on January 30, 2014, in US Provisional Patent Application No. 62/025,161, filed on July 16, 2014.

[0145] It should be noted that if there is a discrepancy between a reported structure and a data for that given structure, the reported structure should be given more weight. Furthermore, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure should be interpreted as encompassing all stereoisomers thereof.

5.3. PHARMACEUTICAL COMPOSITIONS

[0146] Pharmaceutical compositions and dosage forms of Compound A are provided herein. In some embodiments, the dosage forms are suitable for oral administration to a patient. In other embodiments, the dosage forms provided herein exhibit advantageous physical and/or pharmacological properties. Such properties include, without limitation, ease of analysis, uniformity of content, flow properties for manufacturing, dissolution and bioavailability, and stability.

[0147] Kits comprising pharmaceutical compositions and dosage forms provided herein are provided herein. Also provided herein are methods of treating, managing and/or preventing a disease or condition, which comprise administering to a patient in need thereof a pharmaceutical composition or dosage form provided herein.

[0148] In certain embodiments, the unit dosage forms provided herein are oral dosage forms.

[0149] In certain embodiments, the pharmaceutical compositions and dosage forms provided herein are tablets.

5.4. FORMULATION A

[0150] In one embodiment, a pharmaceutical composition comprising Compound A, and one or more pharmaceutically acceptable excipients or carriers is provided herein. In one embodiment, the pharmaceutical composition is Formulation A comprising excipients or carriers described in Table 1.

[0151] In one embodiment, a pharmaceutical composition comprising Compound A and one or more pharmaceutically acceptable excipients and carriers selected from diluents, surfactants, disintegrants and lubricants is provided herein. In certain embodiments, the pharmaceutical compositions may be coated.

[0152] In certain embodiments, diluents include, without limitation, mannitol (e.g., Mannitol 200), cellulose (e.g., microcrystalline cellulose, such as AVICEL® PH 101 and AVICEL® PH 102). In one embodiment, the diluent is mannitol. In yet another embodiment, the diluent is Mannitol 200. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL® PH 101. In yet another embodiment, the diluent is AVICEL® PH 102.

[0153] In certain embodiments, the surfactants include, without limitation, hydroxypropylmethylcellulose (HPMC) (e.g., Methocel™ K3). In one embodiment, the surfactant is Methocel™ K3.

[0154] In certain embodiments, the disintegrants include, without limitation, carboxymethylcellulose (e.g., croscarmellose sodium, such as AC-DI-SOL®). In one embodiment, the disintegrant is carboxymethylcellulose. In another embodiment, the disintegrant is croscarmellose sodium. In yet another embodiment, the disintegrant is AC-DI-SOL®.

[0155] In one embodiment, the lubricant is magnesium stearate.

[0156] In certain embodiments, the coating includes, without limitation, Opadry (e.g., Opadry yellow, Opadry white, and Opadry brown). In one embodiment, the coating is Opadry. In another embodiment, the coating is yellow Opadry. In another embodiment, the coating is white Opadry. In another embodiment, the coating is brown Opadry.

[0157] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, cellulose, HPMC, carboxymethylcellulose and magnesium stearate, are provided herein. In certain embodiments, the pharmaceutical compositions are coated with Opadry.

[0158] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, microcrystalline cellulose, HPMC, croscarmellose sodium and magnesium stearate, are provided herein. In certain embodiments, the pharmaceutical compositions are coated with Opadry.

[0159] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from Mannitol 200, AVICEL® PH 101, AVICEL® PH 102, Methocel™ K3, are provided herein. AC-DI-SOL® and magnesium stearate. In certain embodiments, the pharmaceutical compositions are coated with white Opadry, yellow Opadry, or brown Opadry.

[0160] In one embodiment, provided herein is a pharmaceutical composition comprising Compound A, a diluent (or diluents)/binder (or binders), a disintegrant (or disintegrants), a surfactant (or surfactants) and a surfactant (or surfactants). In certain embodiments, the pharmaceutical compositions are coated.

[0161] In one embodiment, a pharmaceutical composition comprising Compound A, mannitol and magnesium stearate is provided herein.

[0162] In one embodiment, a pharmaceutical composition comprising Compound A, mannitol, cellulose and magnesium stearate is provided herein.

[0163] In certain embodiments, pharmaceutical compositions comprising Compound A, mannitol, microcrystalline cellulose, carboxymethylcellulose and magnesium stearate are provided herein.

[0164] In certain embodiments, pharmaceutical compositions comprising Compound A, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate are provided herein.

[0165] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 101, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0166] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 102, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0167] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 101, AVICEL®PH 102, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0168] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 50 to 70% by weight of diluent (or diluents)/binder (or binders), about 1 to 10% by weight of disintegrant (or disintegrants), about 1 to 10% by weight of surfactant (or surfactants) and about 0.1 to 2% by weight of lubricant (or lubricants).

[0169] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 63.43% by weight of diluent (or diluents)/binder (or binders), about 4% by weight of disintegrant (or disintegrants), about 3% by weight of surfactant (or surfactants) and about 1% by weight of lubricant (or lubricants).

[0170] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 30 to 50% by weight of cellulose, about 20 to 40% by weight of mannitol, about from 1 to 10% by weight of carboxymethylcellulose, about 1 to 10% by weight of hydroxypropylmethylcellulose (HPMC) and about 0.1 to 2% by weight of magnesium stearate.

[0171] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 37.43% by weight cellulose, about 26% by weight mannitol, about 4 % by weight of carboxymethylcellulose, about 3% by weight of HPMC and about 1% by weight of magnesium stearate.

[0172] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 30-50% by weight of microcrystalline cellulose, about 20 to 40% by weight of mannitol, about 1 to 10% by weight carboxymethylcellulose, about 1 to 10% by weight HPMC and about 0.1 to 2% by weight magnesium stearate.

[0173] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 37.43% by weight microcrystalline cellulose, about 26% by weight mannitol, about 4% by weight of carboxymethyl cellulose, about 3% by weight of HPMC and about 1% by weight of magnesium stearate.

[0174] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 30-50% by weight of AVICEL® PH 101 or AVICEL® PH 102, about 20 to 40% by weight of Mannitol 200, about 1 to 10% by weight of AC-DI-SOL®, about 1 to 10% by weight of Methocel™ K3 and about 0.1 to 2% by weight of magnesium.

[0175] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 37.43% by weight of AVICEL® PH 101 or AVICEL® PH 102, about 26% by weight of Mannitol 200, about 4% by weight of AC-DI-SOL®, about 3% by weight of Methocel™ K3 and about 1% by weight of magnesium stearate.

[0176] In one embodiment, the pharmaceutical composition additionally comprises a coating adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating adding about 3% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 3% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 3% by weight.

[0177] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 100 to 400 mg of diluent (or diluents)/binder (or binders), about 7 to 30 mg of disintegrant (or disintegrants), around 5 to 20 mg of surfactant (or surfactants) and around 0.1 to 10 mg of lubricant (or lubricants).

[0178] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 222 mg of diluent (or diluents)/binder (or binders), about 14 mg of disintegrant (or disintegrants) , around 10.5 mg of surfactant (or surfactants) and around 3.5 mg of lubricant (or lubricants).

[0179] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 60 to 260 mg of cellulose, about 40 to 180 mg of mannitol, about 7-30 mg of carboxymethylcellulose, about 5 to 20 mg of hydroxypropylmethylcellulose (HPMC) and about 0.1 to 10 mg of magnesium stearate.

[0180] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 131.01 mg of cellulose, about 91 mg of mannitol, about 14 mg of carboxymethylcellulose, about 10. 5 mg of HPMC and about 3.5 mg of magnesium stearate.

[0181] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 60 to 260 mg of microcrystalline cellulose, about 40 to 180 mg of mannitol, about 7 to 30 mg of carboxymethylcellulose, about 5 to 20 mg of HPMC and about 0.1 to 10 mg of magnesium stearate.

[0182] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 131.01 mg of microcrystalline cellulose, about 91 mg of mannitol, about 14 mg of carboxymethylcellulose, about 10 .5 mg of HPMC and about 3.5 mg of magnesium stearate.

[0183] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 60 to 260 mg of AVICEL® PH 101 or AVICEL® PH 102, about 40 to 180 mg of Mannitol 200, around 7 to 30 mg of AC-DI-SOL®, around 5 to 20 mg of Methocel™ K3 and around 0.1 to 10 mg of magnesium stearate.

[0184] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 131.01 mg of AVICEL® PH 101 or AVICEL® PH 102, about 91 mg of Mannitol 200, about 14 mg of AC-DI-SOL®, around 10.5 mg of Methocel™ K3 and around 3.5 mg of magnesium stearate.

[0185] In one embodiment, the pharmaceutical composition additionally comprises a coating adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating adding about 10.5 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 5-20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 10.5 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 10.5 mg by weight.

[0186] In certain embodiments, single unit dosage forms of Formulation A are provided herein. In particular embodiments, the single unit dosage forms are 30 mg, 100 mg, or 200 mg tablets.

[0187] In such an embodiment, Compound A is Compound 1. In another embodiment, Compound A is a pharmaceutically acceptable salt of Compound 1. In yet another embodiment, Compound A is a solid form of Compound 1.

5.5. FORMULATION B

[0188] In one embodiment, a pharmaceutical composition comprising Compound A, and one or more pharmaceutically acceptable excipients or carriers is provided herein. In one embodiment, the pharmaceutical composition is Formulation B comprising excipients or carriers described in Table 4.

[0189] In one embodiment, a pharmaceutical composition comprising Compound A and one or more pharmaceutically acceptable excipients and carriers selected from diluents, surfactants, disintegrants and lubricants is provided herein. In certain embodiments, the pharmaceutical compositions may be coated.

[0190] In certain embodiments, diluents include, without limitation, mannitol (e.g., Mannitol 200), cellulose (e.g., microcrystalline cellulose, such as AVICEL® PH 101 and AVICEL® PH 102). In one embodiment, the diluent is mannitol. In yet another embodiment, the diluent is Mannitol 200. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL® PH 101. In yet another embodiment, the diluent is AVICEL® PH 102.

[0191] In certain embodiments, the surfactants include, without limitation, hydroxypropylmethylcellulose (HPMC) (e.g., Methocel™ K3). In one embodiment, the surfactant is Methocel™ K3.

[0192] In certain embodiments, the disintegrants include, without limitation, carboxymethylcellulose (e.g., croscarmellose sodium, such as AC-DI-SOL®). In one embodiment, the disintegrant is carboxymethylcellulose. In another embodiment, the disintegrant is croscarmellose sodium. In yet another embodiment, the disintegrant is AC-DI-SOL®.

[0193] In one embodiment, the lubricant is magnesium stearate.

[0194] In certain embodiments, the coating includes, without limitation, Opadry (e.g., Opadry yellow, Opadry white, and Opadry brown). In one embodiment, the coating is Opadry. In another embodiment, the coating is yellow Opadry. In another embodiment, the coating is white Opadry. In another embodiment, the coating is brown Opadry.

[0195] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, cellulose, HPMC, carboxymethylcellulose and magnesium stearate, are provided herein. In certain embodiments, the pharmaceutical compositions are coated with Opadry.

[0196] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, microcrystalline cellulose, HPMC, croscarmellose sodium and magnesium stearate, are provided herein. In certain embodiments, the pharmaceutical compositions are coated with Opadry.

[0197] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from Mannitol 200, AVICEL® PH 101, AVICEL® PH 102, Methocel™ K3, are provided herein. AC-DI-SOL® and magnesium stearate. In certain embodiments, the pharmaceutical compositions are coated with white Opadry, yellow Opadry, or brown Opadry.

[0198] In one embodiment, provided herein is a pharmaceutical composition comprising Compound A, a diluent (or diluents)/binder (or binders), a disintegrant (or disintegrants), a surfactant (or surfactants) and a surfactant (or surfactants). In certain embodiments, the pharmaceutical compositions may be coated.

[0199] In one embodiment, a pharmaceutical composition comprising Compound A, mannitol and magnesium stearate is provided herein.

[0200] In one embodiment, a pharmaceutical composition comprising Compound A, mannitol, cellulose and magnesium stearate is provided herein.

[0201] In certain embodiments, pharmaceutical compositions comprising Compound A, mannitol, microcrystalline cellulose, carboxymethylcellulose and magnesium stearate are provided herein.

[0202] In certain embodiments, pharmaceutical compositions comprising Compound A, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate are provided herein.

[0203] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 101, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0204] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 102, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0205] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 101, AVICEL®PH 102, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0206] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 50 to 70% by weight of diluent (or diluents)/binder (or binders), about 1 to 20% by weight of disintegrant (or disintegrants), about 1 to 10% by weight of surfactant (or surfactants) and about 0.1 to 2% by weight of lubricant (or lubricants).

[0207] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 59.43% by weight of diluent (or diluents)/binder (or binders), about 8% by weight of disintegrant (or disintegrants), about 3% by weight of surfactant (or surfactants) and about 1% by weight of lubricant (or lubricants).

[0208] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 20 to 40% by weight of cellulose, about 20 to 40% by weight of mannitol, about from 1 to 20% by weight of carboxymethylcellulose, about 1 to 10% by weight of hydroxypropylmethylcellulose (HPMC) and about 0.1 to 2% by weight of magnesium stearate.

[0209] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 33.43% by weight cellulose, about 26% by weight mannitol, about 8 % by weight of carboxymethylcellulose, about 3% by weight of HPMC and about 1% by weight of magnesium stearate.

[0210] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 20 to 40% by weight of microcrystalline cellulose, about 20 to 40% by weight of mannitol, about 1 to 20% by weight carboxymethylcellulose, about 1 to 10% by weight HPMC and about 0.1 to 2% by weight magnesium stearate.

[0211] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 33.43% by weight microcrystalline cellulose, about 26% by weight mannitol, about 8% by weight carboxymethyl cellulose, about 3% by weight HPMC and about 1% by weight magnesium stearate.

[0212] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 20 to 40% by weight of AVICEL® PH 101 or AVICEL® PH 102, about 20 to 40% by weight of Mannitol 200, about 1 to 20% by weight of AC-DI-SOL®, about 1 to 10% by weight of Methocel™ K3 and about 0.1 to 2% by weight of magnesium.

[0213] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 33.43% by weight of AVICEL® PH 101 or AVICEL® PH 102, about 26% by weight of Mannitol 200, about 8% by weight of AC-DI-SOL®, about 3% by weight of Methocel™ K3 and about 1% by weight of magnesium stearate.

[0214] In one embodiment, the pharmaceutical composition additionally comprises a coating adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating adding about 3% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 3% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 3% by weight.

[0215] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 100 to 400 mg of diluent (or diluents)/binder (or binders), about 10-60 mg of disintegrant (or disintegrants), around 5 to 20 mg of surfactant (or surfactants) and around 0.1 to 10 mg of lubricant (or lubricants).

[0216] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 208.1 mg of diluent (or diluents)/binder (or binders), about 28 mg of disintegrant (or disintegrants), about 10.5 mg of surfactant (or surfactants) and about 3.5 mg of lubricant (or lubricants).

[0217] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 60 to 240 mg of cellulose, about 40 to 180 mg of mannitol, about 10 to 60 mg of carboxymethylcellulose, about 5 to 20 mg of hydroxypropylmethylcellulose (HPMC) and about 0.1 to 10 mg of magnesium stearate.

[0218] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 117.1 mg of cellulose, about 91 mg of mannitol, about 28 mg of carboxymethylcellulose, about 10. 5 mg of HPMC and about 3.5 mg of magnesium stearate.

[0219] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 60 to 240 mg of microcrystalline cellulose, about 40 to 180 mg of mannitol, about 10 to 60 mg of carboxymethylcellulose, about 5 to 20 mg of HPMC and about 0.1 to 10 mg of magnesium stearate.

[0220] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 117.1 mg of microcrystalline cellulose, about 91 mg of mannitol, about 28 mg of carboxymethylcellulose, about 10 .5 mg of HPMC and about 3.5 mg of magnesium stearate.

[0221] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 60 to 240 mg of AVICEL® PH 101 or AVICEL® PH 102, about 40 to 180 mg of Mannitol 200, around 10 to 60 mg of AC-DI-SOL®, around 5 to 20 mg of Methocel™ K3 and around 0.1 to 10 mg of magnesium stearate.

[0222] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 117.1 mg of AVICEL® PH 101 or AVICEL® PH 102, about 91 mg of Mannitol 200, about 28 mg of AC-DI-SOL®, around 10.5 mg of Methocel™ K3 and around 3.5 mg of magnesium stearate.

[0223] In one embodiment, the pharmaceutical composition additionally comprises a coating adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating adding about 10.5 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 5-20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 10.5 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 10.5 mg by weight.

[0224] In certain embodiments, single unit dosage forms of Formulation B are provided herein. In particular embodiments, the single unit dosage forms are 30 mg, 100 mg, or 200 mg tablets.

[0225] In such an embodiment, Compound A is Compound 1. In another embodiment, Compound A is a pharmaceutically acceptable salt of Compound 1. In yet another embodiment, Compound A is a solid form of Compound 1.

5.6. FORMULATION C

[0226] In one embodiment, a pharmaceutical composition comprising Compound A, and one or more pharmaceutically acceptable excipients or carriers is provided herein. In one embodiment, the pharmaceutical composition is Formulation C comprising excipients or carriers described in Table 5.

[0227] In one embodiment, a pharmaceutical composition comprising Compound A and one or more pharmaceutically acceptable excipients and carriers selected from diluents, surfactants, disintegrants and lubricants is provided herein. In certain embodiments, the pharmaceutical compositions may be coated.

[0228] In certain embodiments, diluents include, without limitation, mannitol (e.g., Mannitol 200), cellulose (e.g., microcrystalline cellulose, such as AVICEL® PH 101 and AVICEL® PH 102). In one embodiment, the diluent is mannitol. In yet another embodiment, the diluent is Mannitol 200. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL® PH 101. In yet another embodiment, the diluent is AVICEL® PH 102.

[0229] In certain embodiments, the surfactants include, without limitation, hydroxypropylmethylcellulose (HPMC) (e.g., Methocel™ K3). In one embodiment, the surfactant is Methocel™ K3.

[0230] In certain embodiments, the disintegrants include, without limitation, carboxymethylcellulose (e.g., croscarmellose sodium, such as AC-DI-SOL®). In one embodiment, the disintegrant is carboxymethylcellulose. In another embodiment, the disintegrant is croscarmellose sodium. In yet another embodiment, the disintegrant is AC-DI-SOL®.

[0231] In one embodiment, the lubricant is magnesium stearate.

[0232] In certain embodiments, the coating includes, without limitation, Opadry (e.g., Opadry yellow, Opadry white, and Opadry brown). In one embodiment, the coating is Opadry. In another embodiment, the coating is yellow Opadry. In another embodiment, the coating is white Opadry. In another embodiment, the coating is brown Opadry.

[0233] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, cellulose, HPMC, carboxymethylcellulose and magnesium stearate, are provided herein. In certain embodiments, the pharmaceutical compositions are coated with Opadry.

[0234] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, microcrystalline cellulose, HPMC, croscarmellose sodium and magnesium stearate, are provided herein. In certain embodiments, the pharmaceutical compositions are coated with Opadry.

[0235] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from Mannitol 200, AVICEL® PH 101, AVICEL® PH 102, Methocel™ K3, are provided herein. AC-DI-SOL® and magnesium stearate. In certain embodiments, the pharmaceutical compositions are coated with white Opadry, yellow Opadry, or brown Opadry.

[0236] In one embodiment, provided herein is a pharmaceutical composition comprising Compound A, a diluent (or diluents)/binder (or binders), a disintegrant (or disintegrants), a surfactant (or surfactants) and a surfactant (or surfactants). In certain embodiments, the pharmaceutical compositions may be coated.

[0237] In one embodiment, a pharmaceutical composition comprising Compound A, mannitol and magnesium stearate is provided herein.

[0238] In one embodiment, a pharmaceutical composition comprising Compound A, mannitol, cellulose and magnesium stearate is provided herein.

[0239] In certain embodiments, pharmaceutical compositions comprising Compound A, mannitol, microcrystalline cellulose, carboxymethylcellulose and magnesium stearate are provided herein.

[0240] In certain embodiments, pharmaceutical compositions comprising Compound A, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate are provided herein.

[0241] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 101, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0242] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 102, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0243] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 101, AVICEL®PH 102, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0244] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 50 to 70% by weight of diluent (or diluents)/binder (or binders), about 1 to 20% by weight of disintegrant (or disintegrants), about 1 to 10% by weight of surfactant (or surfactants) and about 0.1 to 2% by weight of lubricant (or lubricants).

[0245] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 57.93% by weight of diluent (or diluents)/binder (or binders), about 8% by weight of disintegrant (or disintegrants), about 4.5% by weight of surfactant (or surfactants) and about 1% by weight of lubricant (or lubricants).

[0246] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 20 to 40% by weight of cellulose, about 20 to 40% by weight of mannitol, about from 1 to 20% by weight of carboxymethylcellulose, about 1 to 10% by weight of hydroxypropylmethylcellulose (HPMC) and about 0.1 to 2% by weight of magnesium stearate.

[0247] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57 wt% Compound A, about 31.93 wt% cellulose, about 26 wt% mannitol, about 8 % by weight of carboxymethylcellulose, about 4.5% by weight of HPMC and about 1% by weight of magnesium stearate.

[0248] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 20 to 40% by weight of microcrystalline cellulose, about 20 to 40% by weight of mannitol, about 1 to 20% by weight carboxymethylcellulose, about 1 to 10% by weight HPMC and about 0.1 to 2% by weight magnesium stearate.

[0249] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 31.93% by weight microcrystalline cellulose, about 26% by weight mannitol, about 8% by weight carboxymethylcellulose, about 4.5% by weight HPMC and about 1% by weight magnesium stearate.

[0250] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 20 to 40% by weight of AVICEL® PH 101 or AVICEL® PH 102, about 20 to 40% by weight of Mannitol 200, about 1 to 20% by weight of AC-DI-SOL®, about 1 to 10% by weight of Methocel™ K3 and about 0.1 to 2% by weight of magnesium.

[0251] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 31.93% by weight of AVICEL® PH 101 or AVICEL® PH 102, about 26% by weight of Mannitol 200, about 8% by weight of AC-DI-SOL®, about 4.5% by weight of Methocel™ K3 and about 1% by weight of magnesium stearate.

[0252] In one embodiment, the pharmaceutical composition additionally comprises a coating adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating adding about 3% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 3% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 3% by weight.

[0253] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 100 to 400 mg of diluent (or diluents)/binder (or binders), about 10 to 60 mg of disintegrant (or disintegrants), around 5 to 30 mg of surfactant (or surfactants) and around 0.1 to 10 mg of lubricant (or lubricants).

[0254] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 202.76 mg of diluent (or diluents)/binder (or binders), about 28 mg of disintegrant (or disintegrants), around 15.75 mg of surfactant (or surfactants) and around 3.5 mg of lubricant (or lubricants).

[0255] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 50 to 220 mg of cellulose, about 40 to 180 mg of mannitol, about 10 to 60 mg of carboxymethylcellulose, about 5 to 30 mg of hydroxypropylmethylcellulose (HPMC) and about 0.1 to 10 mg of magnesium stearate.

[0256] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 111.76 mg of cellulose, about 91 mg of mannitol, about 28 mg of carboxymethyl cellulose, about 15. 75 mg of HPMC and about 3.5 mg of magnesium stearate.

[0257] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 50 to 220 mg of microcrystalline cellulose, about 40 to 180 mg of mannitol, about 10 to 60 mg of carboxymethyl cellulose, about 5 to 30 mg of HPMC and about 0.1 to 10 mg of magnesium stearate.

[0258] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 111.76 mg of microcrystalline cellulose, about 91 mg of mannitol, about 28 mg of carboxymethylcellulose, about 15 .75 mg of HPMC and about 3.5 mg of magnesium stearate.

[0259] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 50 to 220 mg of AVICEL® PH 101 or AVICEL® PH 102, about 40 to 180 mg of Mannitol 200, around 10 to 60 mg of AC-DI-SOL®, around 5 to 30 mg of Methocel™ K3 and around 0.1 to 10 mg of magnesium stearate.

[0260] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 111.76 mg of AVICEL® PH 101 or AVICEL® PH 102, about 91 mg of Mannitol 200, about 28 mg of AC-DI-SOL®, around 15.75 mg of Methocel™ K3 and around 3.5 mg of magnesium stearate.

[0261] In one embodiment, the pharmaceutical composition additionally comprises a coating adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating adding about 10.5 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 10.5 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 10.5 mg by weight.

[0262] In certain embodiments, single unit dosage forms of Formulation C are provided herein. In particular embodiments, the single unit dosage forms are 30 mg, 100 mg, or 200 mg tablets.

[0263] In such an embodiment, Compound A is Compound 1. In another embodiment, Compound A is a pharmaceutically acceptable salt of Compound 1. In yet another embodiment, Compound A is a solid form of Compound 1.

5.7. FORMULATION D

[0264] In one embodiment, a pharmaceutical composition comprising Compound A, and one or more pharmaceutically acceptable excipients or carriers is provided herein. In one embodiment, the pharmaceutical composition is Formulation C comprising excipients or carriers described in Table 6.

[0265] In one embodiment, a pharmaceutical composition comprising Compound A and one or more pharmaceutically acceptable excipients and carriers selected from diluents, surfactants, disintegrants and lubricants is provided herein. In certain embodiments, the pharmaceutical compositions may be coated.

[0266] In certain embodiments, diluents include, without limitation, mannitol (e.g., Mannitol 200), cellulose (e.g., microcrystalline cellulose, such as AVICEL® PH 101 and AVICEL® PH 102). In one embodiment, the diluent is mannitol. In yet another embodiment, the diluent is Mannitol 200. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL® PH 101. In yet another embodiment, the diluent is AVICEL® PH 102.

[0267] In certain embodiments, the surfactants include, without limitation, hydroxypropylmethylcellulose (HPMC) (e.g., Methocel™ K3). In one embodiment, the surfactant is Methocel™ K3.

[0268] In certain embodiments, the disintegrants include, without limitation, carboxymethylcellulose (e.g., croscarmellose sodium, such as AC-DI-SOL®). In one embodiment, the disintegrant is carboxymethylcellulose. In another embodiment, the disintegrant is croscarmellose sodium. In yet another embodiment, the disintegrant is AC-DI-SOL®.

[0269] In one embodiment, the lubricant is magnesium stearate.

[0270] In certain embodiments, the coating includes, without limitation, Opadry (e.g., Opadry yellow, Opadry white, and Opadry brown). In one embodiment, the coating is Opadry. In another embodiment, the coating is yellow Opadry. In another embodiment, the coating is white Opadry. In another embodiment, the coating is brown Opadry.

[0271] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, cellulose, HPMC, carboxymethylcellulose and magnesium stearate, are provided herein. In certain embodiments, the pharmaceutical compositions are coated with Opadry.

[0272] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from mannitol, microcrystalline cellulose, HPMC, croscarmellose sodium and magnesium stearate, are provided herein. In certain embodiments, the pharmaceutical compositions are coated with Opadry.

[0273] In certain embodiments, pharmaceutical compositions comprising Compound A and one or more pharmaceutically acceptable excipients or carriers, each independently selected from Mannitol 200, AVICEL® PH 101, AVICEL® PH 102, Methocel™ K3, are provided herein. AC-DI-SOL® and magnesium stearate. In certain embodiments, the pharmaceutical compositions are coated with white Opadry, yellow Opadry, or brown Opadry.

[0274] In one embodiment, provided herein is a pharmaceutical composition comprising Compound A, a diluent (or diluents)/binder (or binders), a disintegrant (or disintegrants), a surfactant (or surfactants) and a surfactant (or surfactants). In certain embodiments, the pharmaceutical compositions may be coated.

[0275] In one embodiment, a pharmaceutical composition comprising Compound A, mannitol and magnesium stearate is provided herein.

[0276] In one embodiment, a pharmaceutical composition comprising Compound A, mannitol, cellulose and magnesium stearate is provided herein.

[0277] In certain embodiments, pharmaceutical compositions comprising Compound A, mannitol, microcrystalline cellulose, carboxymethylcellulose and magnesium stearate are provided herein.

[0278] In certain embodiments, pharmaceutical compositions comprising Compound A, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate are provided herein.

[0279] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 101, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0280] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 102, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0281] In certain embodiments, pharmaceutical compositions comprising Compound A, Mannitol 200, AVICEL®PH 101, AVICEL®PH 102, AC-DI-SOL®, Methocel™ K3 and magnesium stearate are provided herein.

[0282] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 50 to 70% by weight of diluent (or diluents)/binder (or binders), about 1 to 10% by weight of disintegrant (or disintegrants), about 1 to 10% by weight of surfactant (or surfactants) and about 0.1 to 2% by weight of lubricant (or lubricants).

[0283] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 61.93% by weight of diluent (or diluents)/binder (or binders), about 4% by weight of disintegrant (or disintegrants), about 4.5% by weight of surfactant (or surfactants) and about 1% by weight of lubricant (or lubricants).

[0284] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 20 to 50% by weight of cellulose, about 20 to 40% by weight of mannitol, about from 1 to 10% by weight of carboxymethylcellulose, about 1 to 10% by weight of hydroxypropylmethylcellulose (HPMC) and about 0.1 to 2% by weight of magnesium stearate.

[0285] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 35.93% by weight cellulose, about 26% by weight mannitol, about 4 % by weight of carboxymethylcellulose, about 4.5% by weight of HPMC and about 1% by weight of magnesium stearate.

[0286] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 20 to 50% by weight of microcrystalline cellulose, about 20 to 40% by weight of mannitol, about 1 to 10% by weight carboxymethylcellulose, about 1 to 10% by weight HPMC and about 0.1 to 2% by weight magnesium stearate.

[0287] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 35.93% by weight microcrystalline cellulose, about 26% by weight mannitol, about 4% by weight carboxymethylcellulose, about 4.5% by weight HPMC and about 1% by weight magnesium stearate.

[0288] In one embodiment, there is provided herein a pharmaceutical composition comprising about 20 to 40% by weight of Compound A, about 20 to 50% by weight of AVICEL® PH 101 or AVICEL® PH 102, about 20 to 40% by weight of Mannitol 200, about 1 to 10% by weight of AC-DI-SOL®, about 1 to 10% by weight of Methocel™ K3 and about 0.1 to 2% by weight of magnesium.

[0289] In one embodiment, there is provided herein a pharmaceutical composition comprising about 28.57% by weight of Compound A, about 35.93% by weight of AVICEL® PH 101 or AVICEL® PH 102, about 26% by weight of Mannitol 200, about 4% by weight of AC-DI-SOL®, about 4.5% by weight of Methocel™ K3 and about 1% by weight of magnesium stearate.

[0290] In one embodiment, the pharmaceutical composition additionally comprises a coating adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating adding about 3% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 3% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 1 to 10% by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 3% by weight.

[0291] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 100 to 400 mg of diluent (or diluents)/binder (or binders), about 7 to 30 mg of disintegrant (or disintegrants), around 5 to 30 mg of surfactant (or surfactants) and around 0.1 to 10 mg of lubricant (or lubricants).

[0292] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 216.76 mg of diluent (or diluents)/binder (or binders), about 14 mg of disintegrant (or disintegrants), around 15.75 mg of surfactant (or surfactants) and around 3.5 mg of lubricant (or lubricants).

[0293] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 60 to 240 mg of cellulose, about 40 to 180 mg of mannitol, about 7 to 30 mg of carboxymethylcellulose, about 5 to 30 mg of hydroxypropylmethylcellulose (HPMC) and about 0.1 to 10 mg of magnesium stearate.

[0294] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 125.76 mg of cellulose, about 91 mg of mannitol, about 14 mg of carboxymethylcellulose, about 15. 75 mg of HPMC and about 3.5 mg of magnesium stearate.

[0295] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 60 to 240 mg of microcrystalline cellulose, about 40 to 180 mg of mannitol, about 7 to 30 mg of carboxymethyl cellulose, about 5 to 30 mg of HPMC and about 0.1 to 10 mg of magnesium stearate.

[0296] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 125.76 mg of microcrystalline cellulose, about 91 mg of mannitol, about 14 mg of carboxymethyl cellulose, about 15 .75 mg of HPMC and about 3.5 mg of magnesium stearate.

[0297] In one embodiment, there is provided herein a pharmaceutical composition comprising about 50 to 200 mg of Compound A, about 60 to 240 mg of AVICEL® PH 101 or AVICEL® PH 102, about 40 to 180 mg of Mannitol 200, around 7 to 30 mg of AC-DI-SOL®, around 5 to 30 mg of Methocel™ K3 and around 0.1 to 10 mg of magnesium stearate.

[0298] In one embodiment, there is provided herein a pharmaceutical composition comprising about 100 mg of Compound A, about 125.76 mg of AVICEL® PH 101 or AVICEL® PH 102, about 91 mg of Mannitol 200, about 14 mg of AC-DI-SOL®, around 15.75 mg of Methocel™ K3 and around 3.5 mg of magnesium stearate.

[0299] In one embodiment, the pharmaceutical composition additionally comprises a coating adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating adding about 10.5 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising Opadry and adding about 10.5 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 5 to 20 mg by weight. In one embodiment, the pharmaceutical composition further comprises a coating comprising yellow Opadry, white Opadry or brown Opadry and adding about 10.5 mg by weight.

[0300] In certain embodiments, single unit dosage forms of Formulation D are provided herein. In particular embodiments, the single unit dosage forms are 30 mg, 100 mg, or 200 mg tablets.

[0301] In such an embodiment, Compound A is Compound 1. In another embodiment, Compound A is a pharmaceutically acceptable salt of Compound 1. In yet another embodiment, Compound A is a solid form of Compound 1.

5.8. METHODS OF USE

[0302] Pharmaceutical compositions and dosage forms of Compound A have utility as pharmaceuticals for treating, preventing or ameliorating conditions in animals or humans. Compound A is active against protein kinases, particularly JNK1 and/or JNK2. Accordingly, many uses of pharmaceutical compositions, dosage forms and salts of Compound A are provided herein, including the treatment or prevention of those diseases set forth below. The methods provided herein comprise administering a pharmaceutical composition, and dosage form of Compound A, to an individual in need thereof. In one aspect, provided herein are methods of inhibiting a kinase in a cell expressing said kinase, comprising contacting said cell with an effective amount of a pharmaceutical composition, and dosage form of Compound A. In one embodiment, the kinase is JNK1, JNK2, or a mutant or isoform thereof, or a combination thereof.

[0303] In another aspect, provided herein are methods for treating or preventing one or more disorders selected from interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection or lupus, comprising administering to an individual in need therefor an effective amount of a pharmaceutical composition, or dosage form of Compound A. In some of these embodiments, the lupus is lupus erymatosus (such as discoid lupus erymatosus or cutaneous lupus erymatosus) or systemic lupus. In some embodiments, the disorder is pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is a documented usual interstitial pneumonia pattern (UIP) or a non-specific interstitial pneumonia pattern (NSIP), e.g., based on computed tomography or a documented fibrotic NSIP or documented UIP pattern, e.g. example, based on surgical lung biopsy. In some embodiments, the underlying disease of pulmonary fibrosis is interstitial lung disease associated with connective tissue disease, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), environmental or chemical-related pulmonary fibrosis, or Hermansky-Pudlak syndrome.

[0304] In another aspect, provided herein are methods for treating or preventing fibrotic disorders of the liver, such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosis cholangitis, primary biliary cirrhosis, hepatitis , hepatocellular carcinoma, and liver fibrosis coincident with chronic or repeated alcohol intake (alcoholic hepatitis), with infection (e.g., viral infection such as HCV), with liver transplantation, or with drug-induced liver injury (e.g., acetaminophen toxicity), comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition, or dosage form of Compound A. In some of these aspects, provided herein are methods for treating or preventing diabetes or metabolic syndrome leading to to fibrotic disorders of the liver, such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosis cholangitis, primary biliary cirrhosis and hepatitis, comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition , or dosage form of Compound A.

[0305] In another aspect, provided herein are methods for treating or preventing conditions treatable or preventable by inhibition of JNK1 and/or JNK2, the method comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition, or form of Compound A. Examples of such conditions include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritated liver syndrome, mucous colitis, ulcerative colitis, Crohn's disease, Huntington's disease, hepatitis, pancreatitis, nephritis, multiple sclerosis, lupus erymatosus, Type II diabetes, obesity, atherosclerosis, restenosis after angioplasty, left ventricular hypertrophy, myocardial infarction, stroke, ischemic lesions of the heart, lung, intestine , kidneys, liver, pancreas, spleen, and brain, acute or chronic organ transplant rejection, organ preservation for transplantation, organ failure, or limb loss (e.g., including, without limitation, that results from ischemia- reperfusion, trauma, serious bodily injury, car accident, crash injury or transplant failure), graft versus host disease, endotoxin shock, multiple organ failure, psoriasis, burns from exposure to fire, chemicals or radiation, eczema, dermatitis, skin graft, ischemia, ischemic conditions associated with surgical or traumatic injuries (e.g., vehicular accident, gunshot wound or crushed limb), epilepsy, Alzheimer's disease, Parkinson's disease, immune response to infections bacterial or viral, cachexia, angiogenic and proliferative diseases, solid tumor, and cancers of a variety of tissues such as colon, rectum, prostate, liver, lung, bronchi, pancreas, brain, head, neck, stomach, skin, kidneys, cervix uterus, blood, larynx, esophagus, mouth, pharynx, urinary bladder, ovary or uterus.

[0306] In one embodiment, provided herein are methods for modulating the levels of a disease marker in an individual who has a JNK1 and/or JNK2-mediated disorder, comprising administering an effective amount of Compound A or a pharmaceutical composition provided in the this document, for said individual. In some embodiments, the JNK1 and/or JNK2-mediated disorder is pulmonary fibrosis. In some of these embodiments, modulation of the disease marker is assessed in a biological sample from the individual, such as in circulating blood, skin biopsy, colon biopsies, synovial tissue and/or urine. In such embodiments, the amount of disease marker modulation is assessed by comparing the amount of disease marker before and after administration of Compound A. In some embodiments, the modulation in the disease biomarker is a reduction of about 5%, 10 %, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, or about 100% compared to line levels base. In some embodiments, the disease marker is mRNA or protein levels of one or more of matrix metalloproteinase-7, Tenascin C, or surfactant Protein-D.

[0307] In such an embodiment, Compound A is Compound 1. In another embodiment, Compound A is a pharmaceutically acceptable salt of Compound 1. In yet another embodiment, Compound A is a solid form of Compound 1.

5.9. ROUTES OF ADMINISTRATION and DOSAGE

[0308] Pharmaceutical compositions and dosage forms of Compound A can be administered to an individual orally, topically or parenterally in the conventional form of preparations, such as tablets, granules, powder, lozenges, pills, suppositories, injections, suspensions, syrups, plasters , creams, lotions, ointments, gels, sprays, solutions and emulsions. The effective amount of Compound A in the pharmaceutical composition may be at a level that will exert the desired effect; for example, about 0.005 mg/kg of an individual's body weight to about 10 mg/kg of an individual's body weight in unit dosage for oral and parenteral administration.

[0309] The dose of Compound A to be administered to an individual is quite variable and can be subject to the judgment of a healthcare professional. In general, Compound A may be administered one to four times per day at a dose of about 0.005 mg/kg of an individual's body weight to about 10 mg/kg of an individual's body weight in an individual, but the above dosage may be appropriately varied depending on the age, body weight and medical condition of the individual and the type of administration. In one embodiment, the dose is from about 0.01 mg/kg of an individual's body weight to about 5 mg/kg of an individual's body weight, to about 0.05 mg/kg of an individual's body weight to about 1 mg/kg of an individual's body weight, about 0.1 mg/kg of an individual's body weight to about 0.75 mg/kg of an individual's body weight or about 0.25 mg/ kg of an individual's body weight to about 0.5 mg/kg of an individual's body weight. In one embodiment, one dose per day is given. In any case, the amount of Compound A administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration. In one embodiment, application of a topical concentration provides intracellular exposures or concentrations of about 0.01 to 10 μM.

[0310] In another embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering a pharmaceutical composition, or dosage form comprising about 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day to about 75 mg/day, about 7.5 mg/day to about 55 mg/day, or about 18 mg/day to about 37 mg/day of Compound A to an individual in need thereof.

[0311] In another embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering a pharmaceutical composition, or dosage form comprising about 1 mg/day to about 1,200 mg/day, about 10 mg/day to about 1,200 mg/day, about 100 mg/day to about 1,200 mg/day, about 400 mg/day to about 1,200 mg/day, about 600 mg/day to about from 1,200 mg/day, about 400 mg/day to about 800 mg/day, about 60 mg/day to about 720 mg/day, about 240 mg/day to about 720 mg/day or about 600 mg/day to about 800 mg/day of Compound A to an individual in need thereof. In a particular embodiment, the methods disclosed herein comprise administering a pharmaceutical composition, or dosage form, comprising about 400 mg/day, about 600 mg/day, or about 800 mg/day of Compound A to an individual. in need of it.

[0312] In another embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering a pharmaceutical composition, or dosage form comprising about 10 mg/day to about 720 mg/day, about 10 mg/day to about 480 mg/day, about 60 mg/day to about 720 mg/day, or about 240 mg/day to about 720 mg/day of Compound A to an individual in need thereof .

[0313] In one embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering a pharmaceutical composition, or dosage form comprising about 10 mg/day, about 30 mg/day, about of 60 mg/day, about 100 mg/day, about 120 mg/day, about 240 mg/day, about 480 mg/day, or about 720 mg/day of Compound A to an individual in need thereof . In one embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering a pharmaceutical composition, or dosage form comprising about 60 mg/day, about 160 mg/day, or about 400 mg/day of Compound A to an individual in need thereof. In one embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering a pharmaceutical composition, or dosage form comprising about 100 mg/day, or about 200 mg/day of Compound A to an individual in need of it. In another embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering a pharmaceutical composition, or dosage form comprising about 100 mg/day of Compound A to an individual in need thereof. In another embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering a pharmaceutical composition, or dosage form comprising about 200 mg/day of Compound A to an individual in need thereof. In one embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering a pharmaceutical composition, or dosage form comprising about 10 mg/day, about 30 mg/day, about 60 mg /day, about 120 mg/day, about 160 mg/day, about 200 mg/day, about 240 mg/day, about 400 mg/day, about 480 mg/day, or about 720 mg /day of Compound A to an individual in need of it.

[0314] In another embodiment, unit dosage formulations comprising between about 10 mg and about 100 mg, about 1 mg and about 200 mg, about 30 mg and about 200 mg, about of 35 mg and about 1,400 mg, about 125 mg and about 1,000 mg, about 250 mg and about 1,000 mg, or about 500 mg and about 1,000 mg of Compound A.

[0315] In another embodiment, unit dosage formulations comprising about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 35 mg, about 50 mg, about 60 mg, about 70 mg, about 100 mg, about 120 mg, about 125 mg, about 140 mg, about 175 mg, about 200 mg, about 240 mg, about 250 mg, about 280 mg, about 350 mg, about 480 mg, about 500 mg, about 560 mg, about 700 mg, about 720 mg, about 750 mg, about 1,000 mg or about 1,400 mg of Compound A.

[0316] In another embodiment, unit dosage forms comprising about 30 mg, about 100 mg or about 200 mg of Compound A are provided herein.

[0317] Pharmaceutical compositions, and dosage forms of Compound A, can be administered one, two, three, four or more times a day. In one embodiment, pharmaceutical compositions, and dosage forms of Compound A, can be administered once daily for 14 days.

[0318] Pharmaceutical compositions, and dosage forms of Compound A, can be administered orally for reasons of convenience. In one embodiment, when administered orally, pharmaceutical compositions, and dosage forms of Compound A, are administered with a meal and water. In another embodiment, pharmaceutical compositions, and dosage forms of Compound A, (e.g., dispersible granules or tablets) are dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.

[0319] Pharmaceutical compositions, and dosage forms of Compound A, can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation , or topically on the ears, nose, eyes or skin. The mode of administration is left to the discretion of the healthcare professional, and may depend in part on the site of the medical condition.

[0320] In such an embodiment, Compound A is Compound 1. In another embodiment, Compound A is a pharmaceutically acceptable salt of Compound 1. In yet another embodiment, Compound A is a solid form of Compound 1.

5.10. PROCESS FOR MANUFACTURED DOSAGE FORMS

[0321] Dosage forms provided herein can be prepared by any of the pharmacy methods, but all methods include the step of bringing the active ingredient into association with the excipient, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly admixing (e.g., direct mixing) the active ingredient with liquid excipients or finely divided solid excipients, or both, and then, if necessary, shaping the product into the desired presentation (e.g. , compaction as a cylinder compaction). If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0322] A dosage form provided herein can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient into a free-flowing form as powder or granules, optionally mixed with an excipient as above and/or a dispersing or surface active agent. Molded tablets can be manufactured by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0323] In some embodiments, the active ingredients and excipients are directly mixed and directly compressed into tablets. A directly blended dosage form may be more advantageous than a compacted dosage form (e.g., cylinder compacted) in certain examples, as direct blending may reduce or eliminate the adverse health effects that may be caused by particles airborne of ingredients during manufacturing using a compaction process.

[0324] Direct blend formulations may be advantageous in certain examples due to the fact that they require only one blending step, of the active ingredient and excipients, before being processed into the final dosage form, e.g., tablet . This can reduce the production of airborne particles or dust to a minimum, while drum compaction processes can be prone to dust production. In the cylinder compaction process, the compacted material is often crushed into smaller particles for further processing. The crushing operation can produce significant amounts of airborne particles, as the purpose of this production step is to reduce the particle size of materials. The material is crushed and then mixed with other ingredients before manufacturing the final dosage form.

[0325] For certain active ingredients, in particular, for a compound with a low solubility, the particle size of the active ingredient is reduced to a fine powder in order to help increase the solubilization rate of the active ingredient. Increasing the rate of solubilization is often necessary for the active ingredient to be absorbed effectively from the gastrointestinal tract. However, for fine powders to be directly blended and compressed into tablets, the excipients must ideally provide certain characteristics that make the ingredients suitable for the direct blending process. Examples of such characteristics include, without limitation, acceptable flow characteristics. In one embodiment, therefore, there is provided herein the use of, and compositions comprising, excipients that can provide characteristics, which make the resulting mixture suitable for the direct mixing process, for example, good flow characteristics.

[0326] In certain embodiments, provided herein are methods for preparing a composition provided herein, comprising: (i) weighing the desired amount of Compound A and the desired amount of a first portion of excipients; (ii) prepare an aqueous solution of surfactant (or surfactants); (iii) passing the mixture of Compound A and the first portion of excipients without the surfactant (or surfactants) through a sieve; (iv) mixing or mixing Compound A, the aqueous surfactant solution (or surfactants) and the first portion of the excipients; (v) dry the mixture; (vi) passing a second portion of the excipients through a sieve; (vii) mixing or mixing the mixture from step (v) and the second portion of the excipients; (viii) weigh the desired quantity of lubricating agents; (ix) pass the lubricating agents through a sieve; (x) mixing or mixing the mixture from step (vii) and the lubricating agents; (xi) compressing the mixture from step (x); and (ix) coating the compressed mixture with a coating agent. In one embodiment, the mixture of Compound A, excipients and lubricating agents are compressed into a tablet form. In one embodiment, the sieve is an 18 mesh sieve. In another embodiment, the sieve is a 1,000 μm sieve. In one embodiment, the sieve is a 20 mesh sieve. In another embodiment, the sieve is an 841 μm sieve. In one embodiment, the sieve is a 30 mesh sieve. In another embodiment, the sieve is a 595 μm sieve.

[0327] In such an embodiment, Compound A is Compound 1. In another embodiment, Compound A is a pharmaceutically acceptable salt of Compound 1. In yet another embodiment, Compound A is a solid form of Compound 1.

5.11. DISSOLUTION PROFILES

[0328] In certain embodiments, tablets comprising Compound A provided herein have a dissolution profile in which about 00% of Compound A is released in about 10-20 minutes, about 30 to 40 minutes, about 50 to 60 minutes, about 70 to 80 minutes, about 90 to 100 minutes, or about 110 to 120 minutes in a 0.1 N aqueous HCl solution, a 0.01 N aqueous HCl solution, or a aqueous buffer of about pH 4.5.

[0329] In certain embodiments, tablets comprising Compound A provided herein have a dissolution profile in which about 50% of Compound A is released in about 5 to 10 minutes in an aqueous solution of 0.1 HCl. N.

[0330] In certain embodiments, tablets comprising Compound A provided herein have a dissolution profile in which about 50% of Compound A is released in about 8 minutes in a 0.1 N aqueous HCl solution.

[0331] In certain embodiments, tablets comprising Compound A provided herein have a dissolution profile in which about 50% of Compound A is released in about 1 to 5 minutes in a 0.01N aqueous HCl solution. .

[0332] In certain embodiments, tablets comprising Compound A provided herein have a dissolution profile in which about 50% of Compound A is released in about 3 minutes in a 0.01N aqueous HCl solution.

[0333] In certain embodiments, tablets comprising Compound A provided herein have a dissolution profile in which about 50% of Compound A is released in about 10 to 15 minutes in an aqueous buffer solution of about pH 4 .5.

[0334] In certain embodiments, tablets comprising Compound A provided herein have a dissolution profile in which about 50% of Compound A is released in about 12 minutes in an aqueous buffer solution of about pH 4.5 .

[0335] In such an embodiment, Compound A is Compound 1. In another embodiment, Compound A is a pharmaceutically acceptable salt of Compound 1. In yet another embodiment, Compound A is a solid form of Compound 1.

5.12. COMPOUND SALTS 1

[0336] Additionally provided herein are pharmaceutically acceptable salts of Compound 1, including salts of hydrochloride, sulfate, phosphate, L-tartrate, L-malate, L-lactate, succinate, p-toluenesulfonate (tosylate), methanesulfonate (mesylate) , benzenesulfonate (besylate), fumarate and citrate.

[0337] In certain embodiments, pharmaceutical compositions and dosage forms of Compound A comprise one or more pharmaceutically acceptable salts of Compound 1, including hydrochloride, sulfate, phosphate, L-tartrate, L-malate, L-lactate, succinate salts. , p-toluenesulfonate (tosylate), methanesulfonate (mesylate), benzenesulfonate (besylate), fumarate and citrate.

[0338] In certain embodiments, the methods of use provided herein comprise administering one or more pharmaceutically acceptable salts of Compound 1, including hydrochloride, sulfate, phosphate, L-tartrate, L-malate, L-lactate, succinate, p-toluenesulfonate (tosylate), methanesulfonate (mesylate), benzenesulfonate (besylate), fumarate and citrate.

[0339] The salts provided herein (e.g., HCl salt, H2SO4 salt, H3PO4 salt, L-tartrate salt, L-lactate salt, L-malate salt, citrate salt, succinate, tosylate salt, mesylate salt, besylate salt, and fumarate salt of Compound 1) can be characterized using a number of methods known to one of skill in the art, including, without limitation, single crystal X-ray diffraction, X (XRPD), microscopy (e.g. scanning electron microscopy (SEM), polarized light microscopy (PLM) and hot stage microscopy)), thermal analysis (e.g. differential scanning calorimetry (DSC)), dynamic vapor (DVS), thermal gravimetric analysis (TGA), spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance), high-performance liquid chromatography (UHPLC), and proton nuclear magnetic resonance spectrum (NMR a 1H). The particle size and size distribution of the salt provided herein can be determined by conventional methods such as laser light scattering technique.

[0340] It should be understood that the numerical values of the peaks of an X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to another, and therefore the quoted values should not be interpreted as absolute, but with allowable variability such as ±0.2° 2θ (see Pharmacopoeia, page 2228 (2003)).

[0341] In certain embodiments, evaporation methods for making a salt of Compound 1 are provided herein, comprising 1) dissolving Compound 1 in a solvent to yield a solution; 2) add an acidic counterion; 3) evaporate the solution to yield a solid; and 4) collect the solid. In certain embodiments, the solvent is ACN, EtOH, EtOAc, Hexane, IPA MeOAc, MTBE, MeNO2 or acetone. In certain embodiments, the acid counterion is provided by HCl, H2SO4, H3PO4, L-tartaric acid, L-lactic acid, L-malic acid, citric acid, succinic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, or fumaric acid .

5.13. HCL SALT OF COMPOUND 1

[0342] In one embodiment, an HCl salt of Compound 1 is provided herein. In certain embodiments, the HCl salt has 7 different forms.

[0343] In certain embodiments, the HCl salt is prepared by evaporating a solution comprising Compound 1 and HCl. In certain embodiments, the HCl salt is prepared by evaporating a solution comprising Compound 1 and HCl in EtOH/IPA, IPA, EtOAc, acetone or water.

[0344] In one embodiment, the salt form of HCl 1 is a hydrate prepared by evaporation of a solution comprising Compound 1 and HCl in ACN, suspension in SGF, or exposure to moisture.

[0345] In one embodiment, the salt form of HCl 2 contains water and is prepared by evaporating a solution comprising Compound 1 and HCl in EtOH/IPA or IPA. In one embodiment, the HCl 2 salt form is converted to a hydrate when exposed to moisture (in the HCl 1 salt form) or suspended in water (in the HCl 7 salt form).

[0346] In one embodiment, the salt form of HCl 3 is prepared by evaporating a solution comprising Compound 1 and HCl in EtOAc.

[0347] In one embodiment, the salt form of HCl 4 is prepared by evaporating a solution comprising Compound 1 and HCl in acetone.

[0348] In one embodiment, the HCl 5 salt form is prepared by heating the HCl 2 salt form to 180°C. In one embodiment, the HCl 5 salt form is converted to a hydrate (HCl 1 salt form) when exposed to moisture.

[0349] In one embodiment, the salt form of HCl 6 is a dehydrated hydrate. In one embodiment, the HCl 6 salt form is prepared by heating the HCl 2 salt form to 220°C. In one embodiment, the HCl 6 salt form is converted to a hydrate (HCl 1 salt form) when exposed to moisture.

[0350] In one embodiment, the salt form of HCl 7 is a hydrate. In one embodiment, the HCl 7 salt form is prepared by suspending the HCl 1 salt form in water at room temperature.

[0351] In one embodiment, the HCl salt is a solid. In one embodiment, the HCl salt is crystalline. In one embodiment, the HCl salt is anhydrous. In one embodiment, the HCl salt is hygroscopic. In another embodiment, the HCl salt is a hydrate. In another embodiment, the salt form of HCl 1 is a monohydrate.

[0352] In one embodiment, the HCl 2 salt form has a TGA thermogram that substantially corresponds to the representative TGA thermogram as depicted in Figure 34. In certain embodiments, the HCl 2 salt form exhibits a TGA thermogram comprising a total mass loss of approximately 2.82% of the total mass of the sample between approximately 25 °C and approximately 119.9 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the HCl 2 salt form loses about 2.82% of its total mass when heated from about room temperature to about 300 °C.

[0353] In one embodiment, the salt form of HCl 2 has a DSC thermogram as depicted in Figure 34 comprising an endothermic event at 163.0 °C when heated from approximately 25 °C to approximately 300 °C. In one embodiment, the DSC thermogram further comprises a melting and decomposition event with an initial temperature of about 220°C when heated from about 25°C to about 300°C.

[0354] In one embodiment, the HCl 2 salt form has an isothermal DVS graph substantially as depicted in Figure 41.

[0355] In certain embodiments, solid forms provided herein, for example, HCl salt forms 1 to 4, are substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. HCl salt forms 1 to 4 have X-ray powder diffraction patterns substantially as shown in Figure 6.

[0356] In one embodiment, HCl salt forms 1 to 4 have Raman spectra substantially as depicted in Figure 7.

[0357] In certain embodiments, a solid form provided herein, for example, the HCl 1 salt form, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. HCl salt form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 75. In one embodiment, HCl salt form 1 has one or more characteristic X-ray powder diffraction peaks and approximately 5 .5, 7.5, 9.0, 9.7, 11.2, 13.1, 13.9, 15.9, 16.5, 17.2, 17.3, 18.3, 19.6 , 19.8, 21.7, 22.0, 22.9, 23.7, 24.6, 24.9, 25.9, 26.4, 27.3, 27.7, 28.2, 28 .5, 29.9, 30.6, 31.0, 31.2, 31.7, 32.0, 32.6, 33.0, 33.4, 33.7, 34.2, 36.3 , 37.8 or 38.8° 2θ as depicted in Figure 75. In a specific embodiment, the salt form of HCl 1 has one, two, three, four, five, six, seven or eight ray powder diffraction peaks Characteristic In another embodiment, the salt form of HCl 1 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 5.5, 13.1, 18.3, 19.6 or 21. 7°2θ. In another embodiment, the salt form of HCl 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-two three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine or forty characteristic X-ray powder diffraction peaks as shown in Table 32.

[0358] In certain embodiments, a solid form provided herein, for example, the HCl 2 salt form, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. HCl 2 salt form has an X-ray powder diffraction pattern substantially as shown in Figure 76. In one embodiment, the HCl 2 salt form has one or more characteristic X-ray powder diffraction peaks at approximately 5, 37, 7.92, 9.23, 9.53, 11.95, 12.40, 12.61, 13.09, 14.90, 15.69, 16.52, 17.92, 18.17, 18.64, 18.94, 20.54, 20.69, 20.93, 21.36, 21.69, 22.05, 22.80, 23.55, 24.28, 24.71, 25, 09, 25.25, 25.78, 25.99, 27.02, 28.42, 28.87, 29.63, 30.74, 31.58, 31.87, 32.33, 32.76, 33.35, 34.02, 35.10, 36.06, 36.61, 37.00, 37.86, 38.10, 39.16 or 39.92° 2θ as depicted in Figure 76. In a specific embodiment , the salt form of HCl 2 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 7.92, 9.23, 18.64, 18.94 , 20.69, 25.25, 27.02 or 29.63° 2θ. In another embodiment, the HCl 2 salt form has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 7.92, 9.23, 18.94, 20.69, or 29. 63°2θ. In another embodiment, the HCl 2 salt form has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 7.92, 9.23, 11.95, 12.40, or 18. 94°2θ. In another embodiment, the salt form of HCl 2 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-two three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two, forty-three, forty-four, forty-five, forty-e six, forty-seven or forty-eight characteristic X-ray powder diffraction peaks as shown in Table 33.

[0359] In certain embodiments, a solid form provided herein, for example, the HCl 3 salt form, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. HCl 3 salt form has an X-ray powder diffraction pattern substantially as shown in Figure 77. In one embodiment, the HCl 3 salt form has one or more characteristic X-ray powder diffraction peaks at approximately 5, 71, 9.48, 9.85, 11.34, 13.24, 14.10, 16.75, 17.86, 18.44, 19.67, 21.82, 23.10, 23.84, 25.03, 26.04, 27.81, 30.65, 31.83 or 38.91° 2θ as depicted in Figure 77. In a specific embodiment, the HCl 3 salt form has one, two, three, four , five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.71, 9.85, 11.34, 13.24, 16.75, 18.44, 19.67 or 21.82 ° 2θ. In another embodiment, the salt form of HCl 3 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 5.71, 11.34, 13.24, 16.75 or 18. 44°2θ. In another embodiment, the salt form of HCl 3 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.71, 9.48, 11.34, 13.24, or 18. 44°2θ. In another embodiment, the salt form of HCl 3 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen or nineteen peaks characteristic X-ray powder diffraction measurements as shown in Table 34.

[0360] In certain embodiments, a solid form provided herein, for example, the HCl 4 salt form, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. salt form of HCl 4 has an X-ray powder diffraction pattern substantially as shown in Figure 78. In one embodiment, the salt form of HCl 4 has one or more characteristic X-ray powder diffraction peaks at approximately 5, 65, 5.73, 7.50, 9.31, 9.77, 11.38, 13.77, 14.23, 16.20, 17.16, 17.54, 18.16, 18.69, 19.06, 20.56, 21.65, 21.75, 22.10, 22.65, 23.05, 24.04, 26.18, 28.30, 28.45, 28.70, 29, 59, 30.90, 32.47 or 35.63° 2θ as depicted in Figure 78. In a specific embodiment, the HCl 4 salt form has one, two, three, four, five, six, seven or eight peaks. characteristic X-ray powder diffraction at approximately 5.65, 5.73, 9.77, 11.38, 13.77, 17.16, 21.65 or 29.59° 2θ. In another embodiment, the salt form of HCl 4 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.65, 5.73, 9.77, 11.38, or 13. 77°2θ. In another embodiment, the salt form of HCl 4 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 5.65, 9.77, 11.38, 13.77 or 21. 65°2θ. In another embodiment, salt form of HCl 4 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty , twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight or twenty-nine characteristic X-ray powder diffraction peaks as shown in Table 35 .

[0361] In certain embodiments, a solid form provided herein, for example, the HCl 5 salt form, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. salt form of HCl 5 has an X-ray powder diffraction pattern substantially as shown in Figure 79. In one embodiment, the salt form of HCl 5 has one or more characteristic X-ray powder diffraction peaks at approximately 5, 63, 6.29, 7.61, 8.45, 9.74, 10.6, 11.27, 12.23, 12.59, 13.16, 14.02, 14.63, 15.97, 16.63, 16.92, 17.35, 17.74, 18.40, 18.69, 19.10, 19.66, 21.80, 22.63, 23.05, 23.80, 24, 58, 24.98, 25.94, 26.51, 27.78, 28.25, 28.57, 30.62, 31.38, 31.78, 32.61, 33.01, 33.40, 35.40, 37.88 or 38.82° 2θ as depicted in Figure 79. In a specific embodiment, the HCl 5 salt form has one, two, three, four, five, six, seven or eight diffraction peaks. characteristic X-ray powder at approximately 5.63, 17.35, 18.40, 18.69, 19.66, 21.80, 23.80 or 25.94° 2θ. In another embodiment, the salt form of HCl 5 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.63, 18.69, 19.66, 21.80, or 23. 80°2θ. In another embodiment, the salt form of HCl 5 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.63, 8.45, 10.76, 14.63, or 21. 80°2θ. In another embodiment, the salt form of HCl 5 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-two three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty or forty-one characteristic X-ray powder diffraction peaks as shown in Table 36.

[0362] In certain embodiments, a solid form provided herein, for example, the HCl 6 salt form, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. salt form of HCl 6 has an X-ray powder diffraction pattern substantially as shown in Figure 80. In one embodiment, the salt form of HCl 6 has one or more characteristic X-ray powder diffraction peaks at approximately 5, 58, 7.61, 8.27, 9.13, 9.74, 11.19, 13.14, 13.99, 15.91, 16.65, 16.87, 17.33, 18.38, 19.67, 19.92, 21.79, 21.99, 23.03, 23.32, 23.77, 24.66, 24.97, 25.33, 25.92, 26.52, 27, 38, 27.76, 28.24, 28.54, 30.62, 31.34, 31.74, 32.63, 33.04, 33.47, 36.38, 37.83 or 38.79° 2θ as depicted in Figure 80. In a specific embodiment, the salt form of HCl 6 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.58, 11 .19, 13.14, 17.33, 18.38, 19.67, 21.79 or 23.77° 2θ. In another embodiment, the salt form of HCl 6 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.58, 17.33, 18.38, 19.67, or 21. 79°2θ. In another embodiment, the salt form of HCl 6 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.58, 8.27, 18.38, 19.67, or 21. 79°2θ. In another embodiment, the salt form of HCl 6 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-two three, thirty-four, thirty-five, thirty-six, thirty-seven or thirty-eight characteristic X-ray powder diffraction peaks as shown in Table 37.

[0363] In certain embodiments, a solid form provided herein, for example, the HCl 7 salt form, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. HCl salt form 7 has an X-ray powder diffraction pattern substantially as shown in Figure 81. In one embodiment, HCl salt form 7 has one or more characteristic X-ray powder diffraction peaks at approximately 5, 54, 7.61, 8.95, 9.85, 11.14, 12.86, 14.14, 15.77, 16.83, 17.29, 17.51, 18.04, 18.33, 18.69, 19.82, 21.94, 23.05, 23.90, 28.28, 30.66, 32.02 or 38.98° 2θ as depicted in Figure 81. In a specific embodiment, the shape of HCl salt 7 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.54, 7.61, 11.14, 18.04, 19.82 , 21.94, 23.05 or 38.98° 2θ. In another embodiment, the salt form of HCl 7 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.54, 7.61, 18.04, 19.82, or 23. 05°2θ. In another embodiment, the salt form of HCl 7 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.54, 7.61, 8.95, 12.86, or 18. 04°2θ. In another embodiment, salt form of HCl 7 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty , twenty-one or twenty-two characteristic X-ray powder diffraction peaks as shown in Table 38.

5.14. H2SO4 SALT OF COMPOUND 1

[0364] In one embodiment, a H2SO4 salt of Compound 1 is provided herein. In certain embodiments, the H2SO4 salt has 3 different forms.

[0365] In one embodiment, the H2SO4 salt form 1 is prepared by evaporating a solution comprising Compound 1 and H2SO4 in ACN, IPA or EtOAc.

[0366] In one embodiment, the salt form of H2SO4 2 is prepared by evaporating a solution comprising Compound 1 and H2SO4 in acetone.

[0367] In one embodiment, the salt form of H2SO4 3 is prepared by storing form 1 at 80°C and 75% relative humidity. In one embodiment, the H2SO4 salt form 3 is prepared by storing form 1 at 80°C and 75% relative humidity for two weeks.

[0368] In one embodiment, the H2SO4 salt is a solid. In one embodiment, the H2SO4 salt is crystalline. In one embodiment, the H2SO4 salt is anhydrous. In one embodiment, the H2SO4 salt is hygroscopic. In another embodiment, the H2SO4 salt is a hydrate.

[0369] In certain embodiments, the H2SO4 salt is prepared by evaporation. In one embodiment, the H2SO4 salt is prepared by evaporating a solution comprising Compound 1 and H2SO4 in ACN, IPA, EtOAc or acetone.

[0370] In one embodiment, the H2SO4 salt form 1 has a TGA thermogram that substantially corresponds to the representative TGA thermogram as depicted in Figure 35. In certain embodiments, the H2SO4 salt form 1 exhibits a TGA thermogram comprising a total mass loss of approximately 0.28% of the total mass of the sample between approximately 25 °C and approximately 119.9 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the salt form of H2SO4 1 loses about 0.28% of its total mass when heated from about room temperature to about 300 ° C.

[0371] In one embodiment, the H2SO4 salt form 1 has a DSC thermogram as depicted in Figure 35 comprising a Tg type event between about 86.0°C and 88.4°C when heated to approximately 25°C at approximately 300 °C. In one embodiment, the DSC thermogram further comprises a melting and decomposition event with an initial temperature of about 235°C when heated from about 25°C to about 300°C.

[0372] In one embodiment, the H2SO4 salt form 1 has an isothermal DVS graph substantially as depicted in Figure 43.

[0373] In certain embodiments, solid forms provided herein, for example, H2SO4 salt forms 1 to 3, are substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. H2SO4 salt forms 1 and 2 have X-ray powder diffraction patterns substantially as shown in Figure 8. In another embodiment, the H2SO4 salt form 3 has an X-ray powder diffraction pattern substantially as shown in Figure 84.

[0374] In one embodiment, H2SO4 salt forms 1 and 2 have Raman spectra substantially as depicted in Figure 9.

[0375] In certain embodiments, a solid form provided herein, for example, the salt form of H2SO4 1, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. H2SO4 salt form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 82. In one embodiment, the H2SO4 salt form 1 has one or more characteristic X-ray powder diffraction peaks at approximately 5, 40, 5.66, 9.02, 10.74, 14.78, 16.16, 16.65, 17.65, 18.18, 18.69, 19.67, 20.50, 21.62, 22.28, 22.75, 24.13, 24.57, 24.88, 25.42, 26.55, 28.49, 29.17, 29.88, 31.29, 32.15, 32, 66, 33.21, 34.02, 35.78, 36.86, 37.43, 38.27 or 39.64° 2θ as depicted in Figure 82. In a specific embodiment, the salt form of H2SO4 1 has a , two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.40, 10.74, 18.18, 18.69, 21.62, 22.28, 22 .75 or 26.55° 2θ. In another embodiment, the salt form of H2SO4 1 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 5.40, 18.18, 18.69, 21.62 or 22, 28°2θ. In another embodiment, the salt form of H2SO4 1 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 5.40, 10.74, 18.18, 18.69 or 22. 28°2θ. In another embodiment, the salt form of H2SO4 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-two three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine or forty characteristic X-ray powder diffraction peaks as shown in Table 39.

[0376] In certain embodiments, a solid form provided herein, for example, the salt form of H2SO4 2, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. H2SO4 2 salt form has an X-ray powder diffraction pattern substantially as shown in Figure 83. In one embodiment, the H2SO4 2 salt form has one or more characteristic X-ray powder diffraction peaks at approximately 5, 63, 5.67, 15.25, 16.08, 17.87, 18.57, 21.83, 22.24, 22.75, 25.90, 26.53 or 27.18° 2θ as represented in Figure 83. In a specific embodiment, the salt form of H2SO4 2 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.63, 5.67, 15 .25, 16.08, 17.87, 18.57, 22.24 or 22.75° 2θ. In another embodiment, the salt form of H2SO4 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.63, 5.67, 17.87, 18.57, or 22. 75°2θ. In another embodiment, the salt form of H2SO4 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.63, 11.30, 15.25, 17.87, or 18. 57°2θ. In another embodiment, the salt form of H2SO4 2 has one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve characteristic X-ray powder diffraction peaks as shown in Table 40.

[0377] In certain embodiments, a solid form provided herein, for example, the salt form of H2SO4 3, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. H2SO4 3 salt form has an X-ray powder diffraction pattern substantially as shown in Figure 84. In one embodiment, the H2SO4 3 salt form has one or more characteristic X-ray powder diffraction peaks at approximately 5, 60, 10.68, 11.22, 12.41, 13.81, 15.11, 15.96, 16.86, 17.67, 18.10, 18.48, 18.78, 19.15, 21.53, 22.10, 22.38, 22.61, 23.65, 24.56, 25.22, 25.85, 26.27, 27.24, 33.38, 34.20 or 37, 96°2θ as depicted in Figure 84. In a specific embodiment, the salt form of H2SO43 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.60 , 17.67, 11.22, 22.38, 15.11, 18.10, 22.61, 22.10, 27.24, 10.68, 18.48 or 15.96° 2θ. In another embodiment, the salt form of H2SO4 3 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 5.60, 17.67, 11.22, 22.38 or 15. 11°2θ. In another embodiment, the salt form of H2SO4 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.60, 11.22, 15.11, 15.96, 17, 67 or 19.15° 2θ. In another embodiment, the salt form of H2SO4 3 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five or twenty-six characteristic X-ray powder diffraction peaks as shown in Table 41.

5.15. COMPOUND 1 H3PO4 SALT

[0378] In one embodiment, an H3PO4 salt is provided herein.

[0379] In one embodiment, the H3PO4 salt is a solid. In one embodiment, the H3PO4 salt is crystalline. In one embodiment, the H3PO4 salt is anhydrous. In one embodiment, the H3PO4 salt is non-hygroscopic.

[0380] In certain embodiments, the H3PO4 salt is provided herein prepared by evaporating a solution comprising Compound 1 and H3PO4. In one embodiment, the H3PO4 salt is prepared by evaporating a solution comprising Compound 1 and H3PO4 in ACN, IPA, EtOAc or acetone.

[0381] In one embodiment, the H3PO4 salt has a TGA thermogram that substantially corresponds to the representative TGA thermogram as depicted in Figure 36. In certain embodiments, the H3PO4 salt exhibits a TGA thermogram comprising a total mass loss of approximately 0.25% of the total mass of the sample between approximately 25°C and approximately 119.9°C when heated from approximately 25°C to approximately 300°C. Thus, in certain embodiments, the H3PO4 salt loses about 0.25% of its total mass when heated from about room temperature to about 300 °C.

[0382] In one embodiment, the H3PO4 salt has a DSC thermogram as depicted in Figure 36 comprising a dehydration event with an initial temperature of about 169.9 °C when heated from approximately 25 °C to approximately 300 °C. In one embodiment, the DSC thermogram further comprises a melting and decomposition event with an initial temperature of about 238.3°C when heated from about 25°C to about 300°C.

[0383] In one embodiment, the H3PO4 salt has an isothermal DVS graph substantially as depicted in Figure 45.

[0384] In certain embodiments, a solid form provided herein, e.g., an H3PO4 salt, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, the H3PO4 salt has an X-ray powder diffraction pattern substantially as shown in Figure 10.

[0385] In one embodiment, the H3PO4 salt has a Raman spectrum substantially as depicted in Figure 11.

[0386] In certain embodiments, a solid form provided herein, e.g., H3PO4 salt, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, the H3PO4 salt has an X-ray powder diffraction pattern substantially as shown in Figure 85. In one embodiment, the H3PO4 salt has one or more characteristic X-ray powder diffraction peaks at approximately 5.58, 5.73, 11.30, 15.27, 16.07, 16.37, 16.95, 17.46, 17.72, 18.37, 20.64, 20.98, 21.73, 22.34, 22.66, 23, 31, 23.65, 24.14, 25.88, 26.42, 28.10, 28.39, 29.89, 30.38, 30.88, 31.35, 33.13, 34.32, 35.08, 35.91, 37.43 or 38.89° 2θ as depicted in Figure 85. In a specific embodiment, the H3PO4 salt has one, two, three, four, five, six, seven or eight diffraction peaks of characteristic X-ray dust at approximately 5.58, 5.73, 11.30, 15.27, 16.95, 23.65, 25.88 or 28.39° 2θ. In another embodiment, the H3PO4 salt has one, two, three, four or five characteristic X-ray powder diffraction peaks - at approximately 5.58, 5.73, 11.30, 15.27 or 28.39 ° 2θ. In another embodiment, the H3PO4 salt has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty and one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, or thirty-two powder diffraction peaks characteristic x-rays as shown in Table 50.

5.16. L-TARTrate SALT OF COMPOUND 1

[0387] In one embodiment, an L-tartrate salt of Compound 1 is provided herein.

[0388] In one embodiment, the L-tartrate salt is a solid. In one embodiment, the L-tartrate salt is crystalline. In one embodiment, the L-tartrate salt is slightly hygroscopic. In another embodiment, the L-tartrate salt is a hydrate. In another embodiment, the L-tartrate salt is a dihydrate. In another embodiment, the L-tartrate salt is a hemi-tartrate dihydrate.

[0389] In certain embodiments, the L-tartrate salt is prepared by evaporating a solution comprising Compound 1 and L-tartaric acid. In one embodiment, the L-tartrate salt is prepared by evaporating a solution comprising Compound 1 and L-tartaric acid in ACN, IPA, EtOAc or acetone.

[0390] In one embodiment, the stoichiometric ratio between Compound 1 and L-tartaric acid is about 2:1 in the L-tartrate salt.

[0391] In one embodiment, the L-tartrate salt has a TGA thermogram that substantially corresponds to the representative TGA thermogram as depicted in Figure 37. In certain embodiments, L-tartrate exhibits a TGA thermogram comprising a total mass loss of approximately 3.97% of the total sample mass between approximately 25°C and approximately 119.9°C when heated from approximately 25°C to approximately 300°C. Thus, in certain embodiments, the L-tartrate salt loses about 3.97% of its total mass when heated from about room temperature to about 300 ° C.

[0392] In one embodiment, the L-tartrate salt has a DSC thermogram as depicted in Figure 37 comprising a dehydration event with an initial temperature of about 89.5°C when heated from approximately 25°C to approximately 300° W. In one embodiment, the DSC thermogram further comprises a melting and decomposition event with an initial temperature of about 201.5°C when heated from about 25°C to about 300°C.

[0393] In one embodiment, the L-tartrate salt has an isothermal DVS graph substantially as depicted in Figure 47.

[0394] In certain embodiments, a solid form provided herein, for example, an L-tartrate salt, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. of L-tartrate has an X-ray powder diffraction pattern substantially as shown in Figure 12.

[0395] In one embodiment, the L-tartrate salt has a Raman spectrum substantially as depicted in Figure 13.

[0396] In certain embodiments, a solid form provided herein, for example, a salt form of L-tartrate 1, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. , the L-tartrate salt form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 88. In one embodiment, the L-tartrate salt form 1 has one or more X-ray powder diffraction peaks. Characteristic .31, 21.14, 22.08, 22.75, 23.21, 23.84, 24.33, 25.92, 26.51, 27.09, 27.75, 28.44, 29.52 , 31.15, 31.83, 32.73, 33.31, 34.99, 35.55, 36.80, 37.25, 37.77 or 38.41° 2θ as depicted in Figure 88. In one embodiment In particular, the L-tartrate salt form 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 6.04, 16.19, 16.68, 17.30, 19.98, 20.31, 23.21 or 24.33° 2θ. In another embodiment, the L-tartrate salt form 1 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 6.04, 16.19, 16.68, 19.98 or 24.33°2θ. In another embodiment, the L-tartrate salt form 1 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 6.04, 12.14, 16.19, 18.27 or 24.33°2θ. In another embodiment, the L-tartrate salt form 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three or thirty-four characteristic X-ray powder diffraction peaks as shown in Table 51.

[0397] In certain embodiments, a solid form provided herein, for example, a salt form of L-tartrate 2, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. , the L-tartrate salt form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 89. In one embodiment, the L-tartrate salt form 2 has one or more X-ray powder diffraction peaks. Characteristic 72, 22.49, 22.71, 24.04, 24.86, 24.95, 27.08, 28.25, 29.30, 30.78, 31.16, 31.30, 33.13, 33.96, 34.36, 34.87, 35.03, 35.14, 35.29, 36.36 or 36.58° 2θ as depicted in Figure 89. In a specific embodiment, the salt form of L- tartrate 2 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 6.29, 6.46, 12.63, 16.51, 17.23, 20 .72, 24.04 or 24.95° 2θ. In another embodiment, the salt form of L-tartrate 2 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 6.29, 6.46, 16.51, 20.72 or 24.04°2θ. In another embodiment, the L-tartrate salt form 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 6.29, 12.63, 16.51, 18.82 or 24.95°2θ. In another embodiment, the salt form of L-tartrate 2 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one or thirty-two peaks characteristic X-ray powder diffraction analysis as shown in Table 52.

5.17. L-LACTATE SALT OF COMPOUND 1

[0398] In one embodiment, an L-lactate salt of Compound 1 is provided herein. In certain embodiments, the L-lactate salt has 2 different forms.

[0399] In certain embodiments, the L-lactate salt is prepared by evaporating a solution comprising Compound 1 and L-lactic acid. In one embodiment, the L-lactate salt is prepared by evaporating a solution comprising Compound 1 and L-lactic acid in hexane or EtOAc.

[0400] In one embodiment, the salt form of L-lactate 1 is prepared by evaporating a solution comprising Compound 1 and L-lactic acid in hexane. In one embodiment, the L-lactate salt form 2 is prepared by evaporating a solution comprising Compound 1 and L-lactic acid in EtOAc.

[0401] In one embodiment, the L-lactate salt is a solid. In one embodiment, the L-lactate salt is crystalline. In one embodiment, the L-lactate salt is moderately hygroscopic. In another embodiment, the L-lactate salt is a hydrate.

[0402] In one embodiment, the L-lactate salt form 2 has a TGA thermogram that substantially corresponds to the representative TGA thermogram as depicted in Figure 39. In certain embodiments, the L-lactate salt form 1 exhibits a thermogram of TGA comprising a total mass loss of approximately 1.74% of the total mass of the sample between approximately 25 °C and approximately 119.9 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the L-lactate salt form 1 loses about 1.74% of its total mass when heated from about room temperature to about 300 ° C.

[0403] In one embodiment, the L-tartrate salt form 2 has a DSC thermogram as depicted in Figure 39 comprising a dehydration event with an initial temperature of about 76.5°C when heated from approximately 25°C to approximately 300°C. In one embodiment, the DSC thermogram further comprises a melting and decomposition event with an initial temperature of about 145.3°C when heated from about 25°C to about 300°C.

[0404] In one embodiment, the L-lactate salt form 2 has an isothermal DVS graph substantially as depicted in Figure 52.

[0405] In certain embodiments, solid forms provided herein, for example, L-lactate salt forms 1-2, are substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. , L-lactate salt forms 1 and 2 have X-ray powder diffraction patterns substantially as shown in Figure 16.

[0406] In one embodiment, L-lactate salt forms 1 and 2 have Raman spectra substantially as depicted in Figure 17.

[0407] In certain embodiments, a solid form provided herein, for example, the L-lactate salt form 1, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. , the L-lactate salt form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 86. In one embodiment, the L-lactate salt form 1 has one or more X-ray powder diffraction peaks. Characteristic 10, 16.89, 17.19, 17.70, 18.89, 19.20, 19.54, 19.72, 20.16, 20.43, 20.96, 21.55, 21.84, 23.12, 24.22, 24.67, 24.92, 25.21, 26.19, 27.06, 28.55, 29.20, 30.43, 32.82, 34.36 or 36, 29°2θ as depicted in Figure 86. In a specific embodiment, the L-lactate salt form 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5 .77, 9.57, 9.81, 16.10, 18.89, 19.54, 20.16 or 24.22°2θ. In another embodiment, the L-lactate salt form 1 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 5.77, 9.57, 16.10, 19.54 or 20.16°2θ. In another embodiment, the L-lactate salt form 1 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.77, 7.93, 16.10, 20.16 or 24.22°2θ. In another embodiment, the L-lactate salt form 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six or thirty-seven characteristic X-ray powder diffraction peaks as shown in Table 53.

[0408] In certain embodiments, a solid form provided herein, for example, the salt form of L-lactate 2, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. , the L-lactate salt form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 87. In one embodiment, the L-lactate salt form 2 has one or more X-ray powder diffraction peaks. Characteristic 55, 18.00, 18.51, 18.97, 19.47, 20.41, 20.98, 21.45, 22.39, 22.64, 23.08, 23.50, 23.84, 24.03, 24.46, 24.88, 25.21, 26.42, 26.86, 27.24, 27.77, 28.23, 28.53, 30.47, 31.04, 31, 58, 32.44, 33.93, 35.53, 36.58, 37.11 or 38.68° 2θ as depicted in Figure 87. In a specific embodiment, the L-lactate salt form 2 has one, two , three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 9.69, 10.23, 13.29, 17.02, 18.51, 18.97, 19.47 or 20.41°2θ. In another embodiment, the L-lactate salt form 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 10.23, 17.02, 18.97, 19.47 or 20.41°2θ. In another embodiment, the L-lactate salt form 2 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 9.69, 10.23, 13.29, 17.02 or 18.97°2θ. In another embodiment, the L-lactate salt form 2 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two or forty-three characteristic X-ray powder diffraction peaks as shown in Table 54.

5.18. L-MALATE SALT OF COMPOUND 1

[0409] In one embodiment, an L-malate salt of Compound 1 is provided herein. In certain embodiments, the L-malate salt has 4 different forms.

[0410] In one embodiment, the L-malate salt is a solid. In one embodiment, the L-malate salt is crystalline. In one embodiment, the L-malate salt is hygroscopic. In another embodiment, the L-malate salt is a hydrate.

[0411] In certain embodiments, the L-malate salt is prepared by evaporating a solution comprising Compound 1 and L-malic acid. In one embodiment, the L-malate salt is prepared by evaporating a solution comprising Compound 1 and L-malic acid in ACN, IPA, EtOAc or acetone.

[0412] In one embodiment, the salt form of L-malate 1 is prepared by evaporating a solution comprising Compound 1 and L-malic acid in ACN.

[0413] In one embodiment, the salt form of L-malate 2 is prepared by evaporating a solution comprising Compound 1 and L-malic acid in MeNO2.

[0414] In one embodiment, the salt form of L-malate 3 is prepared by evaporating a solution comprising Compound 1 and L-malic acid in EtOAc.

[0415] In one embodiment, the salt form of L-malate 4 is prepared by evaporating a solution comprising Compound 1 and L-malic acid in IPA.

[0416] In one embodiment, the stoichiometric ratio between Compound 1 and L-malic acid is about 1:1 in the L-malic salt.

[0417] In one embodiment, the L-malate salt form 2 has a TGA thermogram that substantially corresponds to the representative TGA thermogram as depicted in Figure 38. In certain embodiments, L-malate exhibits a TGA thermogram comprising a loss of total mass of approximately 1.21% of the total mass of the sample between approximately 25 °C and approximately 94.8 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the L-malate salt loses about 1.21% of its total mass when heated from about room temperature to about 300 °C.

[0418] In one embodiment, the L-malate salt form 2 has a DSC thermogram as depicted in Figure 38 comprising a dehydration event with an initial temperature of about 94.8°C when heated from approximately 25°C to approximately 300°C. In one embodiment, the DSC thermogram further comprises a solid-solid transition event with an initial temperature of about 100.8 °C when heated from about 25 °C to about 300 °C.

[0419] In one embodiment, the L-malate salt form 2 has an isothermal DVS graph substantially as depicted in Figure 50.

[0420] In certain embodiments, solid forms provided herein, e.g., L-malate salt forms 1-4, are substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. , L-malate salt forms 1 to 4 have an X-ray powder diffraction pattern substantially as shown in Figure 18.

[0421] In one embodiment, L-malate salt forms 1 to 4 have Raman spectra substantially as depicted in Figure 19.

[0422] In certain embodiments, a solid form provided herein, for example, the salt form of L-malate 1, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. , the L-malate salt form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 90. In one embodiment, the L-malate salt form 1 has one or more x-ray powder diffraction peaks. characteristic characteristic X-ray powder diffraction at approximately 5.52, 11.12, 15.86 or 17.18° 2θ. In another embodiment, the L-malate salt form 1 has one, two, three or four characteristic X-ray powder diffraction peaks as shown in Table 55.

[0423] In certain embodiments, a solid form provided herein, for example, the salt form of L-malate 2, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. , the L-malate salt form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 91. In one embodiment, the L-malate salt form 2 has one or more x-ray powder diffraction peaks. characteristic x-rays at approximately 5.48, 6.15, 7.56, 8.50, 8.99, 9.50, 11.08, 12.21, 12.97, 15.23, 16.09, 17 .16, 17.50, 18.01, 18.48, 19.21, 19.69, 20.38, 21.09, 21.75, 22.47, 22.72, 23.70, 24.44 , 24.96, 25.23, 25.80, 26.20, 26.51, 27.78, 28.41, 30.01, 30.41, 32.95, 34.90, 35.28, 35 .91, 36.41 or 37.63° 2θ as depicted in Figure 91. In a specific embodiment, the salt form of L-malate 2 has one, two, three, four, five, six, seven or eight diffraction peaks of characteristic X-ray dust at approximately 5.48, 6.15, 7.56, 12.97, 15.23, 17.16, 18.48 or 21.09° 2θ. In another embodiment, the salt form of L-malate 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.48, 6.15, 7.56, 18.48 or 21.09°2θ. In another embodiment, the L-malate salt form 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.48, 6.15, 7.56, 15.23 or 21.09°2θ. In another embodiment, the salt form of L-malate 2 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight or thirty-nine characteristic X-ray powder diffraction peaks as shown in Table 56.

[0424] In certain embodiments, a solid form provided herein, for example, the salt form of L-malate 3, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. , the L-malate salt form 3 has an X-ray powder diffraction pattern substantially as shown in Figure 92. In one embodiment, the L-malate salt form 3 has one or more x-ray powder diffraction peaks. characteristic as depicted in Figure 92. In a specific embodiment, the salt form of L-malate 3 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.89, 5.49, 7.25, 11.74, 12.39, 15.76, 16.73 or 20.54° 2θ. In another embodiment, the salt form of L-malate 3 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 4.89, 5.49, 7.25, 15.76 or 20.54°2θ. In another embodiment, the salt form of L-malate 3 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 4.89, 5.49, 7.25, 11.74 or 15.76°2θ. In another embodiment, the salt form of L-malate 3 has one, two, three, four, five, six, seven, eight, nine, ten or eleven characteristic X-ray powder diffraction peaks as shown in Table 57.

[0425] In certain embodiments, a solid form provided herein, for example, the salt form of L-malate 4, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. , the L-malate salt form 4 has an X-ray powder diffraction pattern substantially as shown in Figure 93. In one embodiment, the L-malate salt form 4 has one or more x-ray powder diffraction peaks. characteristic x-rays at approximately 5.91, 8.34, 10.45, 10.91, 12.67, 13.10, 13.48, 15.34, 16.71, 17.49, 17.89, 18 .22, 18.72, 18.95, 19.41, 19.84, 20.21, 20.77, 21.22, 21.62, 21.91, 22.60, 23.99, 24.56 , 25.03, 26.20, 27.19, 27.52, 28.45, 29.19, 29.60, 29.96, 30.24, 30.99, 31.61, 34.44, 35 .66, 36.10, 36.86, 37.19, 37.83, 38.58 or 39.05° 2θ as depicted in Figure 93. In a specific embodiment, the L-malate salt form 4 has a, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.91, 10.91, 18.22, 18.72, 20.77, 21.22, 21, 91 or 26.20° 2θ. In another embodiment, the salt form of L-malate 4 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.91, 10.91, 18.72, 20.77 or 21.22°2θ. In another embodiment, the salt form of L-malate 4 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.91, 10.91, 12.67, 18.72 or 20.77°2θ. In another embodiment, the salt form of L-malate 4 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two or forty-three characteristic X-ray powder diffraction peaks as shown in Table 58.

5.19. CITRATE SALT OF COMPOUND 1

[0426] In one embodiment, a citrate salt of Compound 1 is provided herein.

[0427] In one embodiment, the citrate salt is a solid. In one embodiment, the citrate salt is amorphous.

[0428] In certain embodiments, the citrate salt is prepared by evaporating a solution comprising Compound 1 and citric acid in MTBE, MeNO2, hexane or MeOAc.

[0429] In one embodiment, the stoichiometric ratio between Compound 1 and citric acid is about 1:1 in the citrate salt.

[0430] In certain embodiments, a solid form provided herein, e.g., a citrate salt, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, the citrate salt has an X-ray powder diffraction pattern substantially as shown in Figure 20.

[0431] In one embodiment, the citrate salt has a Raman spectrum substantially as depicted in Figure 21.

5.20. COMPOUND 1 SUCCINATE SALT

[0432] In one embodiment, a succinate salt of Compound 1 is provided herein. In certain embodiments, the succinate salt has 3 different forms.

[0433] In one embodiment, the succinate salt is a solid. In one embodiment, the succinate salt is crystalline.

[0434] In certain embodiments, the succinate salt is prepared by evaporating a solution comprising Compound 1 and succinic acid. In one embodiment, the succinate salt is prepared by evaporating a solution comprising Compound 1 and succinic acid in ACN, IPA, EtOAc or acetone.

[0435] In one embodiment, the succinate salt form 1 is prepared by evaporating a solution comprising Compound 1 and succinic acid in ACN or EtOH. In one embodiment, the succinate salt form 2 is prepared by evaporating a solution comprising Compound 1 and succinic acid in EtOAc.

[0436] In certain embodiments, solid forms, for example, succinate salt forms 1 and 2, are substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. of succinate 1 and 2 have X-ray powder diffraction patterns substantially as shown in Figure 22.

[0437] In one embodiment, succinate salt forms 1 and 2 have Raman spectra substantially as depicted in Figure 23.

[0438] In certain embodiments, a solid form provided herein, for example, the succinate salt form 1, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. Succinate salt form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 94. In one embodiment, succinate salt form 1 has one or more characteristic X-ray powder diffraction peaks at approximately 5 .86, 8.43, 11.07, 11.79, 12.67, 13.55, 13.69, 14.47, 16.84, 17.38, 17.74, 18.77, 18.97 , 19.22, 20.59, 21.11, 21.33, 21.43, 21.83, 21.90, 22.23, 22.78, 23.74, 23.97, 24.84, 25 .12, 26.29, 27.42, 28.10, 28.20, 28.39, 28.88, 29.35, 29.57, 29.82, 30.88, 31.61, 33.87 , 34.33, 35.36, 39.11 or 39.85° 2θ as depicted in Figure 94. In a specific embodiment, the succinate salt form 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.86, 11.79, 17.74, 18.77, 21.90, 23.74, 26.29, or 31.61°2θ. In another embodiment, the succinate salt form 1 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.86, 11.79, 23.74, 26.29, or 31. 61°2θ. In another embodiment, the succinate salt form 1 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.86, 11.79, 13.69, 21.33, or 23. 74°2θ. In another embodiment, the succinate salt form 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-two three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one or forty-two characteristic X-ray powder diffraction peaks as shown in Table 59.

[0439] In certain embodiments, a solid form provided herein, for example, the succinate salt form 2, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. Succinate salt form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 95. In one embodiment, succinate salt form 2 has one or more characteristic X-ray powder diffraction peaks at approximately 5 .69, 5.90, 6.18, 11.02, 16.48, 17.31, 18.49, 20.99, 22.30, 23.16, 29.01 or 30.85° 2θ as depicted in Figure 950. In a specific embodiment, the succinate salt form 2 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.69, 5.90, 6.18, 11.02, 16.48, 18.49, 20.99 or 30.85° 2θ. In another embodiment, the succinate salt form 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.69, 5.90, 6.18, 18.49, or 20. 99°2θ. In another embodiment, the succinate salt form 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.69, 6.18, 11.02, 18.49, or 20. 99°2θ. In another embodiment, the succinate salt form 2 has one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve characteristic X-ray powder diffraction peaks as shown in Table 60.

5.21. TOSYLATE SALT OF COMPOUND 1

[0440] In one embodiment, a tosylate salt of Compound 1 is provided herein. In certain embodiments, the tosylate salt has 3 different forms.

[0441] In one embodiment, the tosylate salt is a solid. In one embodiment, the tosylate salt is crystalline.

[0442] In certain embodiments, the tosylate salt is prepared by evaporating a solution comprising Compound 1 and p-toluenesulfonic acid. In one embodiment, the tosylate salt is prepared by evaporating a solution comprising Compound 1 and p-toluenesulfonic acid in ACN, IPA, EtOAc or acetone.

[0443] In one embodiment, tosylate salt form 1 is prepared by evaporating a solution comprising Compound 1 and p-toluenesulfonic acid in ACN. In one embodiment, the tosylate salt form 2 is prepared by evaporating a solution comprising Compound 1 and p-toluenesulfonic acid in MeNO2 or acetone. In one embodiment, tosylate salt form 3 is prepared by evaporating a solution comprising Compound 1 and p-toluenesulfonic acid in EtOAc.

[0444] In certain embodiments, solid forms provided herein, for example, tosylate salt forms 1-3, are substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. Tosylate salt forms 1 to 3 have X-ray powder diffraction patterns substantially as shown in Figure 24.

[0445] In one embodiment, tosylate salt forms 1 to 3 have Raman spectra substantially as depicted in Figure 25.

[0446] In certain embodiments, a solid form provided herein, for example, the tosylate salt form 1, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. Tosylate salt form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 96. In one embodiment, tosylate salt form 1 has one or more characteristic X-ray powder diffraction peaks at approximately 4, 50, 6.22, 8.88, 9.55, 9.67, 12.19, 13.25, 13.89, 14.86, 15.71, 17.14, 17.73, 18.29, 18.63, 19.45, 19.90, 21.06, 21.71, 22.64, 23.12, 23.88, 24.27, 25.43, 25.84, 26.06, 26, 37, 27.71, 28.45, 28.82, 29.20, 30.62, 31.45, 33.81, 34.89 or 35.38° 2θ as depicted in Figure 96. In a specific embodiment, the Tosylate salt form 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 6.22, 8.88, 12.19, 13.89, 17 .14, 19.45, 21.71 or 22.64° 2θ. In another embodiment, the tosylate salt form 1 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 6.22, 8.88, 13.89, 19.45, or 21. 71°2θ. In another embodiment, the tosylate salt form 1 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 6.22, 8.88, 12.19, 13.89 or 21. 71°2θ. In another embodiment, the tosylate salt form 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-two three, thirty-four or thirty-five characteristic X-ray powder diffraction peaks as shown in Table 61.

[0447] In certain embodiments, a solid form provided herein, for example, the tosylate salt form 2, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. Tosylate salt form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 97. In one embodiment, tosylate salt form 2 has one or more characteristic X-ray powder diffraction peaks at approximately 5. 78, 6.24, 6.48, 7.01, 8.13, 9.79, 11.67, 12.04, 12.60, 14.25, 15.04, 15.57, 16.42, 17.53, 18.13, 18.31, 18.89, 19.55, 19.90, 21.36, 21.61, 21.94, 22.49, 22.74, 23.05, 23, 35, 23.59, 24.36, 24.55, 25.53, 25.78, 26.54, 27.40, 28.07, 28.49, 29.32, 30.44, 32.58, 33.16, 33.62, 35.52 or 36.88° 2θ as depicted in Figure 97. In a specific embodiment, the tosylate salt form 2 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 6.24, 6.48, 8.13, 11.67, 15.04, 18.31, 18.89 or 23.59°2θ. In another embodiment, the tosylate salt form 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 6.24, 8.13, 11.67, 15.04, or 18. 31°2θ. In another embodiment, the tosylate salt form 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.78, 6.24, 6.48, 8.13, or 21. 36°2θ. In another embodiment, the tosylate salt form 2 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-two three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one or forty-two characteristic X-ray powder diffraction peaks as shown in Table 62.

[0448] In certain embodiments, a solid form provided herein, for example, the tosylate salt form 3, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. Tosylate salt form 3 has an X-ray powder diffraction pattern substantially as shown in Figure 98. In one embodiment, tosylate salt form 3 has one or more characteristic X-ray powder diffraction peaks at approximately 5. 59, 7.44, 8.91, 11.22, 13.13, 13.78, 14.05, 14.89, 15.62, 17.78, 18.15, 19.24, 19.70, 20.77, 21.72, 21.96, 22.40, 23.49, 24.97, 25.97, 26.66, 28.92 or 31.46° 2θ as depicted in Figure 98. In a specific embodiment , the tosylate salt form 3 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.59, 11.22, 13.13, 17.78 , 18.15, 20.77, 21.96 or 22.40° 2θ. In another embodiment, the tosylate salt form 3 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 5.59, 11.22, 18.15, 20.77 or 22. 40°2θ. In another embodiment, the tosylate salt form 3 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.59, 7.44, 11.22, 18.15, or 2077° 2θ. In another embodiment, the tosylate salt form 3 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two or twenty-three characteristic X-ray powder diffraction peaks as shown in Table 63.

5.22. COMPOUND 1 MESYLATE SALT

[0449] In one embodiment, a mesylate salt of Compound 1 is provided herein. In certain embodiments, the mesylate salt has 2 different forms.

[0450] In one embodiment, the mesylate salt is a solid. In one embodiment, the mesylate salt is crystalline.

[0451] In certain embodiments, the mesylate salt is provided herein prepared by evaporating a solution comprising Compound 1 and methanesulfonic acid. In one embodiment, the mesylate salt is prepared by evaporating a solution comprising Compound 1 and methanesulfonic acid in ACN/IPA, EtOH/IPA, EtOAc or acetone.

[0452] In one embodiment, the mesylate salt form 1 is prepared by evaporating a solution comprising Compound 1 and methanesulfonic acid in ACN/IPA, EtOH/IPA or acetone. In one embodiment, the mesylate salt form 2 is prepared by evaporating a solution comprising Compound 1 and methanesulfonic acid in EtOAc.

[0453] In certain embodiments, solid forms provided herein, for example, mesylate salt forms 1-2, are substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. Mesylate salt forms 1 and 2 have X-ray powder diffraction patterns substantially as shown in Figure 26.

[0454] In one embodiment, mesylate salt forms 1 and 2 have Raman spectra substantially as depicted in Figure 27.

[0455] In certain embodiments, a solid form provided herein, for example, the mesylate salt form 1, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. Mesylate salt form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 99. In one embodiment, mesylate salt form 1 has one or more characteristic X-ray powder diffraction peaks at approximately 5. 78, 7.87, 10.30, 10.71, 11.61, 11.86, 12.39, 13.50, 13.83, 14.17, 15.05, 15.56, 15.80, 16.29, 17.06, 17.49, 17.74, 18.10, 18.30, 18.54, 19.25, 19.89, 20.18, 20.58, 20.98, 21, 56, 21.95, 23.41, 24.22, 24.82, 25.53, 26.08, 26.77, 27.27, 28.17, 28.38, 29.03, 29.31, 29.87, 30.81, 32.02, 32.99, 34.03, 35.01, 35.45, 35.72, 36.33 or 37.65° 2θ as depicted in Figure 99. In a specific embodiment , mesylate salt form 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.78, 10.71, 11.61, 17.49 , 18.10, 18.30, 18.54 or 23.41° 2θ. In another embodiment, the mesylate salt form 1 has one, two, three, four or five characteristic X-ray powder diffraction peaks at approximately 5.78, 10.71, 11.61, 18.10 or 23, 41°2θ. In another embodiment, the mesylate salt form 1 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.78, 7.87, 10.71, 18.10, or 19. 25°2θ. In another embodiment, the mesylate salt form 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-two three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two, forty-three, forty-four, forty-five, forty-e six, forty-seven or forty-eight characteristic X-ray powder diffraction peaks as shown in Table 64.

[0456] In certain embodiments, a solid form provided herein, for example, the mesylate salt form 2, is substantially crystalline, as indicated by, for example, X-ray powder diffraction measurements. Mesylate salt form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 100. In one embodiment, mesylate salt form 2 has one or more characteristic X-ray powder diffraction peaks at approximately 5. 14, 5.26, 10.45, 16.37, 18.36, 20.41, 20.95, 21.59, 21.86, 22.14, 22.63, 23.33, 24.24, 25.76, 26.16, 28.41 or 31.70° 2θ as depicted in Figure 100. In a specific embodiment, the mesylate salt form 2 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.14, 5.26, 10.45, 18.36, 20.41, 20.95, 21.59 or 26.16°2θ. In another embodiment, the mesylate salt form 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.14, 5.26, 10.45, 18.36, or 20. 95°2θ. In another embodiment, the mesylate salt form 2 has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.14, 10.45, 18.36, 20.41, or 20. 95°2θ. In another embodiment, the mesylate salt form 2 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen or seventeen powder diffraction peaks. of characteristic X-rays as shown in Table 65.

5.23. BESYLATE SALT OF COMPOUND 1

[0457] In one embodiment, a besylate salt of Compound 1 is provided herein.

[0458] In one embodiment, the besylate salt is a solid. In one embodiment, the besylate salt is crystalline.

[0459] In certain embodiments, the besylate salt is provided herein prepared by evaporating a solution comprising Compound 1 and benzenesulfonic acid. In one embodiment, the besylate salt is prepared by evaporating a solution comprising Compound 1 and benzenesulfonic acid in MeNO2.

[0460] In certain embodiments, a solid form provided herein, e.g., a besylate salt, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, the besylate salt has an X-ray powder diffraction pattern substantially as shown in Figure 28.

[0461] In one embodiment, a besylate salt has a Raman spectrum substantially as depicted in Figure 29.

[0462] In certain embodiments, a solid form provided herein, e.g., besylate salt, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, the besylate salt has an X-ray powder diffraction pattern substantially as shown in Figure 101. In one embodiment, the besylate salt has one or more characteristic X-ray powder diffraction peaks at approximately 6.29, 7.84, 9.64, 11.32, 12.63, 14.38, 15.89, 16.81, 17.44, 19.09, 19.39, 19.82, 20.31, 20.79, 21.63, 22, 35, 22.82, 23.87, 25.30, 26.12, 27.64, 28.94 or 34.90° 2θ as depicted in Figure 101. In a specific embodiment, the besylate salt has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 6.29, 9.64, 11.32, 14.38, 19.39, 20.79, 23.87 or 27.64°2θ. In another embodiment, the besylate salt has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 6.29, 11.32, 14.38, 19.39, or 23.87°2θ . In another embodiment, the besylate salt has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 6.29, 7.84, 11.32, 14.38, or 20.79°2θ . In another embodiment, the besylate salt has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty and one, twenty-two or twenty-three characteristic X-ray powder diffraction peaks as shown in Table 66.

5.24. COMPOUND 1 FUMARATE SALT

[0463] In one embodiment, a fumarate salt of Compound 1 is provided herein.

[0464] In one embodiment, the fumarate salt is a solid. In one embodiment, the fumarate salt is crystalline. In one embodiment, the fumarate salt is a hemifumarate salt.

[0465] In certain embodiments, the fumarate salt is prepared by evaporating a solution comprising Compound 1 and fumaric acid. In one embodiment, the fumarate salt is prepared by evaporating a solution comprising Compound 1 and fumaric acid in ACN.

[0466] In one embodiment, the stoichiometric ratio between Compound 1 and fumaric acid is about 2:1 in the fumarate salt.

[0467] In certain embodiments, a solid form provided herein, e.g., a fumarate salt, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, the fumarate salt has an X-ray powder diffraction pattern substantially as shown in Figure 28.

[0468] In one embodiment, a fumarate salt has a Raman spectrum substantially as depicted in Figure 29.

[0469] In certain embodiments, a solid form provided herein, e.g., fumarate salt, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, the fumarate salt has an X-ray powder diffraction pattern substantially as shown in Figure 102. In one embodiment, the fumarate salt has one or more characteristic X-ray powder diffraction peaks at approximately 5.97, 8.31, 11.09, 11.92, 12.38, 12.97, 13.53, 14.72, 15.81, 16.66, 18.51, 18.92, 20.94, 21.36, 21.76, 22, 34, 23.33, 24.08, 24.65, 25.58, 26.31, 28.74, 29.20, 29.83, 30.96, 31.72, 34.86 or 36.34° 2θ as depicted in Figure 102. In a specific embodiment, the fumarate salt has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.97, 11.09, 18.92, 21.36, 21.76, 26.31, 28.74 or 31.72°2θ. In another embodiment, the fumarate salt has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.97, 11.09, 21.36, 21.76, or 26.31°2θ . In another embodiment, the fumarate salt has one, two, three, four, or five characteristic X-ray powder diffraction peaks at approximately 5.97, 8.31, 11.09, 20.94, or 24.08°2θ . In another embodiment, the fumarate salt has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty and one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven or twenty-eight characteristic X-ray powder diffraction peaks as shown in Table 67.

6. EXAMPLES

[0470] The following Examples are presented by way of example, not limitation. The following abbreviations are used in the descriptions and examples: ACN: Acetonitrile DSC: Differential Scanning Calorimetry DVS: Dynamic Vapor Sorption EtOAc: Ethyl Acetate EtOH: Ethanol HPLC: High Performance Liquid Chromatography IPA: Isopropanol MeNO2: Nitromethane MeOH: Methanol mp: Melting point MTBE: Methyl tert-butyl ether NMR: Nuclear magnetic resonance RH: Relative humidity SGF: Simulated gastric fluid (without Pepsin) XRPD: X-ray powder diffraction

[0471] Certain compositions comprising Compound A have been prepared and tested for numerous chemical and physical properties. Modifications were then made and subsequent formulations were also tested, until formulations were found that possessed the physical and chemical properties. The following example describes these formulations and their tests.

6.1. FORMULATION A

[0472] Table 1 provides a dosage formulation for a single unit dose of Compound 1 at 100 mg strength (Formulation A). TABLE 1. FORMULATION A *Amount of purified water, USP, dispensed, based on 5% granulation solution.

[0473] The process for preparing Formulation A comprises the steps of:

[0474] a) wash excipients.

[0475] b) weigh API.

[0476] c) prepare granulation binder solution (5%).

[0477] d) prepare 570 g of purified water, USP, by heating it to ~70 °C.

[0478] e) slowly disperse 30 g of HPMC in water while mixing and mix continuously until the material is fully dissolved.

[0479] f) pass Compound 1, Avicel 101, Mannitol 200 and Ac-Di-Sol (Portion 1) through an 18/20 mesh sieve.

[0480] g) load Compound 1, Avicel 101, Mannitol 200 and Ac-Di-Sol (Portion 1) into the KG5 Granulator, equipped with an appropriately sized bowl, and dry mix for 10 minutes.

[0481] h) equip the KG5 with a spray tip and peristaltic tubing sufficient to produce an adequate spray rate that allows consistent application of the granulation binder solution. Add additional water as needed.

[0482] i) moisten the dough material sufficiently to ensure that the granulation appears visually consistent throughout the bowl.

[0483] j) unload the wet mass from the granulator and transfer it to the expansion chamber of the GPCG-1 Fluidized Bed Granulator. Dry until the test end point < 2 Loss on Drying was reached. TABLE 2 DRYING PROCESS *Can be changed as needed to achieve appropriate bed characteristics.

[0484] k) grind the dry granules using Comil®, equipped with an appropriate sieve (0.075 R).

[0485] l) perform bulk/compacted density tests and particle size distribution analysis. After testing has been completed, return the test materials to crushed granulation.

[0486] m) obtain a net weight for the crushed granule.

[0487] n) calculate percentage of yield through crushing.

[0488] o) recalculate and reweigh the extragranular excipients according to the yield in Step n.

[0489] p) pass the Avicel 102 and Ac-Di-Sol (Portion 2) through an 18/20 mesh sieve.

[0490] q) combine the crushed granulation with Avicel 102 and Ac-Di-Sol sieved in a V-casing blender of appropriate size and blend for 100 revolutions (adjust blender speed to achieve desired blending time).

[0491] r) pass the magnesium stearate through a 30 mesh sieve.

[0492] s) add the sieved magnesium stearate to the blender and blend for 50 revolutions (adjust blender speed to achieve desired blend time).

[0493] t) unload the mixture into a suitable container and label it appropriately. Perform bulk/compacted density tests and particle size distribution analysis. After testing has been completed, return the test materials for final blend material.

[0494] u) Adjust Compacta tablet press compression stations using selected tools.

[0495] v) adjust the tablet weight until the following specifications in Table 3 for tablet weights are met. Ensure that initial tablet physical properties are acceptable, (i.e. friability less than 0.3% without capping), before proceeding to compression. Hardness, tablet thickness and disintegration times were measured and documented.

[0496] w) Compress tablets and collect acceptable core tablets in a colored container, double lined with polyethylene bags. TABLE 3

[0497] Friability tests were performed on 10 tablets at the beginning of the compression cycle and on a composite sample of 10 tablets after the batch was completed. The device and method were defined in USP/NF <1216> and in SOP PHARM 0008. Specification - weight loss was less than 0.3% without capping.

[0498] Disintegration time tests were performed on 6 samples at the beginning of the compression cycle and on a 6-tablet composite sample after the batch was completed. The apparatus and method were defined in USP/NF <701> with a disk.

[0499] Hardness tests were carried out on 10 samples taken at the beginning, middle and end of the compression cycle. The hardness of 10 tablets was measured and the average was calculated.

[0500] Thickness tests were performed on a sample of 10 tablets taken at the beginning of the cycle and on 10 tablets of a composite sample after the cycle was completed. The thickness of 10 tablets was measured and an average was calculated.

[0501] Weigh 10 tablets individually at the beginning, in the middle and at the end of the cycle. Record weights to 0.1 mg. Acceptance Criteria: +/- 7% of theoretical tablet weight (350.0 mg). Acceptance limit: 325.5 to 374.5 mg.

[0502] 10 tablets were sampled and weighed together at the beginning, middle and end of the cycle, and an average tablet weight (ATW) was calculated. Record ATW for 0.1 mg. Acceptance Criteria: Average weight of 10 tablets must be within +/- 5% of theory. Average tablet weight (350.0 mg). Acceptance limit: 332.5 to 367.5 mg.

6.2. FORMULATION B

[0503] Table 4 provides a dosage formulation for a single unit dose of Compound 1 at 100 mg strength (Formulation B).

[0504] The process for preparing Formulation B comprises the same steps in preparing Formulation A. TABLE 4. FORMULATION B *Amount of purified water, USP, dispensed, based on 5% granulation solution.

6.3. FORMULATION C

[0505] Table 5 provides a dosage formulation for a single unit dose of Compound 1 at 100 mg strength (Formulation C).

[0506] The process for preparing Formulation C comprises the same steps in preparing Formulation A. TABLE 5. FORMULATION C *Amount of purified water, USP, dispensed, based on 5% granulation solution.

6.4. FORMULATION D

[0507] Table 6 provides a dosage formulation for a single unit dose of Compound 1 at 100 mg strength (Formulation D).

[0508] The process for preparing Formulation D comprises the same steps in preparing Formulation A. TABLE 6. FORMULATION D *Amount of purified water, USP, dispensed, based on 5% granulation solution.

6.5. FORMULATION DEVELOPMENT

[0509] Objective: The objective of this exercise was to provide confirmation of the scalability of the common Compound 1 blend granulation process previously used for the development of the 100 mg dosage form and to evaluate the compression and dosage form coating processes. dosage of 30 mg and 200 mg. The primary purposes of these experiments were to acquire technical knowledge in preparation for subsequent CTM fabrication of all three intensities.

[0510] Development: In order to allow for a range of dosage forms from 30 mg to 200 mg, while producing a common granulation, the following formulation in Table 7 was selected as the basis for this exercise. TABLE 7.

[0511] Based on this 28.57% Compound 1 loading in a common granulation, three distinct dosage forms were prepared, to meet the following specifications in Table 8. TABLE 8.

[0512] The processes and equipment for the wet granulation process are provided in Figure 1.

[0513] Granulation: First, 5% binder solution was prepared comprising 1) heating 2,850 g of purified water, USP to 70 °C; 2) disperse 150 g of Hypromellose 3 tbsp (Methocel K3) in water; and 3) mix until dissolved. Secondly, the intragranular material was sieved through a 20 mesh sieve, which includes Compound 1, microcrystalline cellulose (Avicel 101), mannitol (pearlitol 200) and croscarmellose sodium (Ac-Di-Sol) portion 1. Thirdly, the granulation process was carried out in the 25 liter bowl of the PMA Granulator according to the parameters in Tables 9 and 10. TABLE 9 *Chopper stopped approx. 15 minutes for adding binder. TABLE 10

[0514] The drying process was carried out in FBD O'Hara with a 45 liter bowl according to the parameters in Tables 11, 12 and 13. TABLE 11 TABLE 12 TABLE 13

[0515] After the mixture was sieved with Sieve 075R050 (1.9 mm (0.075”)), the mixture was crushed at 1,400 RPM.

[0516] The amount of extragranular excipients including microcrystalline cellulose (Avicel 102) and croscarmellose sodium (Ac-Di-Sol) portion 2 was adjusted in proportion to the crushed granule yield. Then, the extragranular excipients were sieved with a 20 mesh sieve.

[0517] The crushed material and extragranular excipients were mixed in a 16 Qt V-Casing Mixer for 4 minutes at 30 RPM (120 revolutions).

[0518] Magnesium stearate was sieved with a 30 sieve and then mixed with the crushed material and extragranular excipients in a 16 V-shell mixer for 2 minutes at 30 RPM (60 revolutions).

[0519] Analytical data for the granular material is provided below in Tables 14, 15 and 16. TABLE 14 TABLE 15 TABLE 16

[0520] Before each compression event, a minimum of three compression forces were evaluated to determine which would provide ideal physical tablet characteristics in the Compacta tablet press. The results of this assessment are provided below in Table 17.TABLE 17

[0521] Compound 1 30 mg tablets were prepared on the Compacta BD tablet press with standard 6.35 mm (0.25”) rounded concave flat/flat tool, 7 stations and target friability < 0.3% without cover. Target tablet weights are provided in Table 18.TABLE 18

[0522] Compound 1 100 mg tablets were prepared on the Compacta BD tablet press with a standard 6.35 mm (0.2220”) x 1.45 mm (0.5720'') modified concave flat/flat tool. , 4 seasons and target friability < 0.3 % without covering. Target tablet weights are provided in Table 19.TABLE 19

[0523] Compound 1 200 mg tablets were prepared on the Compacta BD tablet press with standard 6.35 mm (0.6693”) x 1.45 mm (0.3937'') concave flat/flat tool, 4 seasons and target friability < 0.3% without covering. Target tablet weights are provided in Table 20.TABLE 20

[0524] In-process compression test results are provided in Table 21. TABLE 21

[0525] Film Coating:

[0526] Compound 1 30 mg tablets were coated with Opadry yellow (03B12885) in 15% solids coating suspension. The minimum suspension mixing time was 45 minutes. The tablets had about 3% weight gain after coating. The casing collector load was 1,358 g. The coating applicator used was O’Hara Labcoat II w/ 30 cm (12”) collector.

[0527] The film coating was applied to the preheated core tablets in the O'Hara coating collector at a weight gain of approximately 3% as follows (record process data in the Table below at least every 15 minutes) :

[0528] a) Average weight of preheated tablet (from step 5) = 104.4 mg

[0529] b) Desired target weight (3% weight gain) = 6a*1.03) = 107.5 mg

[0530] c) Target supply temperature = 60 °C (can be adjusted to maintain nominal exhaust temp.)

[0531] d) Target airflow (cfm) = 60 to 120

[0532] Atomization air: 0.13 MPa (19 psi); standard air: 0.13 MPa (19 psi);distance from gun: 10 cm (4'')TABLE 22

[0533] e) Record the average weight of tablet coated with Opadry: 107.6mg.

[0534] Compound 1 100 mg tablets were coated with white Opadry (YS-1-18202-A) in 15% solids coating suspension. The minimum suspension mixing time was 45 minutes. The tablets had about 3% weight gain after coating. The liner collector load was 2487 g. The coating applicator used was O’Hara Labcoat II w/ 30 cm (15”) collector.

[0535] The film coating was applied to the preheated core tablets in the O'Hara coating collector at a weight gain of approximately 3% as follows (record process data in the Table below at least every 15 minutes) :

[0536] a) Average weight of preheated tablet (from step 5) = 349.9 mg

[0537] b) Desired target weight (3% weight gain) = 6a*1.03 = 360.4 mg

[0538] c) Target supply temperature = 60 °C (can be adjusted to maintain nominal exhaust temp.)

[0539] d) Target airflow (cfm) = 60 to 120

[0540] Atomization air: 0.13 MPa (20 psi); standard air: 0.13 MPa (20 psi);distance from gun: 10 cm (5'')TABLE 23

[0541] e) Record the average weight of tablet coated with Opadry: 360.5 mg.

[0542] Compound 1 200 mg tablets were coated with brown Opadry (03B16878) in 15% solids coating suspension. The minimum suspension mixing time was 45 minutes. The tablets had about 3% weight gain after coating. The liner collector load was 4252 g. The coating applicator used was O’Hara Labcoat II w/ 30 cm (19”) collector.

[0543] The film coating was applied to the preheated core tablets in the O'Hara coating collector at a weight gain of approximately 3% as follows (record process data in the Table below at least every 15 minutes) :

[0544] a) Average weight of preheated tablet (from step 5) = 698.9 mg

[0545] b) Desired target weight (3% weight gain) = 6a*1.03 = 719.9 mg

[0546] c) Target supply temperature = 60 °C (can be adjusted to maintain nominal exhaust temp.)

[0547] d) Target airflow (cfm) = 60 to 120

[0548] Atomization air: 0.13 MPa (20 psi); standard air: 0.13 MPa (20 psi);distance from gun: 10 cm (5'')TABLE 24

[0549] e) Record the average weight of tablet coated with Opadry: 360.5 mg.

[0550] Figure 2 represents dissolution profiles of Compound 1 tablets in HCl at 0.1 N.

[0551] Figure 3 represents dissolution profiles of Compound 1 tablets in HCl at 0.01 N.

[0552] Figure 4 represents dissolution profiles of Compound 1 tablets in an aqueous solution with pH 4.5.

6.6. Dog PHARMACOKINETIC STUDY PROTOCOL

[0553] A total of 4 male beagle dogs (as close to 10 kg as possible) were assigned to the study. For each phase, all animals were fasted for at least 8 hours before dosing and throughout the first 4 hours of blood sample collection (food was returned 30 minutes after collection of the last blood sample in the collection interval). 4 hours, where applicable). Total fasting time exceeded 24 hours.

[0554] Phase 1: Each animal in Group 1 received a single capsule dose of Compound 1 as depicted in the Table below.

[0555] Phase 2: After a washout of approximately 5 days, each animal in Group 1 will receive a single tablet dose of Compound 1 as depicted in the Table below. TABLE 25 All capsule/tablet formulations were supplied pre-formulated and were used as received. B Blood samples were collected pre-dose and 0.5 (30 min), 1, 2, 4, 8, 12 and 24 hours post-dose, and processed for plasma. TABLE 26 BLOOD COLLECTION PHARMACOKINETICS TABLE 27 ASSESSMENTS BEFORE DEATH

[0556] Figure 5 represents pK data of Compound 1 capsule and tablets in a dog.

6.7. CLINICAL PROTOCOL: A TWO-PART PHASE 1 STUDY TO EVALUATE THE PHARMACOKINETICS AND PHARMACODYNAMICS OF MULTIPLE DOSES OF COMPOUND 1 AND THE EFFECTS OF FOOD AND FORMULATION ON THE PHARMACOKINETICS OF SINGLE DOSE COMPOUND 1 IN HEALTHY INDIVIDUALS PRIMARY OBJECTIVES:

[0557] Part 1: To evaluate the effect of multiple oral doses of Compound 1 on JNK activity after ultraviolet (UV) irradiation of human skin

[0558] Part 2: To evaluate the pharmacokinetics of Compound 1 tablets formulated in the presence of food, and the relative bioavailability of Compound 1 tablets formulated in comparison to the active ingredient capsule (AIC) formulation after a single oral dose.

SECONDARY OBJECTIVES:

[0559] Part 1: To evaluate the safety of single and multiple oral doses of Compound 1.

[0560] Part 2: To evaluate the safety and tolerance of formulated Compound 1 tablets when administered with food.

[0561] Study design: This is a two-part Phase 1 study to evaluate the pharmacokinetics and pharmacodynamics of multiple doses of Compound 1 and the effects of food and formulation on the pharmacokinetics of a single dose of Compound 1 in healthy subjects.

[0562] Part 1: This is an open-label, multi-dose, 3-period fixed sequence study to evaluate the effect of Compound 1 on JNK activity following UV irradiation.

[0563] The study will consist of a scan phase (Day -21 to -2), minimal erythema dose (MED) determination prior to dosing, baseline (Day -1), 3 treatment/assessment periods during the which increasing doses of Compound 1 are administered, and a follow-up visit. There will be no washing between periods.

[0564] On the first day prior to dosing (baseline), and on the 6th day of each dosing period (Days 6, 12 and 18), twice the MED intensity of UV light will be administered to delineated sites on the subject's buttocks . Irradiation at baseline (Day -1) should be administered at approximately the same time as irradiation is scheduled on Days 6, 12, and 18, which is 2 hours post dose. Eight hours after UV irradiation, a skin punch biopsy will be taken from the UV exposure site. The end of confinement will be on Day 19. The follow-up visit will occur 7 to 10 days (i.e., Day 25 to Day 28) after the last dose in Period 3. An early completion (ET) visit will occur 10 days into the period. day of interruption.

[0565] The MED will be determined over 10 days of dosing in Period 1. It is recommended that MED be performed before Day -2 in case MED is not successful on the first attempt. Confinement is not required for MED assessment.

[0566] Sixteen healthy eligible scanned subjects with valid MEDs must report to the study site on Day -1 of Period 1 for baseline assessments (including 2x MED irradiation with biopsy), and to begin confinement.

[0567] Following the programmed entry procedures, a skin test site will be outlined on the individual's upper buttock between the waist line and the natal cleft on the right side. The test site will be a minimum of 3 cm x 3 cm, and will be drawn in ink (using a skin marker) with the individual lying face down. Subjects will receive 2x UV MED irradiation at a site on the buttocks. A baseline skin punch biopsy will be taken from the UV-exposed site 8 hours (+/- 10 minutes) after UV-irradiation.

[0568] On Day 1, after a minimum of 8 hours of fasting, subjects will receive the first dose of study drug at approximately 8 AM:

[0569] All individuals will receive the following doses of Compound 1 in the fixed sequence below:

[0570] Treatment A: 60 mg of Compound 1 as active in the capsule (AIC), QD x 6 days, followed by

[0571] Treatment B: 160 mg of Compound 1 AIC, QD x 6 days, followed by

[0572] Treatment C: 400 mg of Compound 1 AIC, QD x 6 days.

[0573] During each period, subjects may be domiciled at the study site beginning on Day -1 (or as early as Day 2, if 2x Baseline MED is scheduled early on Day -1), and will be unloaded at the Day 19 upon satisfactory safety review and after completion of study-related procedures.

[0574] The study drug (as AIC) will be given orally with approximately 240 ml of still water (at room temperature). The first meal after the morning dose on day 6 of each dosing period will be 4 hours after the dose. On all other dosing days, the next meal/snack may be served after fasting for a minimum of 2 hours after dosing.

[0575] At Baseline (Day -1), Days 6, 12 and 18, skin test sites will be outlined on the subject's upper buttock between the waist line and the natal cleft on the right side. The right side of the buttock will be divided into three (3) different test sites, one site positioned for 2x MED irradiation at Baseline and at each of the 3 periods (Day 6, Day 12 and Day 18). Each test site will be as large as possible (minimum 3 cm x 3 cm). Test site areas will be marked in ink (using a skin marker) with the individual lying face down.

[0576] Subjects will receive 2x MED UV irradiation to a site on the buttock 2 hours (+/- 10 minutes) after study drug administration on Days 6, 12, and 18. Baseline ultraviolet irradiation should be scheduled approximately 2 hours after the planned dosing time for Day 1. It is suggested that the UV exposure sites be in sequential order starting with the far left and moving to the far right (i.e., exposure site 1 for Line Base; and exposure site 4 for Period 3).

[0577] A skin puncture biopsy will be taken from the UV-exposed site 8 hours (+/- 10 minutes) after UV-irradiation. Four biopsies will be taken throughout the study; that is, the baseline and one biopsy per period. Biopsies will be processed into tissue slides by a third party to be designated by Celgene and analyzed by immunohistochemistry (ICH). This outsourced person will be blind to the treatment periods (Baseline and doses).

[0578] Subjects will be released from the clinical site on Day 19 after all scheduled procedures have been completed.

[0579] Adverse event (AE) monitoring, physical examinations, vital signs, electrocardiograms (ECGs), laboratory safety assessment, and wound healing assessment will be performed at specified time points for safety analyses.

[0580] Serial blood samples will be collected at predefined time points (Days 6, 12 and 18: pre-dose, 0.5, 2, 4, 6, 10, 12 and 24 hours post-dose) for analysis of Compound 1 levels. All assessments will be carried out in accordance with the Table of Events and Procedures.

[0581] Procedures (except for change in treatment) will be consistent throughout all 3 periods.

[0582] Activities, environment, food, procedures and programming between treatment periods should be kept as consistent as possible.

[0583] Part 2: Part 2 will be a 3-period open-label randomized crossover study. The study will consist of a scan phase (Day -21 to -2), baseline (Day -1), 3 treatment/analysis periods, and a follow-up telephone call.

[0584] Twelve eligible subjects will enter the study center on Day -1 of Period 1 for baseline analyses. On Day 1 of Period 1, subjects who remain eligible for study participation will be randomly assigned to one of three dosing sequences during which they will receive one of the following dosing regimens:

[0585] Treatment D: 2 x 100 mg of Compound 1 as AIC, single oral dose administered under fasting conditions.

[0586] Treatment E: 1 x 200 mg of Compound 1 (formulated tablet (or tablets)) single oral dose administered under fasting conditions.

[0587] Treatment F: 1 x 200 mg of Compound 1 (formulated tablet (or tablets)) single oral dose administered under fed conditions (standard high-calorie breakfast). TABLE 28: FOOD EFFECT TREATMENT SEQUENCES

[0588] All individuals will fast overnight for at least 10 hours prior to dosing. Subjects receiving Treatments D and E (fasted) will continue to fast for at least 4 hours after dosing.

[0589] For Treatment F, subjects will receive a high-fat (approximately 50% of the total calorie content of the meal) high-calorie (approximately 800 to 1,000 calories) breakfast 30 minutes prior to dosing (based on FDA Center for Drug Evaluation and Research Food Effect Guidance, (FDA, 2002)). The meal should derive approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively. Individuals should consume the entire meal within 30 minutes of serving. Dosing should occur 30 minutes (±5 minutes) after the meal has been served.

[0590] During each study period, subjects will be housed in the study center beginning on Day -1. Subjects will be dismissed from the study center on Day 5 of the last period upon completion of study procedures. Each treatment period will be separated by a washout period of at least 7 but no more than 10 days from the last dose of Compound 1 to the next scheduled dose. Serial blood samples will be collected during each period at pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, 48, 72 and 96 hours post-dose to determine the levels of Compound 1 in plasma.

[0591] If necessary, individuals may leave the clinic after scheduled procedures on the morning of Day 5 of Period 1 and/or 2, and return for the following period. In certain cases, a longer wash may be acceptable if mutually agreed upon.

[0592] Study population. Healthy male and female subjects. Sixteen individuals will be recruited in Part 1. Twelve volunteers will be recruited in Part 2. Individuals can participate in either Part 1 or Part 2 only.

[0593] Duration of Study. Part 1: approximately 7 weeks (including scan). Part 2: approximately 6 weeks (including scan).

[0594] End of Test is defined as either the date of the last individual's last visit to complete the study, or the date of receipt of the last individual's last data point that is requested for primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or Statistical Analysis Plan, whichever is most recent.

[0595] Study Treatments. Compound 1 as AIC (30 mg and 100 mg dose intensities) and formulated tablets (200 mg) will be supplied in bulk containers by Celgene.

[0596] Part 1: Treatment A (60 mg): 2 x 30 mg of Compound 1 as AIC, QD x 6 days; Treatment B (160 mg): 2 x 30 mg + 1 x 100 mg of Compound 1 as AIC, QD x 6 days; Treatment C (400 mg): 4 x 100 mg Compound 1 as AIC, QD x 6 days

[0597] Part 2: Treatment D: 2 x 100 mg of Compound 1 as AIC (200 mg), given QD in the fasted state; Treatment E: Compound 1 as formulated tablets (1 x 200 mg), given QD in the fasted state; Treatment F: Compound 1, as formulated tablets (1 x 200 mg), given QD in the fed state

[0598] Safety Analysis Overview: Safety will be monitored throughout the study. Safety assessments will include adverse event (AE) reporting, PEs, vital signs, 12-lead ECGs, clinical laboratory safety testing (including liver function tests (LFTs), total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)) in addition to standard clinical chemistry tests, hematology and urinalysis tests), review of concomitant medications/procedures, assessment of wound healing, and pregnancy testing for individuals of the same sex feminine.

[0599] All AEs will be monitored and recorded throughout the study from the time the informed consent form (ICF) is signed until the end of the study, and when known to the Investigator within 28 days after the last dose of Compound 1 (and those serious adverse events (SAEs) brought to the attention of the Investigator at any time thereafter that are suspected of being reported to the PI). All concomitant medications and procedures will be reviewed and recorded from the moment the individual signs the ICF until the end of the study. A follow-up visit (Part 1) or follow-up phone call (Part 2) will be scheduled for all subjects. If an individual is removed from the study for any reason, an ET visit will be performed.

[0600] Pharmacokinetic Assessments Overview: In both parts of the study, blood samples will be collected at specified times to determine plasma levels of Compound 1.

[0601] Part 1: Collect blood/plasma on Days 6, 12 and 18: pre-dose, 0.5, 2, 4, 6, 10, 12 and 24 hours after dose;

[0602] Steady-state plasma PK parameters including, without limitation, the following: AUC (area under the plasma concentration-time curve from time zero to tau, where tau is the dosing interval) ; Cmax (maximum observed plasma concentration), Cmin (minimum observed plasma concentration), Tmax (time to Cmax).

[0603] Part 2: Collect blood/plasma at each period: pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, 48, 72 and 96 hours after dose.

[0604] PK parameters at steady state including, without limitation, the following: AUC0-t, (area under the plasma concentration-time curve from time zero to the last quantifiable concentration); AUC- (area under the plasma concentration-time curve from time zero extrapolated to infinity); CL/F (apparent total plasma clearance when dosed orally); Vz/F (apparent total volume of distribution when dosed orally, based on terminal phase); t1/2 (phase-terminal elimination half-life); Cmax (maximum observed plasma concentration); and Tmax (time to Cmax).

[0605] Pharmacodynamic Assessments Overview: Individual Ultraviolet B (UVB) Exposure for MED Determination:

[0606] UVB exposure 10 days from the first dosage in Period 1 consisting of UVB exposure to 6 sites on the left buttock with incrementally increasing UV intensity

[0607] determination of MED approximately 24 hours after UVB exposure

[0608] individual UVB exposure (2x MED):

[0609] at Baseline (Day -1) and on Days 6, 12 and 18: 2x MED UVB exposure to a single site on the upper buttock 2 hours after the dose of Compound 1.

[0610] Biopsy Collection: A punch biopsy (approximately 3 mm in diameter by approximately 0.8 mm in depth) from each test site will be collected at baseline (Day -1), and on Days 6, 12 and 18: eight (8) hours after UVB irradiation (a total of 4 punch biopsies).

[0611] Analysis of biopsy samples: biopsies will be analyzed and phospho-cJun expression will be analyzed by immunohistochemistry (IHC) assays. Other biomarkers such as, but not limited to, c-Jun, can be explored using the same skin biopsies and can be reported separately.

[0612] Phospho-cJun IHC data can be analyzed by an analog classification system or by an integrated automated optical density measurement by trained individuals who are blind to treatments. For Part 1, only phospho-c-Jun IHC data will be subjectively scored on a scale of 0 to 4 based on the intensity and number of epidermal keratinocyte nuclei stained on the tissue section by trained individuals blinded to treatment.

6.8. A TWO-PART PHASE 1 STUDY TO EVALUATE THE PHARMACOKINETICS AND PHARMACODYNAMICS OF MULTIPLE DOSES OF COMPOUND 1 AND THE EFFECTS OF FOOD AND FORMULATION ON THE PHARMACOKINETICS OF SINGLE DOSE OF COMPOUND 1 IN HEALTHY INDIVIDUALS

[0613] Primary Objectives: Part 1: To evaluate the effect of multiple oral doses of Compound 1 on JNK activity after ultraviolet (UV) irradiation of human skin; and Part 2 To evaluate the PK of Compound 1 tablets formulated in the presence of food, and the relative bioavailability of Compound 1 tablets formulated compared to the active ingredient capsule (AIC) formulation after a single oral dose.

[0614] Secondary Objectives: Part 1: To evaluate the safety of single oral dose and multiple oral doses of Compound 1; and Part 2: To evaluate the safety and tolerability of the formulated Compound 1 tablets when administered with food.

INVESTIGATION PLAN

[0615] Model and General Study Plan:

[0616] This was a two-site, two-part Phase 1 study to evaluate the PK and pharmacodynamics (PD) of multiple doses of Compound 1 and the effects of food and formulation on the PK of a single dose of Compound 1 in healthy individuals. Part 1 and Part 2 of the study were conducted at two different sites.

[0617] Part 1:

[0618] Part 1 was an open-label, three-period, multiple-dose, fixed-sequence study to evaluate the effect of Compound 1 on JNK activity following UV irradiation.

[0619] The study consisted of a scan phase (Day -21 to -2), minimal erythema dose determination (MED) prior to dosing, baseline (Day -1), three treatment/assessment periods during which escalating doses of Compound 1 were administered, and a follow-up visit. There was no washing between dosing periods.

[0620] The MED was determined before Day -2 in the event that the MED determination was unsuccessful on the first attempt. Confinement was not required for MED assessment. Sixteen healthy subjects with valid MEDs reported to the study center on Day -1 for baseline assessments (including 2x MED irradiation with biopsy) and to begin confinement.

[0621] On Day 1, after a minimum 8-hour fast, subjects received the first dose of Compound 1. All subjects received the following oral doses of Compound 1 in the fixed sequence below:

[0622] • Treatment A: 60 mg of Compound 1 as AIC, QD x 6 days;

[0623] • Treatment B: 160 mg of Compound 1 as AIC, QD x 6 days; It is

[0624] • Treatment C: 400 mg of Compound 1 as AIC, QD x 6 days.

[0625] There was no washing between treatments. The end of confinement was on Day 19. The follow-up visit occurred 7 to 10 days (i.e., Days 25 to 28) after the last dose in the third treatment period. An early completion (ET) visit occurred 10 days from the day of discontinuation.

[0626] Part 2:

[0627] Part 2 was an open-label randomized crossover study with three periods. The study consisted of a scan phase (Day -21 to -2), baseline (Day -1), three treatment/analysis periods, and a follow-up telephone call.

[0628] Twelve eligible subjects reported to the study center on Day -1 of Period 1 for confinement and baseline assessments. On Day 1 of Period 1, subjects who continued to be eligible for study participation were randomly assigned to one of three dosing sequences (Table 29) during which they received one of the following dosing regimens:

[0629] • Treatment D: 2 x 100 mg of Compound 1 as AIC, single oral dose administered under fasting conditions;

[0630] • Treatment E: 1 x 200 mg formulated tablet of Compound 1, single oral dose administered under fasting conditions; It is

[0631] • Treatment F: 1 x 200 mg formulated tablet of Compound 1, single oral dose administered under fed conditions (standard high-calorie breakfast). TABLE 29: TREATMENT SEQUENCES - PART 2

[0632] All subjects fasted overnight for at least 10 hours before dosing. For Treatment F, subjects received a standard high-calorie breakfast 30 minutes prior to dosing. Dosing occurred 30 minutes (± 5 minutes) after the meal was served.

[0633] Each treatment period was separated by a washout period of 7 to 8 days. Subjects were discharged from the study center on Day 5 of the last period upon completion of study procedures. An end-of-study (EOS) telephone call occurred 7 days after the last dose in the third period.

DISCUSSION OF THE STUDY MODEL, INCLUDING CHOICE OF CONTROL GROUP

[0634] Part 1:

[0635] This is a fixed sequence multiple treatment (from high dose to high dose) model to evaluate the effect of Compound 1 on JNK inhibition in human skin. Three dose levels of Compound 1 were explored to obtain an exposure response relationship. A fixed sequence allowed efficient conduct of the test. Although there was no washout between treatments, effects of persistence of PD and PK residues were not anticipated on Day 6 of each treatment period when Compound 1 concentrations are expected to reach a steady state and PK and PD are assessed. . The confusional time factor with the fixed sequence model was limited to the PK and PD perspectives. As such, this fixed sequence model allowed for adequate assessment of the study objectives.

[0636] The study was open label to the investigators, subjects and sponsor; however, it was blinded to third parties processing and analyzing skin biopsy samples.

[0637] Each treatment was QD for 6 days. It was anticipated that steady-state exposure would be reached on Day 6.

[0638] Ultraviolet exposure occurred at baseline and 2 hours post dose on Day 6 of each treatment, which was the anticipated Compound 1 Tmax at steady state. The UV dose was 2x MED UVB, which has been shown to activate JNK. A skin biopsy was taken 8 hours after UV exposure, as this is the time when cJun phosphorylation reached a plateau. A total of four skin biopsies were taken, one at baseline and one on every sixth day of each treatment period.

[0639] The 2x MED UV exposure and skin biopsy procedures were well tolerated by healthy individuals.

[0640] Part 2:

[0641] This was a randomized single-dose three-way crossover model to evaluate the relative bioavailability and food effect of Compound 1. A single formulated 200 mg Compound 1 tablet administered under fasting conditions (Treatment E) was evaluated for relative bioavailability of 2 x 100 mg of Compound 1 as AIC (Treatment D). The effect of food was explored by comparing the 200 mg Compound 1 formulated tablet administered under fasting conditions (Treatment E) and the 200 mg Compound 1 formulated tablet administered under fed conditions (Treatment F).

STUDY POPULATION SELECTION INCLUSION CRITERIA

[0642] Subjects must meet all of the following criteria to be eligible for study participation:

[0643] 1. Must have understood and voluntarily signed a written informed consent document (ICD) before any study-related assessments/procedures are performed.

[0644] 2. Must have the ability to communicate with the investigator and understand and adhere to the study visit schedule and other protocol requirements.

[0645] 3. They must be male or female*, aged 18 to 65 (inclusive) at the time of signing the ICD.

[0646] * A woman of childbearing potential (WCBP) needs to be compliant with an ongoing pregnancy test during the course of the study and at the end of the study. This applies even if the individual has practiced true abstinence from heterosexual contact. A WCBP was a sexually mature woman who had not undergone a hysterectomy or who had not yet entered the postmenopausal period naturally for at least 24 consecutive months (i.e., who had menstruated at any time in the preceding 24 consecutive months).

[0647] a. Women must have committed to true abstinence** from heterosexual contact (which needs to be reviewed monthly) or have agreed to use, and be able to comply with, two highly effective contraceptive methods without interruption 28 days prior to starting study drug , during study therapy (including dose interruptions), and for at least 28 days after stopping study drug.

[0648] b. Women of non-childbearing potential must have been surgically sterilized at least 6 months prior to the scan (hysterectomy or bilateral tubal ligation) or be postmenopausal (defined as 24 months without menstruation prior to the scan and on a follicle-stimulating hormone in plasma > 40 IU/l on scan). Documentation was required in cases of tubal ligation.

[0649] 4. Men must have practiced true abstinence** or have agreed to use a condom (a latex condom was recommended) during sexual contact with a pregnant woman or WCBP while on study drug, or while participating in this study , during dose interruptions and for at least 28 days after stopping study drug, even if the subject has successfully undergone a vasectomy.

[0650] ** True abstinence was acceptable when this was in line with the individual's preferred and usual lifestyle (periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and removal was an unacceptable contraceptive method) .

[0651] 5. They must have a body mass index (BMI = weight (kg)/(height (m)2) between 18 and 33 kg/m2 (inclusive).

[0652] 6. Must be healthy as determined by the investigator based on medical history, PE, clinical laboratory test results, vital signs, and 12-variant ECGs.

[0653] a. They must be afebrile (febrile was defined as > 38°C or 100.3°F).

[0654] b. They need to have systolic blood pressure in the range of 80 to 140 mmHg, diastolic blood pressure in the range of 40 to 90 mmHg and pulse rate in the range of 40 to 110 beats per minute.

[0655] c. They must have a QT interval corrected for heart rate using Fridericia's formula value < 430 ms for males and < 450 ms for females. An ECG may be repeated up to three times to determine an individual's eligibility.

[0656] 7. Additional criteria for Part 1 only:

[0657] a. They need to have a Fitzpatrick I or II skin type.

[0658] b. Must have a valid MED obtained 10 days prior to dosing.

EXCLUSION CRITERIA

[0659] The presence of any of the following excludes an individual from participation in the study:

[0660] 1. Have a history (i.e., within 3 years) of any clinically significant neurological, gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, endocrine, hematological, dermatological, psychological, or other major disorders.

[0661] 2. Have any condition, including the presence of laboratory abnormalities, that would place the individual at unacceptable risk if the individual participated in the study or impaired the ability to interpret study data.

[0662] 3. Have used any prescribed systemic or topical medication, including vaccines, 30 days before the first dose.

[0663] 4. Have used any non-prescription systemic or topical medication (including herbal medicines) 14 days prior to first dose administration (with the exception of vitamin/mineral supplements).

[0664] 5. Have used any metabolic enzyme inhibitor or inducer (i.e. cytochrome P450 [CYP] 3A inducer or inhibitor or St. John's wort) 30 days before administration of the first dose.

[0665] a. “Cytochrome P450 Drug Interaction Table” from Indiana University was used to determine inhibitors and/or inducers of CYP3A4.

[0666] 6. Have any surgical or medical condition that possibly affects drug absorption, distribution, metabolism and excretion (e.g. bariatric procedure).

[0667] a. Appendectomy and cholecystectomy were acceptable.

[0668] 7. Blood or plasma donated 8 weeks before administration of the first dose.

[0669] 8. Have a history of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual (DSM)) 2 years prior to dosing or a positive drug scan test that reflects illicit drug use.

[0670] 9. Have a history of alcohol abuse (as defined by the current version of the DSM) 2 years prior to dosing or positive alcohol screen.

[0671] 10. Known to have serum hepatitis, known to be a carrier of hepatitis B surface antigen or hepatitis C antibody, or have a positive test result for the presence of human immunodeficiency virus antibodies on scan.

[0672] 11. Exposed to an investigational drug (new chemical entity) 30 days preceding administration of the first dose or five half-lives of that investigational drug, if known (whichever is longer).

[0673] 12. Have smoked more than 10 cigarettes per day or equivalent in other tobacco products (self-reported).

[0674] 13. Have a history of allergies to multiple drugs (i.e., two or more).

[0675] Additional exclusion criteria for individuals in Part 1 only:

[0676] 1. Being unable to evaluate the skin in and around test sites due to sunburn, tans, uneven skin tone, tattoos, scars, excess hair, numerous freckles or any other disfigurement.

[0677] 2. Have used any cream or lotion (i.e., containing sun protection factor (SPF)) on the test area (i.e., buttocks) 7 days prior to the start of the study (Day 1).

[0678] 3. Have participated in testing for irrigation or sensitization or any test involving UV exposures in the test area 4 weeks prior to the start of the study.

[0679] 4. Have participated in another study requiring biopsy (in the planned test area) within the last 2 months.

[0680] 5. Have a history of wound healing or blood clotting abnormalities.

[0681] 6. Have a history of keloid formation or hypertrophic scarring following skin injury.

[0682] 7. Have a history of severe reactions from exposure to sunlight.

[0683] 8. Have a history of allergy to lidocaine or another similar local anesthetic.

[0684] 9. Have a history of allergy to epinephrine.

REMOVAL OF INDIVIDUALS FROM THERAPY OR EVALUATION

[0685] The following events were considered sufficient reasons to remove an individual from the investigational product and/or the study:

[0686] • Adverse event;

[0687] • Removal by the individual;

[0688] • Death;

[0689] • Lost to follow-up; It is

[0690] • Protocol violation.

[0691] The reason for removal was recorded in the original documents and case record form (CRF).

[0692] The decision to remove an individual remained the responsibility of the treating physician, which was not delayed or refused by the sponsor. However, before removing an individual, the investigator could have contacted the medical monitor and forwarded appropriate supporting documents for review and discussion.

[0693] In the event that an individual was removed from the study for any reason, an ET visit was performed. Every effort was made to ensure that procedures scheduled for the follow-up visit were performed at the ET visit.

TREATMENTS TREATMENTS ADMINISTERED

[0694] Part 1:

[0695] All subjects received the following oral doses of Compound 1 as AIC:

[0696] • Days 1 to 6: Treatment A: 60 mg of Compound 1 AIC, QD x 6 days;

[0697] • Days 7 to 12: Treatment B: 160 mg of Compound 1 AIC, QD x 6 days; and

[0698] • Days 13 to 18: Treatment C: 400 mg of Compound 1 AIC, QD x 6 days.

[0699] Treatments were administered in the morning after an overnight fast of at least 8 hours. All doses were administered with 240 ml of room temperature still water. Water was allowed as desired except 1 hour before and 1 hour after drug administration. The first meal after the morning dose on the sixth day of each dosing period was 4 hours after the dose. On all other dosing days, the next meal/snack was served a minimum of 2 hours after dosing. TABLE 30: DOSAGE REGIME-PART 1

[0700] Individuals remained semi-recumbent for at least 2 hours after the dose.

[0701] Part 2:

[0702] On Day 1 of each period, subjects were administered each treatment (D, E or F):

[0703] • Treatment D: 2 x 100 mg of Compound 1 as AIC, single oral dose administered under fasting conditions;

[0704] • Treatment E: 1 x 200 mg of Compound 1 (formulated tablet) single oral dose administered under fasting conditions.

[0705] • Treatment F: 1 x 200 mg of Compound 1 (formulated tablet) single oral dose administered under fed conditions (standard high-calorie breakfast).

[0706] Treatments D and E were administered in the morning after an overnight fast of at least 10 hours. Subjects receiving Treatments D and E (fasted) continued to fast for at least 4 hours after dosing. For Treatment F, subjects received a high-fat (approximately 50% of the total calorie content of the meal) high-calorie (approximately 800 to 1,000 calories) breakfast 30 minutes before dosing. The meal derived approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, and fat, respectively. Subjects consumed the entire meal within 30 minutes of serving. Dosing occurred 30 minutes (±5 minutes) after the meal was served.

[0707] Subjects received two 100 mg tablets of Compound 1 as AIC or one 200 mg tablet depending on the assigned treatment. All doses were administered with 240 ml of room temperature still water. Water was allowed as desired except 1 hour before and 1 hour after drug administration. IDENTITY OF INVESTIGATIONAL PRODUCTS TABLE 31: TEST MATERIALS

METHOD OF ASSIGNING INDIVIDUALS TO TREATMENT GROUPS

[0708] Prior to dosing, individuals were identified by their initials and unique scan number assigned by the clinical site. On the morning of Day 1, Period 1 and prior to dosing, each subject was assigned a unique subject number.

[0709] For Part 2, subjects were randomly assigned to one of three treatment sequences prior to dosing on the morning of Day 1, Period 1 according to a computer-generated randomization code.

DOSE SELECTION IN THE STUDY

[0710] Part 1:

[0711] The doses of Compound 1 were 60, 160, and 400 mg QD x 6 days. Based on available preclinical pharmacology and human PK data, doses were anticipated to provide a range of PD effects including minimal and maximal inhibition of JNK. The dose range also covered the dose (240 mg QD) that yielded AUC comparable to the AUC (23,400 ng^h/ml) in rats in which antifibrotic activity was observed.

[0712] Furthermore, the selected doses of Compound 1 were supported by toxicology studies and human experience. Compound 1 was tested in GLP repeat dose toxicology studies in rats and dogs for 28 days. The AUC in the dog did not indicate an adverse effect level of 81,200 ng^h/ml. This was greater than the AUC observed in humans receiving 480 mg QD at steady state, and doses of Compound 1 up to 480 mg QD x 14 days were well tolerated by healthy subjects.

[0713] Part 2:

[0714] The highest unit strength of the formulated tablet was 200 mg of Compound 1. Tablets with other unit strengths are of the same formulation. The intensities available for the AIC were 10, 30 and 100 mg. Therefore, the bioavailability of a single 200 mg tablet (Treatment E) was tested in comparison to the reference 2 x 100 mg AIC (Treatment D).

[0715] The formulated tablets were planned to be used in future clinical trials; therefore, the food effect evaluated the PK of 200 mg Compound 1 formulated tablet administered under fasting conditions (Treatment E) compared to 200 mg Compound 1 formulated tablet administered under fed conditions (Treatment F).

PHARMACOKINETICS, PHARMACODYNAMICS AND SAFETY VARIABLES PHARMACOKINETIC PARAMETERS PHARMACOKINETIC SAMPLE COLLECTION METHOD AND TIMING

[0716] Part 1:

[0717] Blood samples for plasma PK analysis of Compound 1 were collected at the following time points on Days 6, 12 and 18: pre-dose and 0.5, 2, 4, 6, 10, 12 and 24 hours after dose.

[0718] Part 2:

[0719] Blood samples for plasma PK analysis of Compound 1 were collected at the following time points in all periods: pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 5 , 8, 12, 24, 36, 48, 72 and 96 hours after the dose.

[0720] During Treatment D (Compound 1 AIC, fasting), DBS specimens (by finger lancet) were collected from subjects at each PK time point and were used to measure Compound 1 concentrations in whole blood.

DETERMINATION OF DRUG CONCENTRATION

[0721] Compound 1 concentrations in plasma were measured using a validated liquid chromatography then mass spectrometry (LC-MS/MS) assay. In Part 2, whole blood concentrations of Compound 1 were measured using a validated LC-MS/MS method.

CALCULATION OF PHARMACOKINETICS PARAMETERS

[0722] PK parameters in plasma and whole blood were derived for Compound 1 by non-compartmental analysis. Actual sampling times were used in calculating PK parameters.

[0723] Part 1:

[0724] AUG: AUC from time zero to tau, where tau is the dosing interval.

[0725] Cmax: maximum observed plasma concentration.

[0726] Cmin: minimum observed plasma concentration.

[0727] Tmax: Time to Cmax.

[0728] Part 2:

[0729] AUCt: AUC from time zero to the last quantifiable concentration.

[0730] AUC-: AUC from time zero extrapolated to infinity.

[0731] Cmax: maximum observed plasma concentration.

[0732] Tmax: Time for Cmax.

[0733] CL/F apparent total plasma clearance when dosed orally.

[0734] Vz/F: apparent total volume of distribution when dosed orally.

[0735] t1/2: terminal phase elimination half-life.

PHARMACODYNAMIC PARAMETERS PHARMACODYNAMIC SAMPLE COLLECTION METHOD AND TIMING

[0736] For Part 1, no more than 2 days prior to participation in Period 1 (i.e., Day -2), six unprotected sites on the left buttock were exposed to UVB at incrementally increasing UV intensity, and the MED was determined approximately 24 hours (± 1 hour) after UVB exposure.

[0737] At baseline (Day -1) and on the sixth day of each dosing period (Days 6, 12 and 18), skin test sites were outlined on the subject's upper buttock between the waist line and the natal cleft on right side. The right side of the buttock was divided into four different test sites, one site for 2x MED irradiation at baseline and each of the three dosing periods. Each test site was a minimum of 3 cm x 3 cm. Subjects received 2x MED UV irradiation at baseline (Day -1) at approximately the same time that irradiation was scheduled on Days 6, 12, and 18, which was 2 hours post-dose. Eight hours after UV irradiation (±10 minutes), a punch skin biopsy was taken from the UV exposure site. Biopsies were processed into tissue slides by a third party and analyzed by immunohistochemistry (IHC). This contractor was blind to treatment periods (baseline and doses).

DETERMINATION OF PHARMACODYNAMIC PARAMETERS

[0738] Phospho-c-Jun expression in biopsies was analyzed by IHC. Phospho-c-Jun IHC data were subjectively scored on a scale of 0 to 4 based on the intensity and number of epidermal keratinocyte nuclei stained on the tissue section by trained subjects blinded to treatment. IHC was also analyzed by automated integrated optical density measurement.

STUDY INDIVIDUALS ARRANGEMENT OF INDIVIDUALS

[0739] Overall, 28 subjects participated in this study and 27 subjects completed the study. In Part 1, 15 of 16 subjects completed the study. All 12 subjects who participated and were randomized in Part 2 completed the study. In Part 1, a subject experienced a treatment-emergent adverse event (TEAE) of viral infection that was assessed by the Investigator as not suspected to be related to Compound 1. The viral infection began on Day 10 and resulted in the interruption of study procedures in the Day 11. The individual remained at the site for monitoring until he was released on Day 13 at his request. A summary of the individual's disposition is presented in Table 32. TABLE 32: INDIVIDUAL DISPOSITION AND ANALYSIS POPULATIONS

[0740] N = total number of individuals; PD = pharmacodynamics; PK = pharmacokinetics.

[0741] Note: Percentages for reasons for removal are based on the number of subjects who were prematurely removed from the study. All percentages are based on the number of individuals participating.

PHARMACOKINETICS/PHARMACODYNAMICS EVALUATION ANALYSIS POPULATION

[0742] Pharmacokinetics Population:

[0743] The pharmacokinetic population includes all 28 subjects (16 in Part 1 and 12 in Part 2) in this study who were administered at least one dose of Compound 1. One subject in Part 1 was removed from study procedures on Day 11. Therefore, PK samples were not collected on Days 12 or 18 for this individual.

[0744] Pharmacodynamics Population:

[0745] The PD population includes 15 of the 16 subjects in Part 1 of this study who received all required doses of Compound 1 within a given period, were exposed to 2x MED, and had evaluable biopsies for at least one treatment period ( excluding baseline biopsy). One subject was excluded from the PD population due to the fact that his baseline phospho-c-Jun optical density score was more than four standard deviations (SDs) lower than the mean of the subjects' baseline scores. other individuals. Another subject was removed from the study on Day 11 and therefore had no evaluable biopsies for Day 12 or 18. He was included in the PD population due to the fact that he had Day 6 biopsy data.

PHARMACOKINETICS/PHARMACODYNAMICS RESULTS PHARMACOKINETICS RESULTS

[0746] Plasma and Whole Blood Concentrations for Compound 1

[0747] Profiles of mean plasma concentrations (±SD) versus time for Compound 1 (Part 1 and Part 2) are displayed in Figures 103, 104 and 105, respectively.

[0748] Review of individual concentration-time data indicated that the vast majority of subjects at all dose levels showed quantifiable Compound 1 plasma concentrations up to 96 hours post-dose. Plasma concentrations were highly correlated with whole blood concentration for Compound 1 as shown in Figure 106.

[0749] Summary statistics of plasma pharmacokinetic parameters for Part 1 and Part 2 are presented in Tables 33 and 34, respectively.

[0750] Part 1:

[0751] Compound 1 was rapidly absorbed after a single dose or multiple oral doses at the evaluated dose levels with an average Tmax of approximately 1.0 to 4 hours post dose. After reaching Cmax, Compound 1 began to decline from the plasma in a biexponential manner. The mean terminal half-life of Compound 1 was estimated to be between approximately 14 and 21 hours after multiple doses. The systemic exposure of Compound 1 (AUC-, AUCt, and Cmax) appeared to increase more than proportionally as the dose increased from 60 mg to 400 mg after multiple oral doses. TABLE 33: SUMMARY OF COMPOUND 1 PHARMACOKINETICS PARAMETERS AFTER MULTIPLE ORAL DOSES OF 60, 160 AND 400 MG (QD X 6 DAYS), PART 1

[0752] AUCO-T = area under the plasma concentration versus time curve from time 0 to T (tau), where T is 24 hours (the duration of the dosing interval); Cmax = maximum observed plasma concentration; Cmin = plasma concentration observed 24 hours after the dose; CV = coefficient of variation; N= total number of individuals; Tmax = time until maximum observed plasma concentration.

[0753] a) Tmax is presented as median (minimum, maximum).

[0754] Treatment A: 60 mg of Compound 1 as AIC, QD x 6 days.

[0755] Treatment B: 160 mg of Compound 1 as AIC, QD x 6 days.

[0756] Treatment C: 400 mg of Compound 1 as AIC, QD x 6 days. TABLE 34: SUMMARY OF PHARMACOKINETICS PARAMETERS OF COMPOUND 1 AFTER A SINGLE ORAL DOSE OF 2 X 100 mg CAPSULES OR A 200 mg TABLET UNDER CONDITIONS FED OR FASTING, PART 2

[0757] AUC/ = area under the plasma concentration versus time curve from time zero to infinity; AUCt = area under the plasma concentration versus time curve from time 0 to the last quantifiable concentration; Cmax = maximum observed plasma concentration; CL/F = total apparent plasma clearance; N= total number of individuals; t% = terminal elimination half-life; Tmax = time until maximum observed plasma concentration; Vz/F = total apparent volume of distribution.

[0758] a) Tmax is presented as median (minimum, maximum).

[0759] Treatment D: 2 x 100 mg of Compound 1 as AIC, single oral dose administered under fasting conditions.

[0760] Treatment E: 1 x 200 mg of Compound 1 as a formulated tablet (or tablets), single oral dose administered under fasting conditions

[0761] Treatment F: 1 x 200 mg of Compound 1 as a formulated tablet (or tablets), single oral dose administered under fed conditions

[0762] In Part 2, Compound 1 was administered as a single oral dose of 2 x 100 mg capsules or 200 mg tablet. Under fasting conditions, the tablet achieved an equivalent AUCt and AUC- compared to capsules, but a lower Cmax (~17%) compared to the capsule formulation (Table 34). Tmax was similar after either formulation.

[0763] As shown in Tables 33 and 35, Compound 1 administered as a single oral dose of 200 mg tablet under fasted or fed conditions resulted in equivalent AUCt and AUC- with a slightly higher Cmax (by ~6%) in the fed state compared to the fasted state. The median Tmax of Compound 1 was delayed by 0.87 hour after administration of a single 200 mg tablet of Compound 1 under fed conditions compared to fasted conditions (Table 36).

STATISTICAL ANALYSIS OF PHARMACOKINETICS PARAMETERS

[0764] As shown in Table 35, 90% CIs of the between-treatment geometric mean ratios for AUCt and AUC- were fully contained within the range of 80% to 125%, but the 90% CIs of the between-treatment geometric mean ratios for Cmax were outside the range of 80% to 125%. Statistical analysis further supports that the 200 mg tablet provides equivalent extent of exposure although the peak concentration (Cmax) is ~17% lower. The results also demonstrate that the presence of food has no effect on the PK of the Compound 1 tablet formulation.

[0765] When Compound 1 was administered as a 200 mg tablet or 2 x 100 mg capsules, there was no statistically significant change (p > 0.05) observed.

[0766] When Compound 1 was administered as a tablet with food, a statistically significant (p < 0.05) increase (by 0.87 hour) in median tmax was observed compared to fasting conditions (90% CI of median difference does not contain zero), but this change (a 0.87 hour delay in absorption) is not considered clinically significant.

[0767] AUCo— = area under the plasma concentration-time curve from time 0 extrapolated to infinity; AUCo—t = AUC from time 0 to time t where t is the last measurable time point; Cmax = maximum observed plasma concentration; LS = least squares.

[0768] Treatment D: 2 x 100 mg of Compound 1 as AIC, single oral dose administered under fasting conditions.

[0769] Treatment E: 1 x 200 mg of Compound 1 as a formulated tablet (or tablets), single oral dose administered under fasting conditions

[0770] Treatment F: 1 x 200 mg of Compound 1 as a formulated tablet (or tablets), single oral dose administered under fed conditions

[0771] Least squares (LS) geometric means, ratio (fed/fasted), and 90% confidence intervals (CIs) of the ratio of LS geometric means were from an analysis of variance (ANOVA) model with treatment, period and sequence as fixed effects, and individual nested in sequence as a random effect on natural logarithm-transformed pharmacokinetics.

[0772] The ratio and 90% CI of the ratio were presented as a percentage.

[0773] Coefficient of variation between individuals = square root of (exp(mean square error of ANOVA) - 1) x 100. TABLE 36: TMAX STATISTICAL ANALYSIS (POPULATION PHARMACOKINETICS)

[0774] tmax = time until maximum observed plasma concentration.

[0775] Treatment D: 2 x 100 mg of Compound 1 as AIC, single oral dose administered under fasting conditions.

[0776] Treatment E: 1 x 200 mg of Compound 1 as a formulated tablet (or tablets), single oral dose administered under fasting conditions

[0777] Treatment F: 1 x 200 mg of Compound 1 as a formulated tablet (or tablets), single oral dose administered under fed conditions

[0778] The median, median difference (fed-fasted), and 90% confidence interval of the median difference were from the Hodges-Lehmann estimate.

[0779] The p value was from the Wilcoxon signed rank test.

PHARMACODYNAMICS RESULTS IMMUNOHistochemistry of Phospho c-Jun: Quantitative Analysis

[0780] IHC images of phospho c-Jun were analyzed in Quintiles for integrated optical density of positive nuclear staining using Aperio imaging software (Leica Biosystems). The phospho c-jun score (Optical Density Scale) reflects the percentage of nuclei with '3+' staining intensity (the cutoff for determining positive staining) as determined by the Aperio nuclear phospho c-jun quantitative image analysis algorithm . The baseline percentage of individual integrated optical density by treatment is presented in Figure 107. Although c-jun phospho staining is not decreased from baseline in the 60 mg dose group, there is a 7.5% decrease in the 160 mg dose group (p = 0.18), and a 29.5% decrease in the 400 mg group (p < 0.0001).

[0781] The following are percentages of individuals with a decrease in optical density score compared to baseline values:

[0782] 60 mg dose: 4/14 = 29%

[0783] 160 mg dose: 11/13 = 85%

[0784] 400 mg dose: 13/13 = 100%

Phospho c-Jun IMMUNOHistochemistry: Histopathology Scores

[0785] Phospho c-Jun immunohistochemistry (IHC) images were graded by 2 independent Quintiles pathologists using a grading scale of 0 to 4. The percentage of nuclei positive for epithelial c-Jun was graded as follows:

[0786] 0 = 0% to 19%

[0787] 1 = 20% to 39%

[0788] 2 = 40% to 59%

[0789] 3 = 60% to 79%

[0790] 4 = 80% to 100%.

[0791] Individual median histopathology scores by treatment are presented in Figure 107, and the absolute change from baseline is presented in Figure 108. The change from baseline in median histopathology scores is not significantly affected by treatment. There are nominally more decreases in score (18) than increases (14) across all three treatment groups, and the percentage of subjects showing no change or a decrease in score increases in a dose-dependent manner: 8/15 = 53% in the 60 mg dose group; 10/14 = 71% in the 160 mg dose group and 11/14 = 79% in the 400 mg dose group.

SUMMARY AND CONCLUSIONS OF PHARMACOKINETICS AND PHARMACODYNAMICS PHARMACOKINETICS SUMMARY AND CONCLUSIONS

[0792] The PK of Compound 1 has been well characterized in healthy subjects after administration of a single oral dose of 200 mg under fasting or fed conditions and multiple oral doses of Compound 1 at QD of 60 mg, 160 mg and 400 mg.

[0793] The systemic exposure of Compound 1 (AUCt and Cmax) appeared to increase more proportionally to the dose as the dose was increased from 60 mg to 400 mg after multiple doses.

[0794] Compound 1 was rapidly absorbed and slowly eliminated from plasma with a terminal t1/2 elimination of approximately 20 hours after a single oral dose of 200 mg.

[0795] Under fasting conditions, administration of the 200 mg tablet resulted in an equivalent AUCt and AUC- compared to administration of the 2 x 100 mg capsule, but a lower Cmax (~17%) relative to the capsule formulation .

[0796] Food had no effect on the PK of a single 200 mg oral tablet of Compound 1 in healthy individuals.

[0797] Plasma concentrations of Compound 1 correlated well with whole blood concentrations.

SUMMARY AND CONCLUSIONS OF PHARMACODYNAMICS

[0798] Compound 1 inhibited UVB-induced phospho c-jun expression in the skin in a dose-dependent manner. At the highest tested Compound 1 dose of 400 mg, the increase in UVB-induced phospho c-jun was 29.5%, at the intermediate dose of 160 - 7.5%, and there was no change at the highest 60 mg dose. low (measured by automated quantitative image analysis of integrated optical density).

[0799] Compound 1-associated inhibition of UVB-induced phospho c-jun expression in the skin did not reach significance using the histopathologist classification system. This may be due to limitations of the assay, which uses subjective classification of the intensity and number of epidermal keratinocyte nuclei stained by trained individuals (on a scale of 0 to 4).

SAFETY SUMMARY AND CONCLUSIONS

[0800] Overall, 11 of 28 subjects (39.3%) reported 17 TEAEs.

[0801] No individual experienced severe SAE or TEAE. Most TEAEs were mild in severity. One subject was removed from the study due to a TEAE of viral infection that was judged by the investigator to be not suspected to be related to Compound 1. Overall, in this study, 11 of 28 subjects (39.3%) reported 17 TEAEs. The most common TEAEs in the study were gastrointestinal in nature and included nausea (observed in 4 subjects) and diarrhea (observed in 2 subjects) which were judged by the investigator to be suspected of being related to Compound 1. No clinically significant changes or findings were observed in clinical laboratory assessments, vital sign measurements or ECGs. Overall, there were no significant clinical safety findings during the study as nausea and diarrhea were previously reported in the Compound 1 SAD/MAD study and are manageable with standard of care.

[0802] Multiple doses of Compound 1 were safe and well tolerated when administered as QD of AIC of 60, 160 and 400 mg for 6 days in healthy male subjects. Single doses of 200 mg as tablets formulated in fed and fasted states and AIC in the fasted state were safe and well tolerated in healthy subjects.

DISCUSSION AND GENERAL CONCLUSIONS DISCUSSION

[0803] The primary objectives of the study were:

[0804] evaluate the effect of multiple oral doses of Compound 1 on JNK activity after UV irradiation of human skin

[0805] evaluate the PK of Compound 1 tablets formulated in the presence of food; It is

[0806] evaluate the relative bioavailability of Compound 1 tablets formulated compared to the AIC formulation after a single oral dose.

[0807] The secondary objective was to evaluate the safety and tolerability of single oral doses and multiple oral doses of Compound 1 and formulated Compound 1 tablets when administered with food.

[0808] In Part 1, Compound 1 was administered as multiple oral doses of 60 mg, 160 mg, and 400 mg QD for 6 days to determine steady-state exposure of Compound 1. The steady-state exposure of Compound 1 ( AUCt and Cmax) appeared to increase in a more dose-proportional manner as the dose was increased from 60 mg to 400 mg after multiple doses. Based on the coefficient of variance, intersubject variability for PK parameters was generally in a moderate range.

[0809] In Part 2, Compound 1 was administered as a single oral dose of 200 mg capsule or 200 mg tablet under fasted and fed conditions to determine whether or not the 200 mg tablet achieved comparable exposure to the 200 mg capsule whether or not the food affects the PK of Compound 1.

[0810] The PK of Compound 1 was characterized by rapid absorption with a median Tmax of approximately between 1.95 and 3 hours post dose for all doses. After reaching Cmax, Compound 1 began to decline from the plasma in a biexponential manner. The mean terminal elimination half-life of Compound 1 was estimated to be approximately 20 hours.

[0811] Under fasting conditions, a single 200 mg tablet administration achieved an equivalent AUCt and AUC- relative to 2 x 100 mg capsule administration, but a lower Cmax (~17%) relative to the capsule formulation. Tmax was similar after dosing with either formulation. The results demonstrate that the 200 mg tablet is equivalent in extent of exposure with lower peak exposure of ~17%; This reduction in peak exposure if expected as food often extends the time to Tmax.

[0812] Compound 1 administered as a single oral dose of 200 mg tablet under fasted or fed conditions resulted in equivalent AUCt and AUC- with a slightly higher Cmax (by ~6%) in the fed state compared to the fed state. In fasting. The median tmax of Compound 1 was delayed by 0.87 hour after administration of a single 200 mg tablet of Compound 1 under fed conditions compared to fasted conditions. As a result of the small differences in Cmax and lack of change in AUC exposure, the food is not considered to significantly affect the PK of Compound 1.

[0813] Compound 1 inhibited UVB-induced phospho c-jun in the skin in a dose-dependent manner as measured by quantitative image analysis of phospho c-jun IHC optical density. The percentage of subjects with a decrease from baseline in optical density score increased from 29% in the 60 mg dose group to 85% in the 160 mg dose group and 100% in the 400 mg dose group. Measured as percentage change from baseline in optical density score, Compound 1 significantly decreased UVB-induced phospho c-jun by 29.5% in the skin at a dose of 400 mg, with a non-significant decrease of 7.5% in a dose of 160 mg.

[0814] Compound 1 was safe and well tolerated when administered to healthy subjects as multiple oral doses of 60, 160 or 400 mg AIC QD for 6 days. A single 200 mg oral dose of Compound 1 was safe and well tolerated when administered to healthy subjects in the fasted state as an AIC or a formulated tablet and in the fed state as a formulated tablet.

[0815] No individual experienced severe SAE or TEAE. Most TEAEs were mild in severity. One subject was removed from the study due to a TEAE of viral infection that was judged by the investigator to be not suspected to be related to Compound 1. Overall, in this study, 11 of 28 subjects (39.3%) reported 17 TEAEs. The most common TEAEs in the study were gastrointestinal in nature and included nausea (observed in 4 subjects) and diarrhea (observed in 2 subjects) which were judged by the investigator to be suspected of being related to Compound 1. No clinically significant changes or findings were observed in clinical laboratory assessments, vital sign measurements or ECGs.

CONCLUSIONS PHARMACOKINETIC CONCLUSIONS

[0816] The systemic exposure of Compound 1 (AUCt and Cmax) appeared to increase more proportionally to the dose as the dose was increased from 60 mg to 400 mg after multiple doses.

[0817] Under fasting conditions, administration of a 200 mg tablet resulted in an equivalent AUCt and AUC- compared to administration of a 200 mg capsule although a lower Cmax (~17%) was observed.

[0818] Food had no effect on the PK of a single 200 mg oral tablet of Compound 1 in healthy individuals.

[0819] Plasma concentrations of Compound 1 correlated well with whole blood concentrations of Compound 1.

PHARMACODYNAMIC CONCLUSIONS

[0820] Compound 1 inhibited UVB-induced phospho c-jun expression in the skin in a dose-dependent manner. At the highest tested Compound 1 dose of 400 mg, the increase in UVB-induced phospho c-jun was 29.5%, at the intermediate dose of 160 - 7.5%, and there was no change at the highest 60 mg dose. low (measured by automated quantitative image analysis of integrated optical density).

[0821] Compound 1-associated inhibition of UVB-induced phospho c-jun expression in the skin did not reach significance using the histopathologist classification system. This may be due to limitations of the assay, which uses subjective classification of the intensity and number of epidermal keratinocyte nuclei stained by trained individuals (on a scale of 0 to 4).

SAFETY CONCLUSIONS

[0822] Compound 1 was safe and well tolerated in healthy male subjects when administered as multiple oral doses of 60, 160 and 400 mg AIC QD for 6 days.

[0823] A single 200 mg oral dose of Compound 1 was safe and well tolerated in healthy subjects when administered in the fasted state as an AIC or a formulated tablet and in the fed state as a formulated tablet.

6.9. A PHASE 1B MULTI-CENTER OPEN-LABEL ECALATED DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF MULTIPLE DOSES OF COMPOUND 1 FOR 12 WEEKS IN INDIVIDUALS WITH PULMONARY FIBROSIS

[0824] Primary Objectives: Evaluate the safety and tolerability of Compound 1 in individuals with pulmonary fibrosis.

[0825] Secondary Objectives: To evaluate the pharmacokinetic (PK) profile of Compound 1 from plasma samples in individuals with pulmonary fibrosis.

[0826] Study Design This is an open-label dose-escalation cohort expansion study that will encompass subjects at multiple study sites in the United States of America (USA) and Australia. The study will consist of two treatment arms:

[0827] - Low dose (100 mg) of Compound 1 administered orally once daily (QD) for 12 continuous weeks.

[0828] - High dose (200 mg) of Compound 1 administered orally QD for 12 continuous weeks.

[0829] The high-dose Compound 1 arm will not begin until at least three subjects complete a minimum of 2 weeks of low-dose Compound 1 and the low-dose treatment arm is determined not to meet the discontinuation criteria. study dose escalation.

[0830] Each individual will participate in a Scan Period (up to 4 weeks prior to treatment), a Treatment Phase in the 12th week, and a Follow-up visit in the 4th week. Individuals will be screened for eligibility. Subjects who met all of these inclusion criteria and none of these exclusion criteria in the Scan will return to the study site on Day 1 for analysis and to begin administration of a QD dose of Compound 1, according to the dose level. in which the individual is participating. Three subjects will initially participate to receive a low dose of Compound 1, 100 mg QD, and will be evaluated for all scheduled analyzes over 2 weeks of treatment. Once a total of three subjects have completed the Week 2 visit, a decision to continue the study at the high dose level (200 mg QD) will be determined.

[0831] If the criteria for escalation toward high dose is met, the low dose subjects (100 mg QD) will remain at the low dose and three additional subjects will participate at the high dose level (200 mg QD). A predefined escalation decision tree will be used to determine the subsequent treatment arm if criteria for escalation to high dose are not met. If one of the three subjects in the low dose (100 mg QD) experiences an event that meets the particular subject's dose interruption criteria, another three subjects will participate in the low dose arm. Dose escalation will not occur if two or more of the three subjects meet the particular subject dose interruption criteria. All subjects (low and high dose) will remain on Compound 1 for a total of 12 weeks unless a particular subject experiences an event that meets any of the individual subject discontinuation criteria. Additionally, the dose of Compound 1 may be reduced to the low dose level (100 mg QD) for any particular subject to the high dose level (200 mg QD) who meets any of the individual subject's dose reduction criteria. . If two or more subjects in the high dose arm experience an event that meets individual discontinuation criteria, the 200 mg QD dose arm may be repeated in three additional subjects, or three additional subjects will participate in the high dose level, or the study may be stopped.

[0832] Study visits will occur on Scan, Day 1, and Weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16. Blood and urine samples will be collected at specified times for laboratory analysis clinical safety tests, PK analysis and PD analysis. Safety will be monitored throughout the study.

[0833] In the event that an individual is removed from the study, an early termination visit will be conducted.

[0834] Study Population. The study population will consist of approximately nine to 18 adult male or female subjects at least 18 years of age with pulmonary fibrosis. Specifically, subjects will have a documented usual interstitial pneumonia (UIP) pattern or a nonspecific interstitial pneumonia (NSIP) pattern based on CT scan or a fibrotic NSIP or UIP pattern documented on surgical lung biopsy. The underlying disease may include, but is not limited to, interstitial lung disease associated with connective tissue disease, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), environmental or chemical-related pulmonary fibrosis, or Hermansky-Pudlak syndrome.

[0835] Duration of Study. The study duration for each subject will be up to 20 weeks and includes a 4-week Scan period, a 12-week Treatment period, and a 4-week Follow-up. The total duration of the study, from the first visit of the first subject to the last visit of the last subject, is expected to be approximately 12 months.

[0836] End of Study. The end of the study is defined as either the date of the last visit by the last subject to complete the study, or the date of receipt of the last data point from the last subject that is requested for primary, secondary and/or exploratory analysis, as pre-defined. specified in the protocol and/or statistical analysis plan, whichever is most recent.

[0837] Study Treatments. The study's treatment arms include:

[0838] - Low dose (100 mg) of Compound 1, administered orally QD for 12 weeks.

[0839] - High dose (200 mg) of Compound 1, administered orally QD for 12 weeks.

[0840] The high-dose Compound 1 arm will begin after at least three subjects complete a minimum of 2 weeks of low-dose Compound 1 and the low-dose treatment arm is determined not to meet the escalation discontinuation criteria. study dose.

[0841] Individual Criteria for Subject Exclusion Compound 1 dosing must be stopped for an individual if any of the following individual subject interruption criteria occur:

[0842] - Nausea, vomiting or diarrhea that results in electrolyte abnormalities (sodium, chloride, potassium, and/or creatinine) and/or that requires intravenous hydration.

[0843] - Intestinal intussusception, bowel obstruction, or moderate/severe gastrointestinal bleeding as determined by the Investigator.

[0844] - Any serious adverse event (SAE) considered by the Investigator to be related to Compound 1.

[0845] - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 8 x upper limit of normal (ULN).

[0846] - ALT or AST > 5 x ULN for more than 2 weeks.

[0847] - ALT or AST > 3 x ULN and total bilirubin > 2 x ULN.

[0848] - ALT or AST > 3 x ULN and with the appearance of fatigue, nausea, vomiting, pain or tenderness in the right upper quadrant, fever, rash and/or eosinophilia (>5%).

[0849] - Any other event considered to constitute an unacceptable risk to the individual.

[0850] Individuals who meet individual dose interruption criteria due to an elevation of AST or ALT aminotransferase or bilirubin should not be rechallenged. Rechallenge for any event other than an AST, ALT, or bilirubin elevation may occur at the discretion of the Investigator. Subjects must be rechallenged at the same dose being administered before meeting individual subject discontinuation criteria. However, an individual in the high-dose group may be dose-reduced to 100 mg if the Investigator and Sponsor decide this is in the best interest of the individual.

[0851] Any subject experiencing an event meeting the subject's individual dose interruption criteria that is considered by the Investigator to be related to the administration of Compound 1 will be considered during the dose escalation decision, even if this subject has not completed a total of 2 weeks of dosage.

[0852] Individual Individual Dose Reduction Criteria. Individual subject dose reduction criteria apply to subjects receiving only high-dose Compound 1. Since there is no dose reduction for subjects receiving low-dose Compound 1, low-dose subjects who meet these criteria should be closely monitored, considering dose interruption prior to rechallenge at 100 mg QD (at Investigator's discretion), considering dose interruption or removal from study when and if the event worsens to the point of meeting individual discontinuation criteria of individual.

[0853] In the event that an individual at the 200 mg QD dose experiences an event that meets the individual's dose reduction criteria, the dose may be reduced to 100 mg QD after the individual has recovered from the event. The individual dosage should be reduced if any of the following individual dose reduction criteria occur:

[0854] - ALT hi AST > 3 x ULN that is confirmed by repeat analysis AND does not meet individual discontinuation criteria AND does not show signs of severe liver toxicity. The Investigator should also consider discontinuing confusional medical products and monitoring the individual closely.

[0855] - Any individual who experiences moderate or severe gastrointestinal adverse events (AEs) such as abdominal discomfort, nausea or vomiting can be treated symptomatically (ondansetron, bismuth subsalicylate, 5-HT3, etc.) at the discretion of the Investigator. If the event does not improve after 5 days, the dose will be continued until the event improves, at which time Compound 1 will be tapered to a reduced dose.

[0856] - Any other condition that is considered by the Investigator to be related to Compound 1 and is considered by the Investigator to improve with a dose reduction. The Investigator must notify Celgene in a timely manner of such dose reductions.

[0857] Study Dose Escalation Interruption Criteria. Criteria for stopping escalation from the 100 mg low dose treatment arm to the 200 mg QD high dose arm will be evaluated after at least three subjects have completed a minimum of 2 weeks of low dose Compound 1. High dose doses (200 mg QD) of Compound 1 will only be enrolled if predefined dose escalation criteria are met.

[0858] Safety parameters prior to each dose escalation will include review of relevant AEs, physical examination findings, vital signs, 12-variant electrocardiograms, clinical laboratory safety testing, and concomitant medications/procedures.

[0859] Overview of Pharmacokinetic Assessments. Pharmacokinetic test endpoints by

[0860] - Sparsely collected Compound 1 plasma sample concentrations

[0861] - Sparsely Collected Compound 1 Dried Blood Spot Sample Concentrations

[0862] Population-based PK approach as appropriate for the following (without limitation) parameters:

[0863] - Apparent debug.

[0864] - Apparent central volume of distribution.

[0865] - First order absorption rate.

[0866] - Disease as a covariate can be explored in population PK analysis. The derived PK parameters such as the maximum plasma drug concentration and the area under the concentration curve in the

[0867] plasma time can also be determined based on the population PK model as appropriate.

[0868] Pharmacodynamics Assessments Overview. Blood drawn for PD biomarkers may include, without limitation:

[0869] - Matrix metalloproteinase-7

[0870] - Tenascin C

[0871] Overview of Effectiveness Assessments. Exploratory effectiveness assessments include:

[0872] - Pulmonary function tests that, at a minimum, must include forced vital capacity, forced expiratory volume in 1 second, and lung diffusion capacity.

[0873] - Oxygen saturation by pulse oximetry.

[0874] Security Assessments Overview. Safety will be monitored throughout the study. The safety of Compound 1 will be assessed based on the following assessments:

[0875] - Complete physical examination.

[0876] - Clinical laboratory evaluations (chemistry, hematology, urine analysis with microscopy).

[0877] - Urine pregnancy tests.

[0878] - Levels of miR-122. Requesting reflex assessments of miR-122 levels will be performed for clinical signs of liver toxicity or liver function test abnormality (AST or ALT > 2.5 x ULN) or at the discretion of the Investigator.

[0879] - Serology (hepatitis B surface antigen, hepatitis C virus antibody and human immunodeficiency virus)

[0880] - Liver ultrasound.

[0881] - INR.

[0882] - Vital signs including heart rate, blood pressure, respiratory rate and temperature.

[0883] - 12-variation electrocardiogram.

[0884] - Adverse Events. All AEs will be monitored and recorded throughout the study from the time the informed consent form is signed until 28 days after the last dose of Compound 1. Any AE known to the Investigator at any time thereafter is suspected to be suspected. of being related to the administration of Compound 1 also needs to be reported.

[0885] - Concomitant medications and procedures will be reviewed and recorded from the moment the individual signs the informed consent form until the end of the study.

[0886] Requesting reflex assessments will be performed for clinical signs of liver toxicity or liver function test abnormality (AST or ALT > 2.5 x ULN) or at the discretion of the Investigator. Liver toxicity reflex assessments include repeat clinical laboratory assessments, miR-122, a liver ultrasound, a serology test for hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus, and an international normalized ratio. Additional assessments should be performed at the investigator's discretion based on the individual's signs and symptoms. The Investigator should also consider discontinuing confusional medical products and monitoring the individual closely.

[0887] Security review meetings will occur:

[0888] - Every 4 weeks following the first individual dosed.

[0889] - After three individuals complete the initial 2 weeks of treatment with a low dose of Compound 1.

[0890] - In the event that significant toxicity is observed in any individual as determined by the Investigator.

[0891] Inclusion Criteria. Potential subjects must meet all of the following criteria to participate in the study: 1. Subject > 18 years of age; 2. Documented clinical diagnosis of a fibrotic lung disease supported by at least one of the following: a. usual interstitial pneumonia (UIP) pattern based on computed tomography (CT scan); or b. A pattern of non-specific interstitial pneumonia (NSIP) based on the CT scan; or c. A fibrotic NSIP documented on surgical lung biopsy; or d. A pattern of PIU documented on surgical lung biopsy. The underlying etiology of fibrotic lung disease may be of any cause, including, WITHOUT LIMITATION, any of the following: connective tissue disease-associated interstitial lung disease, idiopathic pulmonary fibrosis (IPF), environmental-related pulmonary fibrosis, or to chemicals, other forms of interstitial pulmonary fibrosis, Hermansky-Pudlak syndrome; 3. must understand and voluntarily sign a written ICF before any study-related procedures are performed; 4. must have the ability to communicate with the Investigator, understand and comply with study requirements, and agree to adhere to restrictions and examination schedules; 5. AST or serum glutamic-oxaloacetic transaminase within normal limits; 6. ALT or serum glutamic-pyruvic transaminase within normal limits; 7. Total bilirubin and INR within normal limits; 8. No clinically significant laboratory test results as determined by the Investigator; 9. Male subjects agree to use barrier contraception NOT made from natural (animal) membrane (e.g., latex or polyurethane condoms are acceptable) when engaging in sexual activity with a female of childbearing potential (FCBP) while on Compound 1 and for at least 28 days after the last dose of study medication. An FCBP is defined as a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or who has not naturally entered the postmenopausal period for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months); 10. All FCBPs must have a negative pregnancy test at Scan and Day 1. Any FCBP entering activity in which conception is possible must use two forms of contraception simultaneously while on Compound 1 and for at least 28 days after taking the last dose of Compound 1: a highly effective form (i.e., hormonal, intrauterine device, tubal ligation, vasectomized partner) and an additional form (latex condom or any non-latex condom NOT made from natural [animal] membrane [e.g. , polyurethane], diaphragm, sponge). If a highly effective form of contraception cannot be used, then two forms of barrier contraception need to be used, i.e. latex condom or any non-latex condom NOT made from natural (animal) membrane [e.g. polyurethane] with any one of the following: sponge with spermicide or diaphragm with spermicide; 11. Female subjects who are postmenopausal (defined as 24 months without menstruation prior to the Scan, with an estradiol level of < 30 pg/ml and an FSH level of > 40 IU/l at the Scan).

[0892] Exclusion Criteria. Potential subjects will be excluded from participation if any of the following occur: 1. Exposed to an investigational drug (new chemical entity) 30 days preceding administration of the first dose of Compound 1 or five half-lives of that investigational drug , if known (whichever is longer); 2 Individuals who are part of the clinical team or family members of the study site team; 3. Sweep FVC < 40% predicted; 4. Scanning DLco < 20% predicted; 5. Any condition other than pulmonary fibrosis that is likely to result in the individual's death or increase the risk of death within a period of signing the ICF; 6. Known clinical diagnosis of pulmonary arterial hypertension that currently requires treatment; 7. Subjects with cystic fibrosis, active aspergillosis, active tuberculosis, or other concomitant respiratory disorder other than pulmonary fibrosis, as determined by the Investigator. Individuals with reactive airway disease, chronic obstructive pulmonary disease, and asthma may be included provided that, in the opinion of the Investigator, fibrosis is the major contributing factor to the individual's respiratory disorder; 8. Use of any cytotoxic agent within 4 weeks of dosing. 9. Be currently administered any targeted therapy for pulmonary fibrosis and not at a stable dose for a duration > 6 weeks prior to the first study dosing (potential subjects should be excluded if a dose increase is planned during the study period); 10. Use of Esbriet® (pirfenidone) or Ofev® (nintedanib) 30 days before the first dose; 11. Be currently administered statins (HMG-CoA reductase inhibitors) and not on a stable dose for a duration > 6 weeks prior to first study dosing (potential subjects should be excluded if a dose increase is planned during the study period ); 12. Be taking medications that are substrates of P-gp, BCRP, OAT3, OATP1B1, OATP1B3 and OCT2 transporters and have a narrow therapeutic index (for example, P-gp substrate digoxin); 13. Use of acetaminophen (paracetamol) at a dosage > 3 grams per day within 2 weeks of the first study dosage; 14. Use of niacin at a dosage > 2 grams/day 2 weeks before the first dose of the study; 15. Any significant medical condition, laboratory abnormality or psychiatric illness that would prevent the individual from participating in the study; 16. History of recurrent bacterial infections (at least three major infections resulting in hospitalization and/or requiring intravenous antibiotic treatment in the last 2 years); 17. History of HIV, HBV or HCV. Individuals treated for HCV who have a prolonged virologic response of 6 months after final HCV treatment may be included; 18. History of active malignancy 5 years prior to signing ICF, excluding skin cancer other than melanoma.

6.10. SALT SCAN 6.10.1 SOLID STATE CHARACTERIZATION OF SALTS

[0893] The physicochemical properties of free base and salts of Compound 1 are summarized in the Physicochemical Property Assessment included crystallinity, melting point, solubility in water and simulated gastric fluid (SGF, without Pepsin), hygroscopicity, physical stability and accelerated solid-state chemistry under stress conditions. The physicochemical properties for the free base and salts of Compound 1 are summarized in Table 38. Among the salts and free base evaluated, the phosphate salt showed better physicochemical properties.

[0894] Details have been presented in the following sections.

[0895] 1H NMR: A portion of the sample was dissolved in dimethyl sulfoxide (DMSO-d6) (containing TMS) and tested using the NMR spectrometer with 32 or 64 scans.

[0896] Elemental Analysis: Elemental analyzes on the salts were performed by Intertek Pharmaceutical Services/QTI.

[0897] Raman: A portion of the sample was placed in a Rigaku zero-bottom XRPD sample holder and analyzed using Raman in reflection mode. The conditions were indicated as follows:

[0898] exposure time: 2 seconds

[0899] accumulations: 2;

[0900] magnitude: 10X; It is

[0901] laser power: 300 mW

[0902] XRPD: A portion of the sample was placed in a Rigaku zero-bottom XRPD sample holder and analyzed using XRPD angle from 3 to 40 degrees 2 theta at a speed of 5 degrees/min with 40 kV and 44 mA.

[0903] Simultaneous TGA/DSC: A portion of the sample was loaded into an aluminum (Al) crucible and tested using the TGA/DSC system at a heating rate of 10°C/min. An empty Al container was used as the blank.

[0904] DSC: A portion of the sample was weighed into an Al sample container, cooled with a perforated Al lid and tested using the Q1000 DSC system at a heating rate of 10°C/min. An empty Al container was used as a reference.

[0905] TGA: A portion of the sample was loaded into an Al sample container and tested using the Q500 TGA system at a heating rate of 10°C/min.

[0906] DVS: A portion of the sample was loaded into a quartz sample holder and tested using the DVS-Advantage system in two continuous adsorption/desorption cycles. The settings are described as follows:

[0907] Solvent: water;

[0908] temperature: 25°C;

[0909] Adsorption/desorption cycle 1: 50 to 95 at 0% RH;

[0910] Adsorption/desorption cycle 2: 0 to 95 to 0% RH;

[0911] Step size: 10% RH; It is

[0912] dm/dt (%/min): 0.001 in 15 min with a minimum of 10 min and a maximum of 180 min.

[0913] PLM: A portion of the sample was placed on a transparent glass slide, dispersed with silicon oil and examined under the microscope with 10x individual and transmitted light.

[0914] Solubility in Water and SGF: A portion of the sample was weighed into a 2 ml transparent HPLC vial. After adding 1 ml of water, the bottle was capped and shaken on an orbital shaker at 300 RPM at room temperature for 24 hours. The sample was removed from the shaker and pH measurement was performed using a calibrated pH meter. Then, a portion of the sample was filtered using 0.2 μm centrifuge tube filter with nylon membrane at 14,000 RPM for 5 min. The filtrate was analyzed using HPLC/UV with appropriate dilution. The filtered solid residues were analyzed using XRPD.

[0915] For solubility in SGF, samples were prepared and analyzed in the same procedures as mentioned above.

6.10.2 SUMMARY OF SALTS

[0916] Salt sweeping was performed on Compound 1 using 13 acidic counterions and a variety of solvents. The crystalline salts obtained were hydrochloride (HCl), sulfate (H2SO4), phosphate (H3PO4), L-tartrate, L-malate, L-lactate, succinate, p-toluenesulfonate (tosylate), methanesulfonate (mesylate), benzenesulfonate (besylate) and fumarate. An amorphous salt was obtained when citric acid was used as the counterion. Multiple forms or polymorphs have been observed for most crystalline salts. The salt sweep results are summarized in Table 37. TABLE 37 SUMMARY OF SALT SCAN RESULTS FOR COMPOUND 1.

[0917] Observations:

[0918] Citrate salts are amorphous.

[0919] Initial recrystallization solvents: A=ACN, B=EtOH, C=EtOAc, D=Acetone.

[0920] Free base: form A (starting material), form D (MeOH solvate). Freebase Forms A, Form B, Form C, and Form G were previously described in US Provisional Patent Application No. 61/933,636, filed January 30, 2014, and US Provisional Patent Application No. 62/025,161 , deposited on July 16, 2014.

[0921] MeOAc=methyl acetate, EtOAc=ethyl acetate, ACN=acetonitrile, EtOH=ethanol, MeOH=methanol, MeNO2=nitromethane, IPA=isopropanol, PsOH=p-toluenesulfonic acid, MsOH=methanesulfonic acid.

[0922] Additional crystalline salts obtained: besylate and fumarate.

[0923] Physicochemical property assessment included crystallinity, melting point, solubility in water and simulated gastric fluid (SGF, without Pepsin), hygroscopicity, accelerated physical and chemical stability in the solid state under stress conditions. The physicochemical properties for the free base and salts of Compound 1 are summarized in Table 38. Among the salts and free base evaluated, the phosphate salt showed better physicochemical properties. TABLE 38 SUMMARY OF PSYCHOCHEMICAL PROPERTIES FOR FREE BASE AND SALTS OF COMPOUND 1.

6.10.3 PREPARATION OF SALTS

[0924] The concentration of 0.12 mol/l was used for all acids except L-aspartic acid. HCl, H2SO4, H3PO4, L-lactic acid, methanesulfonic acid and benzenesulfonic acid were prepared in ACN, L-tartaric acid, L-malic acid, citric acid, succinic acid, p-toluenesulfonic acid and fumaric acid were prepared in MeOH. L-aspartic acid (0.03 mol/l) was prepared in water. Compound 1 (free base) of 604.8 mg was dissolved in methanol/dichloromethane (MeOH/DCM, 1/1 in pre-mixed volume) of 50 ml, resulting in a clear solution with a concentration of 12.1 mg/ml after sonicated for 5 min. This was used for the salt preparations except for besylate and fumarate samples.

[0925] Salt samples were prepared based on a stoichiometric ratio of 1:1.05 between free base and acid. A 1.04 ml aliquot of free base solution (i.e., 0.039 mmol free base) was mixed with 0.342 ml of acid (i.e., 0.041 mmol acid) to obtain a salt sample in a clear glass vial. 2 ml or 4 ml. Four salt samples for each acid were prepared in the same procedure.

[0926] Like the besylate and fumarate samples, Compound 1 (free base) of 33.3 mg was dissolved in 2 ml of MeOH/dichloromethane to generate a 16.7 mg/ml solution. One ml of free base solution was mixed with 0.453 ml of acid to obtain a salt sample, resulting in only one sample for each acid.

[0927] The preparation of the salt samples comprised the steps of:

[0928] 1) cover (for 2 ml vials) or cap (for 4 ml vials) the sample vial containing the Compound 1 solution and shake in an orbital shaker at 150 RPM at room temperature for 2 hours;

[0929] 2) remove cover or lids;

[0930] 3) evaporate the solvent in the sample bottles under nitrogen purge in a fume hood;

[0931] 4) add ACN, EtOH, EtOAc or acetone to 4 sample vials, respectively, corresponding to each acidic counterion based on the form of a solvent for a sample;

[0932] 5) add an acidic counterion;

[0933] 6) cover or cap and shake the sample bottle at 200 RPM at room temperature for 24 hours;

[0934] 7) remove cover and lids;

[0935] 8) evaporate the solvent in the sample bottles under nitrogen purge in a fume hood;

[0936] 9) adding additional solvent in an attempt to generate powder-like solids if no powder-like solids are visually observed upon drying;

[0937] 10) filter the sample using a 0.45 μm nylon membrane centrifuge tube filter at 14,000 RPM for 5 min if powder-like solids are visually observed during drying;

[0938] 11) collect and dry the solids in a closed chamber connected to a residential vacuum for 2 hours; It is

[0939] 12) collect the solids at the end.

[0940] The solids were subjected to analysis using Raman, XRPD, proton NMR (1H NMR), TGA/DSC and/or PLM.

6.10.4 ELEMENTAL ANALYSIS

[0941] The results of the elemental analysis are presented in Table 39. They are in accordance with the theoretical values for the elements tested. TABLE 39 RESULTS OF ELEMENTAL ANALYSIS OF COMPOUND 1 SALTS

[0942] Note: Theoretical calculations for L-tartrate were based on hemi-tartrate dihydrate.

6.10.5 SALT SCAN RESULTS

[0943] As shown in Table 37, crystalline salts were obtained for the acids, HCl, H2SO4, H3PO4, L-tartaric acid, L-lactic acid, L-malic acid, succinic acid, p-toluenesulfonic acid and methanesulfonic acid. An amorphous salt was obtained for citric acid.

[0944] Based on XRPD and Raman data, multiple forms were observed for the salts, except for the H3PO4 salt and the L-tartrate salt. 1H NMR and simultaneous TGA/DSC indicated some forms contained water or organic solvents.

6.10.5.1. HCL SALT OF COMPOUND 1

[0945] In total, 7 different forms of the HCl salt were prepared.

[0946] In summary, seven HCl salt forms were prepared as follows:

[0947] HCl 1 salt form: hydrate, obtained through crystallization in ACN, or suspended in SGF or exposed to moisture;

[0948] HCl 2 salt form: containing water, obtained through crystallization in EtOH/IPA or IPA, converted into hydrate when exposed to moisture (in form 1) or suspended in water (in form 7);

[0949] HCl 3 salt form: obtained through crystallization in EtOAc;

[0950] HCl 4 salt form: obtained through crystallization in acetone;

[0951] HCl salt form 5: obtained by heating form 2 to 180°C, converted into hydrate form 1 when exposed to moisture;

[0952] HCl salt form 6: dehydrated hydrate, obtained by heating form 2 to 220°C, converted into hydrate form 1 when exposed to moisture; It is

[0953] HCl salt form 7: hydrate, obtained by suspending form 1 in water at room temperature.

[0954] XRPD patterns and Raman spectra of HCl salt forms 1 to 4 of Compound 1 are provided in Figures 6 and 7, respectively.

[0955] The HCl 1 salt form had a crystalline XRPD pattern as shown in Figure 75.

[0956] A list of X-ray Diffraction Peaks for the salt form of HCl 1 is provided below in Table 40. TABLE 40. X-RAY DIFFRACTION PEAKS FOR THE SALT FORM OF HCL 1

[0957] The HCl 2 salt form had a crystalline XRPD pattern as shown in Figure 76. A list of X-ray Diffraction Peaks for the HCl 2 salt form is provided below in Table 41. TABLE 41. PEAKS X-RAY DIFFRACTION FOR THE SALT FORM OF HCL 2

[0958] The HCl 3 salt form had a crystalline XRPD pattern as shown in Figure 77.

[0959] A list of X-ray Diffraction Peaks for the salt form of HCl 3 is provided below in Table 42. TABLE 42. X-RAY DIFFRACTION PEAKS FOR THE SALT FORM OF HCL 3

[0960] The HCl 4 salt form had a crystalline XRPD pattern as shown in Figure 78.

[0961] A list of X-ray Diffraction Peaks for the salt form of HCl 4 is provided below in Table 43. TABLE 43. X-RAY DIFFRACTION PEAKS FOR THE SALT FORM OF HCL 4

[0962] The HCl 5 salt form had a crystalline XRPD pattern as shown in Figure 79.

[0963] A list of X-RAY DIFFRACTION PEAKS for the HCl 5 salt form is provided below in Table 44. TABLE 44.

[0964] The HCl 6 salt form had a crystalline XRPD pattern as shown in Figure 80.

[0965] A list of X-ray diffraction peaks for the salt form of HCl 6 is provided below in Table 45. TABLE 45. X-RAY DIFFRACTION PEAKS FOR THE SALT FORM OF HCL 6

[0966] The HCl 7 salt form had a crystalline XRPD pattern as shown in Figure 81.

[0967] A list of X-ray Diffraction Peaks for the salt form of HCl 7 is provided below in Table 46. TABLE 46. X-RAY DIFFRACTION PEAKS FOR THE SALT FORM OF HCL 7

[0968] In the TGA/DSC thermogram of the HCl 2 salt form (Figure 34), 2.82 wt% loss upon heating to 119.9°C in TGA is attributed to the water content in the material. A small endothermic peak at 163.0°C in the DSC thermogram is likely a solid-solid transition followed by melting and decomposition at about 220°C.

[0969] The sorption/desorption of HCl salt form 2 is shown in Figure 41. This demonstrated that the current HCl salt (form 2) was hygroscopic in nature, and probably formed a monohydrate upon water absorption. The water absorption is 4.89% at 40% RH of the Cycle 2 sorption isotherm. This is close to the theoretical water content value (4.79%) for HCl salt monohydrate. It appears that the hydrate is not hygroscopic, but the water leaves quickly when the RH is below 20% even at 25°C. As shown in Figure 42, the XRPD pattern of the sample after DVS is different from that of the starting material.

[0970] The XRPD patterns of the HCl salt of Compound 1 under stress conditions are shown in Figure 55. Compared to that of the starting material, the XRPD pattern of the HCl 2 salt form stored under 80 ° C for two weeks remained unchanged, but the XRPD pattern of HCl salt stored under 80°C/75% RH is different. The results indicated that the current HCl salt is physically stable under dry condition at 80°C, but is not stable under wet condition.

[0971] The HCl 2 salt form was heated in DSC to 180°C at 10°C/min. Raman and XRPD were immediately analyzed for the presence of solid residues at the end of the DSC run when the sample container was unloaded at between 35 to 45°C. Then, the solid waste was stored at 40°C/75% RH for up to 6 days and tested using XRPD.

[0972] The HCl 2 salt form was heated in DSC to 220°C at 10°C/min. Raman and XRPD were immediately analyzed for the presence of solid residues at the end of the DSC run when the sample container was unloaded at between 35 to 45°C. Then, the solid waste was stored at 40°C/75% RH for up to 64 hours and tested using XRPD.

[0973] As indicated by Raman in Figure 56 and XRPD in Figure 57, two new forms of HCl salts were obtained when the HCl 2 salt form was heated to 180°C and 220°C, respectively. They were designated as form 5 for the material heated to 180°C and form 6 for the material heated to 220°C. After being stored at 40°C/75% RH, the two forms showed the same XRPD patterns as that of unheated HCl salt (starting material) stored in the same condition for two weeks. This demonstrated that form 5 and form 6 tend to become hydrates when exposed to moisture at 40°C. This was confirmed by TGA/DSC (Figure 58) that the HCl salt sample stored at 40°C/75% RH for the physical stability test was a hydrate. As indicated by XRPD in Figure 57, the hydrate is different from the solid residue (tentatively assigned as form 7) obtained from the HCl salt solubility test in water.

[0974] Simultaneous TGA/DSC were also conducted in HCl salt (form 2) by heating it to 220°C, cooling back to 25°C and then heating to 280°C. The heating/cooling rate was 10°C/min. The TGA/DSC thermograms were presented in Figure 59. From the first heating process, a weight loss of 2.91% was observed at the TGA up to 131.2°C. No weight loss or other thermal events were observed during the second heating to 210°C, showing that form 6 (HCl salt heated to 220°C) did not contain water. HCl salt form 1 was first obtained through crystallization using ACN (no ACN contained in the sample based on 1H NMR), and was likely the same material as the HCl salt suspended in SGF or exposed to moisture. As shown in Figure 60, form 1 appeared to be a hydrate. Since form 6 did not contain water, but converted to a hydrate when exposed to moisture, it was probably a dehydrated hydrate.

6.10.5.2. H2SO4 SALT OF COMPOUND 1

[0975] H2SO4 salt form 1 was prepared by evaporating a solution comprising Compound 1 and H2SO4 in ACN, IPA or EtOAc. The salt form of H2SO4 2 was prepared by evaporating a solution comprising Compound 1 and H2SO4 in acetone.

[0976] XRPD patterns and Raman spectra of H2SO4 salt forms 1 and 2 of Compound 1 are provided in Figures 8 and 9, respectively.

[0977] The H2SO4 salt form 1 had an XRPD crystalline pattern as shown in Figure 82.

[0978] A list of X-ray Diffraction Peaks for the salt form of H2SO41 is provided below in Table 47. TABLE 47. X-RAY DIFFRACTION PEAKS FOR THE SALT FORM OF H2SO4 1

[0979] The salt form of H2SO4 2 had an XRPD crystalline pattern as shown in Figure 83.

[0980] A list of X-ray Diffraction Peaks for the salt form of H2SO42 is provided below in Table 48. TABLE 48. X-RAY DIFFRACTION PEAKS FOR THE SALT FORM OF H2SO4 2

[0981] In the TGA/DSC thermogram of the H2SO4 salt form 1 (Figure 35), 0.28% weight loss upon heating to 119.9°C in TGA is attributed to the trace amount of water in the material. A small Tg-type event between 86.0°C and 88.4°C on the DSC thermogram was observed and no further investigation was carried out in this study. The TGA thermogram indicated continued weight loss starting at 119.9°C, while DSC indicated that significant melting and decomposition began at about 220°C.

[0982] The sorption/desorption of H2SO4 salt form 1 is shown in Figure 43. This demonstrated that the current H2SO4 salt (form 1) was hygroscopic in nature. As shown in Figure 44, the XRPD pattern of solid waste after DVS testing is different from that of the starting material.

[0983] The XRPD patterns of the H2SO4 salt of Compound 1 under stress conditions are shown in Figure 61. Compared with that of the starting material, the XRPD pattern of the H2SO4 salt stored under 80 ° C for two weeks remained unchanged , but the XRPD pattern of H2SO4 salt stored under 80°C/75% RH is different. The results indicated that the current H2SO4 salt is physically stable under dry condition at 80°C, but is not stable under wet condition. Chemical stability indicated that the H2SO4 salt was stable under stress conditions, therefore, a new form (form 3) of the H2SO4 salt was obtained when it was stored under 80°C/75% RH conditions for two weeks. .

[0984] The salt form of H2SO4 3 had an XRPD crystalline pattern as shown in Figure 84.

[0985] A list of X-ray Diffraction Peaks for the salt form of H2SO4 3 is provided below in Table 49. TABLE 49. X-ray Diffraction Peaks for the salt form of H2SO4 3

6.10.5.3. H3PO4 SALT OF COMPOUND 1

[0986] The H3PO4 salt of Compound 1 was prepared by evaporating a solution comprising Compound 1 and H3PO4 in ACN, EtOH, EtOAc or acetone.

[0987] The XRPD pattern and Raman spectrum of H3PO4 salt of Compound 1 are provided in Figures 10 and Figure 11, respectively.

[0988] The H3PO4 salt had an XRPD crystalline pattern as shown in Figure 85.

[0989] A list of X-ray Diffraction Peaks for H3PO4 salt is provided below in Table 50. TABLE 50 X-ray Diffraction Peaks for H3PO4 salt

[0990] In the TGA/DSC thermogram of the H3PO4 salt 1 (Figure 36), 0.25% by weight loss upon heating at 119.9°C in TGA is attributed to the trace amount of water in the material. TGA results indicated continued weight loss starting from about 169.9°C, while DSC indicated melting and decomposition with an initial temperature of 238.3°C.

[0991] The sorption/desorption of the H3PO4 salt is shown in Figure 45, indicating that the H3PO4 salt is not hygroscopic. As shown in Figure 46, the XRPD pattern of the solid waste after the DVS test remained unchanged from that of the starting material.

[0992] The XRPD patterns of the H3PO4 salt of Compound 1 under stress conditions are shown in Figure 62. Compared to those of the starting material, the XRPD patterns of the H3PO4 salt remained the same as those of the starting material, showing that it was physically stable under 80°C and 80°C/75% RH conditions for two weeks.

6.10.5.4. L-TARTrate SALT OF COMPOUND 1

[0993] The L-tartrate salt of Compound 1 was prepared by evaporating a solution comprising Compound 1 and L-tartaric acid in ACN, EtOH, EtOAc or acetone.

[0994] The XRPD pattern and Raman spectrum of the L-tartrate salt of Compound 1 are provided in Figures 12 and 13, respectively.

[0995] L-tartrate salt form 1 has an XRPD crystalline pattern as shown in Figure 88.

[0996] A list of X-ray Diffraction Peaks for L-tartrate salt form 1 is provided below in Table 51. TABLE 51.

[0997] The salt form of L-tartrate 2 has an XRPD crystalline pattern as shown in Figure 89.

[0998] A list of X-ray Diffraction Peaks for L-tartrate 2 salt form is provided below in Table 52. TABLE 52.

[0999] The L-tartrate salt was a hemi-tartrate dihydrate as indicated by 1H NMR in Figure 14 and TGA/DSC in Figure 15. 1H NMR indicated a stoichiometric ratio of approximately 2:1 between the free base of Compound 1 and L-tartaric acid. TGA/DSC indicated similar weight loss and dissolution event when different solvents were used for recrystallization of L-tartrate salt, which indicated that it was a hydrate.

[01000] In the TGA/DSC thermogram of the L-tartrate salt form (Figure 37), 3.97% weight loss upon heating to 119.9°C in TGA is attributed to the water content in the material. This corresponds to a dehydration event in DSC with an initial temperature of 89.5°C. This showed that the sample was probably a dihydrate with a theoretical value of 4.34% for water content. The dehydrated product melted and decomposed starting at about 201.5°C as evidenced by both TGA and DSC.

[01001] L-tartrate salt sorption/desorption is shown in Figure 47. L-tartrate is a hydrate, but water is partially lost when dried in a vacuum oven during salt preparation. Upon exposure in the sorption test, water is first consumed to meet hydrate formation, therefore hydrated L-tartrate is only slightly hygroscopic. As shown in Figure 49, the XRPD pattern of the solid waste after the DVS test remained unchanged from that of the starting material. The additional DVS study was performed by preheating the L-tartrate salt to 50°C for 3 hours, immediately starting the two-cycle sorption/desorption process (i.e., 0 to 95 to 0 to 95 to 0% of RH). The weight loss of 5.53% was greater than the 3.97% observed in TGA for the starting material, showing that the L-tartrate salt quickly regained water after removal from the vacuum oven. The sorption/desorption isotherms after preheating that were presented in Figure 48 clearly demonstrated that a hydrate formed quickly even at 20% RH. The test reaches 20% RH in less than 2 hours. The sorption of cycle 1 at 20% RH was 4.32%, which corresponds well with the theoretical value of the water content (4.34%) in a hemitartrate dihydrate salt. The water absorption of the hydrate at 80% RH is estimated as 0.81% (i.e., the difference between 20% RH and 80% RH in cycle 1 sorption). Sorption/desorption is reproducible via Cycle 2 sorption/desorption at 25°C. At the end of the DVS test, the solid residues remained in the same XRPD patterns as those of the starting material and solids from the previous DVS test without preheating step.

[01002] As shown in Figure 63, the XRPD patterns of the L-tartrate salt of Compound 1 under stress conditions remained the same as those of the starting material, showing that it was physically stable under 80°C and 80°C/75°C conditions. % RH for two weeks.

[01003] A combination XRD-DSC experiment was performed on the L-tartrate salt by heating the sample at 5°C/min and scanning XRD at 12°/min 2 theta. The data was illustrated in Figure 64. The XRPD pattern (left side) changed between 96.5°C and 131.5°C, corresponding to an endothermic peak observed in DSC (right side). This demonstrated that dehydration occurred within the temperature range, resulting in an anhydrate.

[01004] In order to isolate the L-tartrate salt anhydrate, a portion of L-tartrate salt was heated in DSC at 130°C at 10°C/min. The solid residue was immediately analyzed using XRPD. As shown in Figure 65, the XRPD patterns were identical for the materials before and after heating, implying that the anhydrate quickly recovers moisture to form the hydrate. Therefore, the hydrate is more stable than the anhydrate.

6.10.5.5. L-LACTATE SALT OF COMPOUND 1

[01005] L-lactate salt form 1 was prepared by evaporating a solution comprising Compound 1 and L-lactic acid in hexane. L-lactate salt form 2 was prepared by evaporating a solution comprising Compound 1 and L-lactic acid in EtOAc.

[01006] The XRPD pattern and Raman spectrum of the L-lactate salt of Compound 1 are provided in Figures 16 and 17, respectively.

[01007] L-lactate salt form 1 has an XRPD crystalline pattern as shown in Figure 86.

[01008] A list of X-ray diffraction peaks for L-lactate salt form 1 is provided below in Table 53. TABLE 53. X-RAY DIFFRACTION PEAKS FOR L-LACTATE SALT FORM 1

[01009] L-lactate salt form 2 has an XRPD crystalline pattern as shown in Figure 87.

[01010] A list of X-ray diffraction peaks for L-lactate salt form 2 is provided below in Table 54. TABLE 54. X-RAY DIFFRACTION PEAKS FOR L-LACTATE SALT FORM 2

[01011] In the TGA/DSC thermogram of L-lactate salt form 2 (Figure 39), continued weight loss upon heating was observed as a result of TGA starting from about 76.5°C. The total weight loss of 1.74% upon heating to 119.9°C was attributed to the water content in the sample. An endothermic peak with an initial temperature of 145.3°C in the DSC curve was associated with significant weight loss in the same temperature range as the TGA curve, showing salt decomposition, which was confirmed by additional experiments.

[01012] The sorption/desorption of the L-lactate salt form 2 is shown in Figure 52, indicating that the L-lactate salt is moderately hygroscopic. As shown in Figure 53, the XRPD pattern of the solid waste after the DVS test is the same as that of the starting material.

[01013] As shown in Figure 67, the XRPD patterns of the L-lactate 2 salt form of Compound 1 under stress conditions were different from those of the starting material, implying that it was not physically stable under 80°C and 80°C /75% RH conditions for two weeks.

6.10.5.6. L-MALATE SALT OF COMPOUND 1

[01014] L-malate salt form 1 was prepared by evaporating a solution comprising Compound 1 and L-malic acid in ACN. The salt form of L-malate 2 was prepared by evaporating a solution comprising Compound 1 and L-malic acid in MeNO2. L-malate salt form 3 was prepared by evaporating a solution comprising Compound 1 and L-malic acid in EtOAc. L-malate salt form 4 was prepared by evaporating a solution comprising Compound 1 and L-malic acid in IPA. 1H NMR of the L-malate salt indicated that the stoichiometry was approximately 1:1 between the free Compound 1 base and L-malic acid.

[01015] The XRPD pattern and Raman spectrum of the L-malate salt of Compound 1 are provided in Figures 18 and 19, respectively.

[01016] L-malate salt form 1 has an XRPD crystalline pattern as shown in Figure 90.

[01017] A list of X-ray diffraction peaks for L-malate salt form 1 is provided below in Table 55. TABLE 55.

[01018] The salt form of L-malate 2 has an XRPD crystalline pattern as shown in Figure 91.

[01019] A list of X-ray diffraction peaks for L-malate 2 salt form is provided below in Table 56. TABLE 56.

[01020] The salt form of L-malate 3 has an XRPD crystalline pattern as shown in Figure 92.

[01021] A list of X-ray diffraction peaks for L-malate 3 salt form is provided below in Table 57. TABLE 57.

[01022] The salt form of L-malate 4 has an XRPD crystalline pattern as shown in Figure 93.

[01023] A list of X-ray diffraction peaks for L-malate salt form 4 is provided below in Table 58. TABLE 58.

[01024] In the TGA/DSC thermogram of the L-malate 2 salt form (Figure 38), 1.21 wt% loss upon heating to 94.8°C in TGA is attributed to the water content in the material. Multiple endothermic events were observed in DSC results. The first with an initial temperature of 100.8°C was probably a solid-solid transition. The second was followed by a large third, which corresponds to the temperature range with continuous and significant weight loss in TGA, implying that melting and decomposition occurred.

[01025] The sorption/desorption of L-malate salt form 2 is shown in Figure 50, indicating that L-malate salt is a hygroscopic material. As shown in Figure 51, the XRPD pattern of solid waste after DVS testing is different from that of the starting material.

[01026] As shown in Figure 66, the XRPD patterns of the L-malate salt of Compound 1 under stress conditions were different from those of the starting material, showing that it was not physically stable under 80°C and 80°C/stress conditions. 75% RH for two weeks.

6.10.5.7. CITRATE SALT OF COMPOUND 1

[01027] The citrate salt of Compound 1 was prepared by evaporating a solution comprising Compound 1 and citric acid in MTBE, MeNO2, Hexane or MeOAc. The XRPD patterns in Figure 20 and the Raman spectra in Figure 21 of the citrate salt showed that the citrate salt was amorphous. 1H NMR of the citrate salt indicated that the stoichiometry was approximately 1:1 between the free base of Compound 1 and citric acid.

6.10.5.8. COMPOUND 1 SUCCINATE SALT

[01028] Succinate salt form 1 was prepared by evaporating a solution comprising Compound 1 and succinic acid in ACN or EtOH. Succinate salt form 2 was prepared by evaporating a solution comprising Compound 1 and succinic acid in EtOAc. When acetone was used to crystallize the succinate salt, a mixture of succinate salt (form 1) and free base (form B) was obtained.

[01029] XRPD patterns and Raman spectra of succinate salt forms 1-2 are provided in Figures 22 and 23, respectively.

[01030] Succinate salt form 1 had a crystalline XRPD pattern as shown in Figure 94.

[01031] A list of X-ray diffraction peaks for the succinate salt form 1 is provided below in Table 59. TABLE 59.

[01032] Succinate salt form 2 had a crystalline XRPD pattern as shown in Figure 95.

[01033] A list of X-ray diffraction peaks for the succinate salt form 2 is provided below in Table 60. TABLE 60.

6.10.5.9. TOSYLATE SALT OF COMPOUND 1

[01034] Tosylate salt form 1 was prepared by evaporating a solution comprising Compound 1 and p-toluenesulfonic acid in ACN. Tosylate salt form 2 was prepared by evaporating a solution comprising Compound 1 and p-toluenesulfonic acid in MeNO2 or acetone. Tosylate salt form 3 was prepared by evaporating a solution comprising Compound 1 and p-toluenesulfonic acid in EtOAc.

[01035] XRPD patterns and Raman spectra of tosylate salt forms 1 to 3 are provided in Figures 24 and 25, respectively.

[01036] Tosylate salt form 1 had a crystalline XRPD pattern as shown in Figure 96.

[01037] A list of X-ray diffraction peaks for tosylate salt form 1 is provided below in Table 61. TABLE 61. X-RAY DIFFRACTION PEAKS FOR TOSYLATE SALT FORM 1

[01038] Tosylate salt form 2 had a crystalline XRPD pattern as shown in Figure 97.

[01039] A list of X-ray diffraction peaks for tosylate salt form 2 is provided below in Table 62. TABLE 62. X-RAY DIFFRACTION PEAKS FOR TOSYLATE SALT FORM 2

[01040] Tosylate salt form 3 had a crystalline XRPD pattern as shown in Figure 98.

[01041] A list of X-ray diffraction peaks for tosylate salt form 3 is provided below in Table 63. TABLE 63. X-RAY DIFFRACTION PEAKS FOR TOSYLATE SALT FORM 3

6.10.5.10. COMPOUND 1 MESYLATE SALT

[01042] Mesylate salt form 1 was prepared by evaporating a solution comprising Compound 1 and methanesulfonic acid in ACN/IPA, EtOH/IPA or acetone. Mesylate salt form 2 was prepared by evaporating a solution comprising Compound 1 and p-methanesulfonic acid in EtOAc.

[01043] XRPD patterns and Raman spectra of mesylate salt forms 1-2 are provided in Figures 26 and 27, respectively.

[01044] Mesylate salt form 1 had a crystalline XRPD pattern as shown in Figure 99. A list of X-ray Diffraction Peaks for mesylate salt form 1 is provided below in Table 64. TABLE 64. PEAKS X-RAY DIFFRACTION TO MESYLATE SALT FORM 1

[01045] Mesylate salt form 2 had a crystalline XRPD pattern as shown in Figure 100.

[01046] A list of X-ray diffraction peaks for the mesylate salt form 2 is provided below in Table 65. TABLE 65.

6.10.5.11. BESYLATE SALT AND FUMARATE SALT OF COMPOUND 1

[01047] Only one sample was prepared for each acid, respectively. Both salts were crystal clear. The fumarate salt of Compound 1 was prepared by evaporating a solution comprising Compound 1 and fumaric acid in ACN. The besylate salt of Compound 1 was prepared by evaporating a solution comprising Compound 1 and benzenesulfonic acid in MeNO2. The 1H NMR spectrum of the fumarate salt indicated that the fumarate salt was probably a hemifumarate, that is, the stoichiometry between free base and fumaric acid was 2:1.

[01048] The XRPD patterns and Raman spectra of the besylate salt and the fumarate salt of compound 1 were presented in Figures 28 and 29, respectively.

[01049] The besylate salt had an XRPD crystalline pattern as shown in Figure 101.

[01050] A list of X-ray diffraction peaks for besylate salt is provided below in Table 66. TABLE 66. X-RAY DIFFRACTION PEAKS FOR BESYLATE SALT

[01051] The fumarate salt had an XRPD crystalline pattern as shown in Figure 102.

[01052] A list of X-ray diffraction peaks for fumarate salt is provided below in Table 67. TABLE 67. X-RAY DIFFRACTION PEAKS FOR FUMARATE SALT

6.10.6 SALT SCALE INCREASE RESULTS

[01053] The crystalline salt forms observed in the scanning study, i.e., HCl (form 2), H2SO4 (form 1), H3PO4 (form 1), L-tartrate (form 1, hemi-tartrate hydrate), L -malate (form 2) and L-lactate (form 2), were successfully scaled up and characterized together with the free base.

[01054] The acid concentrations were different from those used in the salt sweep experiments. The amounts of Compound 1 and acids used for salt scaling were summarized in Table 68. TABLE 68 SALT SCALING OF COMPOUND 1

[01055] The free base of Compound 1 was weighed and dissolved in MeOH/DCM, then mixed with the acid counterion solution based on the specified molar ratio in a 40 ml clear glass vial. The vial was then capped and shaken at 200 RPM at room temperature for 2 hours. Then, the lid was removed and the vial was stored in a fume hood to dry under nitrogen purge. The recrystallization solvent was then added to the sample to generate a suspension sample. All salts were prepared in the same procedure. The final 6 ml of recrystallization solvents were added to the samples as follows:

[01056] IPA to HCl salt sample;

[01057] IPA to the H2SO4 salt sample;

[01058] EtOAc to the H3PO4 salt sample;

[01059] Acetone to L-tartrate salt sample;

[01060] Nitromethane and 1 ml acetone to the L-malate salt sample; and

[01061] n-Hexane to the L-lactate salt sample.

[01062] Furthermore, the L-malate sample and the L-lactate sample were seeded with crystalline sample obtained during salt scanning using the corresponding counterion, respectively.

[01063] All samples in the recrystallization solvents were stirred with stir bars at room temperature for approximately 3 days. They were filtered using centrifuge tube filters with 0.2 μm nylon membrane at 14,000 RPM for 5 minutes, respectively. The solids were covered and dried in a vacuum oven at room temperature for 2 days. Both the HCl salt and the L-malate salt were further dried in a vacuum oven at 60°C for one day after 1H NMR tests indicated that they contained a small amount of recrystallization solvents. The H2SO4 salt was again slurried in-Hexane and recovered through filtration and drying in a vacuum oven at 60°C overnight.

[01064] Ultimately, both the salts and the free base were stored in closed vials at room temperature prior to analysis using a variety of solid state characterization techniques. The compounds used were free base (form A), HCl salt (form 2), H2SO4 salt (form 1), H3PO4 salt (form 1), L-tartrate salt (form 1), L-malate salt (form 2) and L-lactate salt (form 2).

6.10.7 SOLID STATE STABILITY

[01065] Physical Stability: A portion of the sample was loaded into a 4 ml clear glass vial. Four samples were prepared for each salt. The (opened) vials were stored under 4 different stress conditions, respectively. The stress conditions were 40°C, 40°C/75% RH, 80°C and 80°C/75% RH. Temperature was controlled using ovens and 75% RH was controlled using saturated sodium chloride solution in water. At the week 2 time point, samples stored at 80°C and 80°C/75% RH were removed for analysis using XRPD.

[01066] Chemical Stability: Approximately 1 mg of Compound 1 was accurately weighed into a 4 ml clear glass vial. Six vials were prepared for each salt. Two samples were stored in the refrigerator. The other four samples in open vials were stored under 4 stress conditions, respectively. At the week 2 time point, samples stored at 80°C and 80°C/75% RH were removed, dissolved in solvent, and analyzed using HPLC with UV detection after appropriate dilution. A set of samples stored in the refrigerator was used to prepare the stock and standard solutions. The HPLC method was presented in Table 69. TABLE 69 HPLC METHOD

[01067] As shown in Table 70, the remaining percentages for free base and salts were within %100±2, except for the L-malate salt, showing that the free base and salts were chemically stable under 80°C and 80° Under conditions of 75% RH for two weeks, except for the L-malate salt. The chromatograms are presented in Figures 68, 69, 70, 71, 72, 73 and 74, respectively. Although extra peaks were observed for salt, except for free base and L-malate salt, the peak area percentage was <0.1%. Similarly for L-malate salt, significant degradations occurred, therefore it was not chemically stable under stress conditions. TABLE 70 REMAINING PERCENTAGE OF FREE BASE AND SALTS OF COMPOUND 1 UNDER STRESS CONDITIONS

6.10.8 CONCLUSIONS

[01068] Crystalline salts were obtained from 11 of 13 acidic counterions used in this study. All salts exhibited higher solubility than the free base in water. Except for the L-malate salt, all salts and free base were chemically stable under 80°C and 80°C/75% RH for two weeks. Compound 1 (free base), H3PO4 salt and L-tartrate salt were physically stable under stress conditions. HCl salt and H2SO4 salt were stable under 80°C condition, but not under 80°C/75% RH. L-lactate salt was not physically stable under stress conditions. L-malate salt was neither physically nor chemically stable under stress conditions. Compound 1 (free base), H3PO4 salt and L-tartrate salt (hydrate) were not hygroscopic. L-lactate salt was moderately hygroscopic and other salts were hygroscopic.

[01069] Numerous references have been cited, their disclosures are incorporated into this document by way of reference in their entirety.

Claims (5)

1. Crystalline salt of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, characterized by the fact that it is a hydrochloride salt, a sulfate salt, a phosphate salt, an L-tartrate salt or an L-lactate salt; wherein the hydrochloride salt comprises X-ray diffraction peaks at 5.5, 7.5, 9.0, 9.7, 11.2 and 13.1 ± 0.2 2θ; or wherein the hydrochloride salt comprises X-ray diffraction peaks at 5.4, 7.9, 9.2, 9.5, 11.9, 12.4 and 12.6 ± 0.2 2θ; or wherein the hydrochloride salt comprises X-ray diffraction peaks at approximately 5.7, 9.5, 9.8, 11.3 and 13.2 ± 0.2 2θ; or wherein the hydrochloride salt comprises X-ray diffraction peaks at approximately 5.6, 5.7, 7.5, 9.3, 9.8, 11.4 and 13.8 ± 0.2 2θ; and wherein the sulfate salt comprises X-ray diffraction peaks at 5.4, 5.7, 10.7, 14.8 and 16.2 ± 0.2 2θ; or wherein the sulfate salt comprises X-ray diffraction peaks at 5.6, 5.7, 15.2, 16.1, 17.9 and 18.6 ± 0.2 2θ; or wherein the sulfate salt comprises X-ray diffraction peaks at 5.6, 11.2, 15.1, 17.7 and 22.4 ± 0.2 2θ; and wherein the phosphate salt comprises X-ray diffraction peaks at 5.6, 5.7, 11.3, 15.3, 16.1, 16.4 and 16.9 ± 0.2 2θ; and wherein the L-tartrate salt comprises X-ray diffraction peaks at 6.0, 9.4, 12.1, 13.7, 14.6, 15.2 and 16.2 ± 0.2 2θ; or wherein the L-tartrate salt comprises X-ray diffraction peaks at 5.0, 6.3, 6.5, 9.7, 12.5, 12.6 and 16.5 ± 0.2 2θ; and wherein the L-lactate salt comprises X-ray diffraction peaks at 5.8, 7.9, 9.6, 9.8, 10.0 and 13.7 ± 0.2 2θ; or wherein the L-lactate salt comprises X-ray diffraction peaks at 9.7, 10.2, 12.1, 12.7, 13.3, 13.5, 17.0 and 17.5 ± 0 ,2 2θ. 2. Pharmaceutical composition, characterized by the fact that it comprises a crystalline salt defined in claim 1 and one or more pharmaceutically acceptable excipients or carriers. 3. Pharmaceutical composition according to claim 2, characterized by the fact that it is a tablet. 4. Use of a crystalline salt defined in claim 1 or a pharmaceutical composition defined in claim 2 or 3, characterized in that it is to prepare a medicament to treat or prevent a disease or disorder treatable or preventable by inhibiting a JNK pathway, wherein the disease or disorder is selected from the group consisting of interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection, and lupus. 5. Use according to claim 4, characterized in that said disease or disorder is a fibrotic liver disorder, diabetes or a metabolic syndrome leading to fibrotic liver disorders.