Crystalline forms of an NLRP3 modulator

Abstract

Described herein are crystalline forms of 2-(6-((R)-hydroxy((R)-1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt or solvate thereof. Also described herein is the preparation of 2-(6-((R)-hydroxy((R)-1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt or solvate thereof, including crystalline forms, and chemical intermediates used in the synthetic processes.

Description

WSGR Docket No. 56756-709.601CRYSTALLINE FORMS OF AN NLRP3 MODULATORCROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No. 63 / 709,314 filed on October 18, 2024 and U.S. Provisional Patent Application No. 63 / 770,247 filed on March 11, 2025, each of which is incorporated herein by reference in its entirety .BACKGROUND

[0002] The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a critical component of the innate immune response and inflammatory process, and its aberrant activity is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis. Current treatments for NLRP3 -related diseases include biologic agents that target IL-1. Small molecule inhibitors of NLRP3 provide an attractive alternative to these biologies, given their potential for improved safety and patient comfort and compliance.SUMMARY OF THE INVENTION

[0003] In one aspect, described herein is a crystalline form of 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt or solvate thereof.

[0004] In one embodiment, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol is a hydrochloride salt and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride is Form 1 having at least one of the following properties:(a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1 ;(b) an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2- Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta;(c) a thermo-gravimetric analysis (TGA) substantially similar to the one set forth in Figure 2;(d) a DSC thermogram substantially similar to the one set forth in Figure 3;(e) a DSC thermogram that shows no melting point before 250°C; orWSGR Docket No. 56756-709.601(f) combinations thereof.

[0005] In another embodiment, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol is a hydrochloride salt and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride is Form 1 with an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 13.3° 2 -Theta, 13.8° 2- Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta.

[0006] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1.

[0007] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta.

[0008] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least eight characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta.

[0009] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta.

[0010] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has a thermo gravimetric analysis (TGA) substantially similar to the one set forth in Figure 2.

[0011] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has a DSC thermogram substantially similar to the one set forth in Figure 3.WSGR Docket No. 56756-709.601

[0012] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has a DSC thermogram that shows no melting point before 250°C.

[0013] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form is characterized as having properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and28.8° 2-Theta; (c) a thermogravimetric analysis (TGA) substantially similar to the one set forth in Figure 2; (d) a DSC thermogram substantially similar to the one set forth in Figure 3; and (e) a DSC thermogram that shows no melting point before 250°C.

[0014] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form is obtained from acetone.

[0015] In some embodiments, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride is an anhydrate.

[0016] In another embodiment, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol is a hydrochloride salt and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride is Form 2 having at least one of the following properties:(a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 4;(b) an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2- Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta;(c) a thermo-gravimetric analysis (TGA) substantially similar to the one set forth in Figure 5;(d) a DSC thermogram substantially similar to the one set forth in Figure 6;(e) a DSC thermogram that shows no melting point before 250°C; or(f) combinations thereof.

[0017] In another embodiment, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol is a hydrochloride salt and theWSGR Docket No. 56756-709.601 crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride is Form 2 with an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 11.6° 2 -Theta, 13.9° 2- Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2- Theta.

[0018] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 4.

[0019] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six characteristic peaks selected from peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta.

[0020] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta.

[0021] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has a thermo gravimetric analysis (TGA) substantially similar to the one set forth in Figure 5.

[0022] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has a DSC thermogram substantially similar to the one set forth in Figure 6.

[0023] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form has a DSC thermogram that shows no melting point before 250°C.

[0024] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the crystalline form is characterized as having properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 4; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-WSGR Docket No. 56756-709.601Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta; (c) a thermogravimetric analysis (TGA) substantially similar to the one set forth in Figure 5; (d) a DSC thermogram substantially similar to the one set forth in Figure 6; and (e) a DSC thermogram that shows no melting point before 250°C.

[0025] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, wherein the crystalline form is obtained from ethanol.

[0026] In some embodiments, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride is an anhydrate.

[0027] In some embodiments is a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, for use in medicine.

[0028] In another aspect, described herein is a pharmaceutical composition comprising a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, and a pharmaceutically acceptable excipient.

[0029] In another aspect, described herein is a method for treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity and gout.

[0030] In another aspect, described herein is a method for treating a liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the liver disease isWSGR Docket No. 56756-709.601 selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis.

[0031] In another aspect, described herein is a method for treating a lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the lung disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and pulmonary idiopathic fibrosis.

[0032] In another aspect, described herein is a method for treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)- 4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)- 4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington’s disease, traumatic brain injury, ischemic stroke and reperfusion, haemorrhagic stroke, epilepsy, and depression.

[0033] In another aspect, described herein is a method for treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammatory bowel disease, Crohn’s disease, and ulcerative colitis.WSGR Docket No. 56756-709.601

[0034] In another aspect, described herein is a method for treating a cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the cardiovascular disease is atherosclerosis or stroke.

[0035] In another aspect, described herein is a process for the preparation of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol(Compound 1), comprising:A) the reaction of compound with the structure:with N-bromosuccinimide, followed by reaction with the compound with the structure:OMewith dicyclohexyl(2',6'-dimethoxy[l,l'-biphenyl]-2-yl)phosphane (SPhos), palladium acetate, and tripotassium phosphate to produce a compound with the structure:B) followed by the reaction of the compounds with the structures:C) the reaction of the compound with the structure:WSGR Docket No. 56756-709.601chlororuthenium(l+);[(lR,2R)-l,2-diphenyl-2-(3- phenylpropylamino)ethyl]-(4-methylphenyl)sulfonylazanide, triethylamine, and formic acid to produce a compound with the structure:D) followed by the reaction of the compound with the structure:hydrochloric acid and N-bromosuccinimide followed by hydrazine hydrate to produce a compound with the structure:E) followed by the reaction of the compound with the structure:boron tribromide to produce 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) having the structure:(Compound 1).WSGR Docket No. 56756-709.601

[0036] In some embodiments, the process further comprises the reaction of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifhioromethyl)phenol (Compound 1) with hydrochloric acid to produce 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifhioromethyl)phenol hydrochloric acid salt (Compound 1, HC1 salt).

[0037] In another aspect, described herein is a process for the preparation of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1):(Compound 1), comprising contacting the compound with the structure:boron tribromide in the presence of a solvent. In some embodiments, the solvent is selected from dichloromethane, 1,2 -dichloroethane, 1,4-dioxane, tetrahydrofuran, dimethoxy ethane, chlorobenzene, and trifluorotoluene. In some embodiments, the solvent is dichloromethane.

[0038] In some embodiments, the compound with the structure:hydrazine hydrate in the presence of a solvent. In some embodiments, the solvent is selected from dimethylformamide, dimethylacetamide (DMA), N-methylpyrrolidone(NMP), 1,4-dioxane, tetrahydrofuran (THF), and 2 -methyltetrahydrofuran. In some embodiments, the solvent is 2- methyltetrahydrofuran.WSGR Docket No. 56756-709.601

[0039] In some embodiments, the compound with the structure:, , phenylpropylamino)ethyl]-(4-methylphenyl)sulfonylazanide, triethylamine, and formic acid in the presence of a solvent. In some embodiments, the solvent is methanol.

[0040] In some embodiments, the compound with the structure:prepared by a process comprising contacting the compounds with the structures:with a base in the presence of a solvent. In some embodiments, the base is n-BuLi. In some embodiments, the solvent is selected from 1,4- dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), 2-methyltetrahydrofuran, and acetonitrile. In some embodiments, the solvent is tetrahydrofuran.

[0041] In some embodiments, the compound with the structure:prepared by a process comprising contacting the compound with the structure:WSGR Docket No. 56756-709.601with N-bromosuccinimide in the presence of a solvent, followed by reaction of the compound with the structure:OMe with dicyclohexyl(2',6'-dimethoxy[l,l '-biphenyl]-2-yl)phosphane (SPhos), palladium acetate, and tripotassium phosphate. In some embodiments, the solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy ethane, dimethylacetamide (DMA), and N-methyl pyrrolidone (NMP). In some embodiments, the solvent is tetrahydrofuran.INCORPORATION BY REFERENCE

[0042] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the extent applicable and relevant and to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE FIGURES

[0043] Figure 1. Illustrates an X-ray powder diffraction (XRPD) pattern of crystalline 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride (Compound 1), Form 1.

[0044] Figure 2. Illustrates a thermogravimetric analysis (TGA) thermogram of crystalline 2-(6- ((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol hydrochloride (Compound 1), Form 1.

[0045] Figure 3. Illustrates a differential scanning calorimetry (DSC) thermogram of crystalline 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol hydrochloride (Compound 1), Form 1.

[0046] Figure 4. Illustrates an X-ray powder diffraction (XRPD) pattern of crystalline 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride (Compound 1), Form 2.

[0047] Figure 5. Illustrates a thermogravimetric analysis (TGA) thermogram of crystalline 2-(6- ((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol hydrochloride (Compound 1), Form 2.

[0048] Figure 6. Illustrates a differential scanning calorimetry (DSC) thermogram of crystalline 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol hydrochloride (Compound 1), Form 2.WSGR Docket No. 56756-709.601

[0049] Figure 7. Illustrates the Ortep image of the single crystal structure of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride (Compound 1), Form 1.

[0050] Figure 8. Illustrates an X-ray powder diffraction (XRPD) pattern of crystalline 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol free base (Compound 1), Form 1.

[0051] Figure 9. Illustrates a thermogravimetric analysis (TGA) thermogram of crystalline 2-(6- ((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol free base (Compound 1), Form 1.

[0052] Figure 10 Illustrates a differential scanning calorimetry (DSC) thermogram of crystalline 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol free base (Compound 1), Form 1.DETAILED DESCRIPTION OF THE INVENTION

[0053] NLRP3 is an intracellular signaling molecule that senses many pathogen -derived, environmental and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form a large aggregate known as an ASC speck.

[0054] Polymerized ASC associates with the cysteine protease caspase-1 to form a complex termed the inflammasome. This results in the activation of active caspase-1, which cleaves the precursor forms of the proinflammatory cytokines IL-1 P and IL-18 (termed pro-IL-rP and pro-IL- 18 respectively) to thereby activate these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC speck aggregate can also recruit and activate caspase-8, which is able to process pro-IL-rP and pro-IL-18 and trigger apoptotic cell death.

[0055] Caspase-1 cleaves pro-IL-rP and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Through its control of the pyroptotic cell death pathway, caspase- 1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2 resultingin its degradation and allowing the release of IL-1 a. In human cells caspase-1 may also control the processing and secretion of IL-37. A number of other caspase-i substrates such as components of the cytoskeleton and glycolysis pathway may contribute to caspase -I dependent inflammation.WSGR Docket No. 56756-709.601

[0056] NLRP3 -dependent ASC specks are released into the extracellular environment where they can activate caspase- 1, induce processing of caspase- 1 substrates and propagate inflammation. Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathway s to shape the immune response to infection and injury. For example, IL-rP signaling induces the secretion of the pro- inflammatory cytokines IL-6 and TNF. IL-ip and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4 Th 17 cells and by 76 T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also synergize to induce IFN-y production from memory T cells and NK cells driving a Thl response.

[0057] The inherited CAPS diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3, thus defining NLRP3 as a critical component of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of a number of complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout.

[0058] A role for NLRP3 in diseases of the central nervous system is emerging, and lung diseases have also been shown to be influenced by NLRP3. Furthermore, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using NLRP3 KO mice, but there have also been insights into the specific activation of NLRP3 in these diseases. In Type 2 diabetes mellitus (T2D), the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-rPsignaling, resulting in cell death and inflammation.

[0059] Current treatments for NLRP3 -related diseases include biologic agents that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-ip antibody canakinumab and the soluble decoy IL1 receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biologic agents have been used in clinical trials for other IL-ip associated diseases. Small molecule inhibitors of NLRP3 provide an attractive alternative to these biologies, given their potential for improved safety (minimal risk of infection and ease of withdrawal compared to biologies) and patient comfort and compliance.Compound 1

[0060] In one embodiment is 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol. “Compound 1” or “2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol” refers to the compound with the following structure:WSGR Docket No. 56756-709.601

[0061] A wide variety of pharmaceutically acceptable salts are formed from Compound 1 and includes:- acid addition salts formed by reacting Compound 1 with an organic acid, which includes aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc. and include, for example, acetic acid, adipic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, salicylic acid, and the like;- acid addition salts formed by reacting Compound 1 with an inorganic acid, which includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.

[0062] The term “pharmaceutically acceptable salts” in reference to Compound 1 refers to a salt of Compound 1, which does not cause significant irritation to a mammal to which it is administered and does not substantially abrogate the biological activity and properties of the compound.

[0063] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms (solvates). Solvates contain either stoichiometric or non -stoichiometric amounts of a solvent, and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert -butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, and the like. In one aspect, solvates are formed using, but not limited to, Class 3 solvent(s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents”, Q3C(R3), (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of Compound 1, or pharmaceutically acceptable salts thereof, are conveniently prepared or formed during the processes described herein. In some embodiments, solvates of Compound 1 areWSGR Docket No. 56756-709.601 anhydrous. In some embodiments, Compound 1, or pharmaceutically acceptable salts thereof, exist in unsolvated form. In some embodiments, Compound 1, or pharmaceutically acceptable salts thereof, exist in unsolvated form and are anhydrous.

[0064] In yet other embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is prepared in various forms, including but not limited to, amorphous phase, crystalline forms, milled forms and nano-particulate forms. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is amorphous and anhydrous. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline and anhydrous.

[0065] While not intending to be bound by any particular theory, certain solid forms are characterized by physical properties, e.g., stability, solubility and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms suitable for the manufacture of a solid dosage form. Such properties can be determined using particular analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis), as described herein and known in the art.Crystalline Forms

[0066] The identification and selection of a solid form of a pharmaceutical compound are complex, given that a change in solid form may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in processing, formulation, stability, bioavailability, storage, and handling (e.g., shipping), among other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline solids and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e.g., an enhanced dissolution profile, while crystalline solids may be desirable for properties such as, e.g., physical or chemical stability.WSGR Docket No. 56756-709.601

[0067] Whether crystalline or amorphous, solid forms of a pharmaceutical compound include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound or active ingredient in the absence of other compounds. Variety among single-component crystalline materials may potentially arise from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound.

[0068] Notably, it is not possible to predict a priori if crystalline forms of a compound even exist, let alone howto successfully prepare them see, e.g., Braga and Grepioni, 2005, “Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem.Commun. .3635-3645 (with respect to crystal engineering, if instructions are not very precise and / or if other external factors affect the process, the result can be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,” MRS Bulletin 37:875-879 (At present it is not generally possible to computationally predict the number of observable polymorphs of even the simplest molecules); Price, 2004, “The computational prediction of pharmaceutical crystal structures and polymorphism,” Advanced Drug Delivery Reviews 56:301-3 19 (“Price”); and Bernstein, 2004, “Crystal Structure Prediction and Polymorphism, ” ACA Transactions 39 4-23 (a greatdeal still needs to be learned and done before one can state with any degree of confidence the ability to predict a crystal structure, much less polymorphic forms)).

[0069] The variety of possible solid forms creates potential diversity in physical and chemical properties for a given pharmaceutical compound. The discovery and selection of solid forms are of great importance in the development of an effective, stable, and marketable pharmaceutical product.Crystalline Compound 1, Hydrochloride Form 1

[0070] In some embodiments, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) is a hydrochloride acid salt (hydrochloride) and the crystalline form of 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) hydrochloride is Form 1. In some embodiments, crystalline Compound 1 hydrochloride is Form 1 characterized as having at least one of the following properties:(a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1;(b) an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-WSGR Docket No. 56756-709.601Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta;(c) a thermo-gravimetric analysis (TGA) substantially similar to the one set forth in Figure 2;(d) a DSC thermogram substantially similar to the one set forth in Figure 3;(e) a DSC thermogram that shows no melting point before 250°C; or(f) combinations thereof.

[0071] In some embodiments, crystalline Compound 1 , hydrochloride Form 1, is characterized as having at least two of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, hydrochloride Form 1, is characterized as having at least three of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, hydrochloride Form 1, is characterized as having at least four of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, hydrochloride Form 1, is characterized as having properties (a) to (e).

[0072] In some embodiments, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol is a hydrochloride salt and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride is Form 1 with an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2- Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta.

[0073] In some embodiments, crystalline Compound 1, hydrochloride Form 1, has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1. In some embodiments, crystalline Compound 1, hydrochloride Form 1, has an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 13.3° 2 -Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 1, has an X-ray powder diffraction (XRPD) pattern with at least five characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 1, has an X- ray powder diffraction (XRPD) pattern with at least six characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2- Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta. In some embodiments,WSGR Docket No. 56756-709.601 crystalline Compound 1, hydrochloride Form 1, has an X-ray powder diffraction (XRPD) pattern with at least seven characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2- Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 1, has an X-ray powder diffraction (XRPD) pattern with at least eight characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2- Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 1, has an X-ray powder diffraction (XRPD) pattern with at least nine characteristic peaks selected from peaks at about 13.3° 2- Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 1, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5°2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and28.8° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 1, has a thermogravimetric analysis (TGA) thermogram substantially similar to the one set forth in Figure 2. In some embodiments, crystalline Compound 1, hydrochloride Form 1, has a DSC thermogram substantially similar to the one set forth in Figure 3. In some embodiments, crystalline Compound 1, hydrochloride Form 1, has a DSC thermogram that shows no melting point before 250°C. In some embodiments, crystalline Compound 1, hydrochloride Form 1, is non-hygroscopic. In some embodiments, crystalline Compound 1, hydrochloride Form 1, is obtained from acetone. In some embodiments, crystalline Compound 1, hydrochloride Form 1, is solvated. In some embodiments, crystalline Compound 1, hydrochloride Form 1, is unsolvated.

[0074] In another embodiment, crystalline Compound 1, hydrochloride Form 1 is substantially pure. In certain embodiments, the substantially pure crystalline Compound 1, hydrochloride Form 1 is substantially free of other solid forms, e.g., amorphous solid. In certain embodiments, the purity of the substantially pure crystalline Compound 1, hydrochloride Form 1 is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. Crystalline Compound 1, Hydrochloride Form 2

[0075] In some embodiments, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) is a hydrochloric acid salt (hydrochloride) and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) hydrochloride isWSGR Docket No. 56756-709.601Form 2. In some embodiments, crystalline Compound 1 hydrochloride is Form 2 characterized as having at least one of the following properties:(a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 4;(b) an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2- Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta;(c) a thermo-gravimetric analysis (TGA) substantially similar to the one set forth in Figure 5;(d) a DSC thermogram substantially similar to the one set forth in Figure 6;(e) a DSC thermogram that shows no melting point before 250°C; or(f) combinations thereof.

[0076] In some embodiments, crystalline Compound 1 , hydrochloride Form 2, is characterized as having at least two of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, hydrochloride Form 2, is characterized as having at least three of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1 , hydrochloride Form 2, is characterized as having at least four of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1 , hydrochloride Form 2, is characterized as having properties (a) to (e).

[0077] In some embodiments, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol is a hydrochloride salt and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol hydrochloride is Form 2 with an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 11.6° 2-Theta, 13.9° 2- Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2- Theta.

[0078] In some embodiments, crystalline Compound 1 , hydrochloride Form 2, has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 3. In some embodiments, crystalline Compound 1 , hydrochloride Form 2, has an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 11.6° 2 -Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 2, has an X- ray powder diffraction (XRPD) pattern with at least five characteristic peaks selected from peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-WSGR Docket No. 56756-709.601Theta, 22.4° 2-Theta, and 23.2° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 2, has an X-ray powder diffraction (XRPD) pattern with at least six characteristic peaks selected from peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 2, has an X-ray powder diffraction (XRPD) pattern with at least seven characteristic peaks selected from peaks at about 11 .6° 2- Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta. In some embodiments, crystalline Compound 1, hydrochloride Form 2, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta. In some embodiments, crystalline Compound 1 , hydrochloride Form 2, has a thermogravimetric analysis (TGA) thermogram substantially similar to the one set forth in Figure 5. In some embodiments, crystalline Compound 1 , hydrochloride Form 2, has a DSC thermogram substantially similar to the one set forth in Figure 6. In some embodiments, crystalline Compound 1 , hydrochloride Form 2, has a DSC thermogram that shows no melting pointbefore 250°C. In some embodiments, crystalline Compound 1 , hydrochloride Form 2, is non-hygroscopic. In some embodiments, crystalline Compound 1 , hydrochloride Form 2, is obtained from ethanol. In some embodiments, crystalline Compound 1 , hydrochloride Form 2, is solvated. In some embodiments, crystalline Compound 1 , hydrochloride Form 2, is unsolvated.

[0079] In another embodiment, crystalline Compound 1, hydrochloride Form 2 is substantially pure. In certain embodiments, the substantially pure crystalline Compound 1, hydrochloride Form 2 is substantially free of other solid forms, e.g., amorphous solid. In certain embodiments, the purity of the substantially pure crystalline Compound 1, hydrochloride Form 2 is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. Crystalline Compound 1, Free Base Form 1

[0080] In some embodiments, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) is a free base and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) free base is Form 1. In some embodiments, crystalline Compound 1 free base is Form 1 characterized as having at least one of the following properties:(a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 8;WSGR Docket No. 56756-709.601(b) an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 12.1° 2-Theta, 13.6° 2-Theta, 17.9° 2-Theta, 19.4° 2- Theta, 20.1° 2-Theta, 20.5° 2-Theta, 22.5° 2-Theta, and 29.0° 2-Theta;(c) a thermo-gravimetric analysis (TGA) substantially similar to the one set forth in Figure 9;(d) a DSC thermogram substantially similar to the one set forth in Figure 10;(e) a DSC thermogram that shows an onset of melting at 125°C; or(f) combinations thereof.

[0081] In some embodiments, crystalline Compound 1, free base Form 1, is characterized as having at least two of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, free base Form 1, is characterized as having at least three of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, free base Form 1, is characterized as having at least four of the properties selected from (a) to (e). In some embodiments, crystalline Compound 1, free base Form 1, is characterized as having properties (a) to (e).

[0082] In some embodiments, the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin- 3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) is a free base and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3 -yl)-5 -(triflu oromethyl)phenol (Compound 1) free base is Form 1 with an X- ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 12.1° 2-Theta, 13.6° 2-Theta, 17.9° 2-Theta, 19.4° 2-Theta, 20.1° 2-Theta, 20.5° 2- Theta, 22.5° 2-Theta, and 29.0° 2-Theta.

[0083] In some embodiments, crystalline Compound 1, free base Form 1, has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 8. In some embodiments, crystalline Compound 1 , free base Form 1 , has an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 12.1° 2-Theta, 13.6° 2-Theta, 17.9° 2-Theta, 19.4° 2-Theta, 20.1° 2-Theta, 20.5° 2-Theta, 22.5° 2-Theta, and 29.0° 2-Theta. In some embodiments, crystalline Compound 1, free base Form 1, has an X-ray powder diffraction (XRPD) pattern with at least five characteristic peaks selected from peaks at about 12.1 ° 2-Theta, 13.6° 2-Theta, 17.9° 2-Theta, 19.4° 2-Theta, 20.1° 2-Theta, 20.5° 2-Theta, 22.5° 2-Theta, and 29.0° 2-Theta. In some embodiments, crystalline Compound 1, free base Form 1, has an X-ray powder diffraction (XRPD) pattern with at least six characteristic peaks selected from peaks at about 12.1° 2-Theta, 13.6° 2-Theta, 17.9° 2-Theta, 19.4° 2-Theta, 20.1° 2-Theta, 20.5° 2-Theta, 22.5° 2-Theta, and 29.0° 2-Theta. In some embodiments, crystalline Compound 1, free baseWSGR Docket No. 56756-709.601Form 1 , has an X-ray powder diffraction (XRPD) pattern with at least seven characteristic peaks selected from peaks at about 12.1° 2-Theta, 13.6° 2-Theta, 17.9° 2-Theta, 19.4° 2-Th eta, 20.1° 2- Theta, 20.5° 2-Theta, 22.5° 2-Theta, and 29.0° 2-Theta. In some embodiments, crystalline Compound 1, free base Form 1, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks selected from peaks at about 12.1° 2-Theta, 13.6° 2-Theta, 17.9° 2-Theta, 19.4° 2-Theta, 20.1° 2-Theta, 20.5° 2-Theta, 22.5° 2-Theta, and 29.0° 2-Theta. In some embodiments, crystalline Compound 1, free base Form 1, has a thermogravimetric analysis (TGA) thermogram substantially similar to the one set forth in Figure 9. In some embodiments, crystalline Compound 1, free base Form 1, has a DSC thermogram substantially similar to the one set forth in Figure 10. In some embodiments, crystalline Compound 1, freebase Form 1, has a DSC thermogram that shows an onset of melting at 125°C. In some embodiments, crystalline Compound 1, free base Form 1, is non-hygroscopic. In some embodiments, crystalline Compound 1, free base Form 1, is obtained from acetone. In some embodiments, crystalline Compound 1, free base Form 1, is solvated. In some embodiments, crystalline Compound 1, free base Form 1, is unsolvated.

[0084] In another embodiment, crystalline Compound 1, freebase Form 1 is substantially pure. In certain embodiments, the substantially pure crystalline Compound 1, free base Form 1 is substantially free of other solid forms, e.g., amorphous solid. In certain embodiments, the purity of the substantially pure crystalline Compound 1, freebase Form 1 is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.Preparation of Crystalline Compound 1

[0085] In some embodiments, Compound 1 is prepared as described in US2023 / 0295113, which is herein incorporated by reference in its entirety. In some embodiments, crystalline forms of Compound 1 are prepared as outlined in the Examples. It is noted that solvents, temperatures and other reaction conditions presented herein may vary.Suitable Solvents

[0086] Therapeutic agents that are administrable to mammals, such as humans, must be prepared by following regulatory guidelines. Such government regulated guidelines are referred to as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable contamination levels of active therapeutic agents, such as, for example, the amount of residual solvent in the final product. In some embodiments, solvents disclosed herein are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements forWSGR Docket No. 56756-709.601Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents Q3C(R6),” (October 2016).

[0087] Solvents are categorized into three classes. Class 1 solvents are toxic and are to be avoided. Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.

[0088] Class 1 solvents, which are to be avoided, include: benzene; carbon tetrachloride; 1,2- dichloroethane; 1,1 -dichloroethene; and 1,1,1 -trichloroethane.

[0089] Examples of Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxy ethane, N,N- dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2 -ethoxy ethanol, ethylene glycol, formamide, hexane, methanol, 2 -methoxy ethanol, methylbutyl ketone, methylcyclohexane, methylisobutylketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene and xylene.

[0090] Class 3 solvents, which possess low toxicity, include: acetic acid, acetone, anisole, 1 - butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl- 1 -butanol, methylethyl ketone, 2-methyl-l -propanol, pentane, 1- pentanol, 1 -propanol, 2-propanol, propyl acetate, and triethylamine.

[0091] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of APIs. In some cases, the solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of APIs may enhance the yield, or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent is a critical parameter in the synthetic process.

[0092] In some embodiments, compositions comprising Compound 1 comprise an organic solvent(s). In some embodiments, compositions comprising Compound 1 comprise a residual amount of an organic solvent(s). In some embodiments, compositions comprising Compound 1 comprise a residual amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methy 1-1 -butanol, methylethyl ketone, 2-methyl-l -propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, andWSGR Docket No. 56756-709.601 triethylamine. In some embodiments, the Class 3 solvent is selected from the group consisting of acetone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0093] In some embodiments, compositions comprising Compound 1 comprise a residual amount of a Class 2 solvent. In some embodiments, the organic solvent is a Class 2 solvent. In some embodiments, the Class 2 solvent is selected from the group consisting of acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2 -dichloroethene, dichloromethane, 1,2- dimethoxy ethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2- ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2 -meth oxy ethanol, methylbutyl ketone, methylcyclohexane, methylisobutylketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1, 2 -trichloroethene and xylene. In some embodiments, the Class 2 solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, and toluene. In some embodiments, the Class 2 solvent is acetonitrile.

[0094] In some embodiments, compositions comprising Compound 1 comprise a residual amount of a solvent for which no adequate toxicological data were found. In some embodiments, the organic solvent is a solvent for which no adequate toxicological data were found. In some embodiments, the solvent is selected from the group consisting of 2-butanone and 2- methyltetrahydrofuran.

[0095] In some embodiments is a process for the preparation of 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1), comprising:A) the reaction of compound with the structure: ccinimide, followed by reaction with the compound with the structure:dicyclohexyl(2',6'-dimethoxy[l,l'-biphenyl]-2-yl)phosphane (SPhos), palladium acetate, and tripotassium phosphate to produce a compound with the structure:B) followed by the reaction of the compounds with the structures:WSGR Docket No. 56756-709.601C) the reaction of the compound with the structure:chlororuthenium(l+);[(lR,2R)-l,2-diphenyl-2-(3- phenylpropylamino)ethyl]-(4-methylphenyl)sulfonylazanide, triethylamine, and formic acid to produce a compound with the structure:D) followed by the reaction of the compound with the structure:hydrochloric acid and N-bromosuccinimide followed by hydrazine hydrate to produce a compound with the structure:E) followed by the reaction of the compound with the structure:WSGR Docket No. 56756-709.601boron tribromide to produce 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) having the structure:(Compound 1).

[0096] In some embodiments, the process further comprises the reaction of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifhioromethyl)phenol (Compound 1) with hydrochloric acid to produce 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifhioromethyl)phenol hydrochloric acid salt (Compound 1, HC1 salt).

[0097] In some embodiments, described herein is a process for the preparation of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1):(Compound 1), comprising contacting the compound with the structure:boron tribromide in the presence of a solvent. In some embodiments, the solvent is selected from dichloromethane, 1,2 -dichloroethane, 1,4-dioxane, tetrahydrofuran, dimethoxy ethane, chlorobenzene, and trifluorotoluene. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is 1,2-dichloroethane.In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is dimethoxy ethane. In some embodiments, the solvent is chlorobenzene. In some embodiments, the solvent is trifluorotoluene.

[0098] In some embodiments, the compound with the structure:WSGR Docket No. 56756-709.601hydrazine hydrate in the presence of a solvent. In some embodiments, the solvent is selected from dimethylformamide, dimethylacetamide (DMA), N-methylpyrrolidone(NMP), 1,4-dioxane, tetrahydrofuran (THF), and 2 -methyltetrahydrofuran. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N-methylpyrrolidone (NMP). In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is tetrahydrofuran (THF). In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0099] In some embodiments, the compound with the structure:, , phenylpropylamino)ethyl]-(4-methylphenyl)sulfonylazanide, triethylamine, and formic acid in the presence of a solvent. In some embodiments, the solvent is methanol.

[0100] In some embodiments, the compound with the structure:WSGR Docket No. 56756-709.601prepared by a process comprising contacting the compounds with the structures:embodiments, the base is n-BuLi. In some embodiments, the solvent is selected from 1,4- dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), 2-methyltetrahydrofuran, and acetonitrile. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is N,N-dimethylformamide. In some embodiments, the solvent is N,N- dimethylacetamide. In some embodiments, the solvent is N-methylpyrrolidone. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is acetonitrile.

[0101] In some embodiments, the compound with the structure:prepared by a process comprising contacting the compound with the structure:with N-bromosuccinimide in the presence of a solvent, followed by reaction of the compound with the structure:dicyclohexyl(2',6'-dimethoxy[l,l'-biphenyl]-2-yl)phosphane (SPhos), palladium acetate, and tripotassium phosphate. In some embodiments, the solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, 1,2 -dimeth oxy ethane, dimethylacetamide (DMA), and N-methyl pyrrolidone (NMP). In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is 1,2- dimeth oxy ethane. In some embodiments, the solvent is dimethylacetamide (DMA). In some embodiments, the solvent is N-methyl pyrrolidone (NMP).WSGR Docket No. 56756-709.601

[0102] In some embodiments is a process for the preparation of 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1), comprising:A) the reaction of compounds with the structures:with bis(triphenylphosphine)palladium chloride and potassium carbonate to produce a compound with the structure:B) followed by the reaction of the compounds with the structures:lithium diisopropylamide (LDA) or lithium tetramethylpiperidine to produce a compound with the structure:C) followed by dynamic kinetic resolution and enzymatic reduction of the compound with the structure:D) followed by the reaction of the compound with the structure:WSGR Docket No. 56756-709.601-dodecanethiol and sodium hydroxide to produce a compound with the structure:

[0103] In some embodiments, the process further comprises the reaction of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) with hydrochloric acid to produce 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloric acid salt (Compound 1, HC1 salt).

[0104] In some embodiments, described herein is a process for the preparation of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1):(Compound 1), comprising contacting the compound with the structure:dodecanethiol and sodium hydroxide in the presence of a solvent. In some embodiments, the solvent is dimethylacetamide.

[0105] In some embodiments, the compound with the structure:prepared by a process comprising dynamic kinetic resolution and enzymatic reduction of the compound with the structure:WSGR Docket No. 56756-709.601ing contacting the compounds with the structures:base in the presence of a solvent. In some embodiments, the base is lithium diisopropylamide. In some embodiments, the base is lithium tetramethylpiperidine. In some embodiments, the solvent is toluene.

[0107] In some embodiments, the compound with the structure:prepared by a process comprising contacting the compounds with the structures:bis(triphenylphosphine)palladium chloridecarbonate in the presence of a solvent. In some embodiments, the solvent is ethanol.

[0108] In some embodiments is a compound selected from:pharmaceutically acceptable salt thereof.

[0109] In some embodiments is a compound selected from:WSGR Docket No. 56756-709.601pharmaceutically acceptable salt thereof.Certain Terminology

[0110] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of" or "consist essentially of' the described features. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range.

[0111] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety.

[0112] The term “acceptable” or “pharmaceutically acceptable”, with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0113] As used herein, “amelioration” of the symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration,WSGR Docket No. 56756-709.601 whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0114] “Bioavailability” refers to the percentage of Compound 1 dosed that is delivered into the general circulation of the animal or human being studied. The total exposure (AUC(o-oo)) of a drug when administered intravenously is usually defined as 100% bioavailable (F%). “Oral bioavailability” refers to the extentto which Compound 1 is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

[0115] “Blood plasma concentration” refers to the concentration of Compound 1 in the plasma component of blood of a subject. It is understood that the plasma concentration of Compound 1 may vary significantly between subjects, due to variability with respect to metabolism and / or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood plasma concentration of Compound 1 may vary from subject to subject.Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC(0.co)) may vary from subject to subject. Due to this variability, the amount necessary to constitute “a therapeutically effective amount” of Compound 1 may vary from subject to subject.

[0116] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0117] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. An appropriate “effective amount” in any individual case maybe determined using techniques, such as a dose escalation study. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effective amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of Compound 1, age, weight, general condition of the subject, the condition being treated, the severity of theWSGR Docket No. 56756-709.601 condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by a dose escalation clinical trial.

[0118] The terms “enhance” or “enhancing” means to increase or prolong either in potency or duration a desired effect. By way of example, “enhancing” the effect of therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents during treatment of a disease, disorder, or condition. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder, or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0119] The term “prophylactically effective amount,” as used herein, refers that amount of a composition applied to a patient which will prevent to some extent one or more of the symptoms of a disease, condition or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's state of health, weight, and the like. As an example, one can determine such prophylactically effective amounts by a dose escalation clinical trial.

[0120] The term “subject” as used herein, refers to an animal which is the object of treatment, observation or experiment. By way of example only, a subject may be, but is not limited to, a mammal including, but not limited to, a human.

[0121] As used herein, the term “target activity” refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.

[0122] The terms “treat,” “treating” or “treatment”, as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms “treat,” “treating” or “treatment”, include, but are not limited to, prophylactic and / or therapeutic treatments.

[0123] As used herein, IC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.Pharmaceutical Compositions / FormulationsWSGR Docket No. 56756-709.601

[0124] Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy , Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference in their entirety.

[0125] A pharmaceutical composition, as used herein, refers to a mixture of Compound 1 with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to a mammal. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of Compound 1 are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compoundused and other factors. The compounds canbe used singly or in combination with one or more therapeutic agents as components of mixtures.

[0126] In some embodiments is a pharmaceutical composition comprising Compound 1, and a pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a crystalline form of Compound 1, and a pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a crystalline form of Compound1, hydrochloride Form 1, and a pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a crystalline form of Compound 1 , hydrochloride Form2, and a pharmaceutically acceptable excipient.

[0127] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. Compound 1, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. Compound 1, and a co-agent, are administered to a patient asWSGR Docket No. 56756-709.601 separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also appliesto cocktail therapy, e.g. the administration of three or more active ingredients.

[0128] Pharmaceutical compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee -making, levigating, emulsifying, encapsulating, entrapping or compression processes.Dosage Forms

[0129] The pharmaceutical compositions described herein can be formulated for administration to a mammal via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal administration routes. As used herein, the term “subject” or “individual” is used to mean an animal, preferably a mammal, including a human or non-human. The terms individual, patient and subject may be used interchangeably.

[0130] Moreover, the pharmaceutical compositions described herein, which include Compound 1 can be formulated into any suitable dosage form, including but not limited to, solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0131] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0132] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push -fit capsules can contain the active ingredients in admixture with filler such asWSGR Docket No. 56756-709.601 lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0133] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapiddisintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal -derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations described herein may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.

[0134] In some embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of Compound 1 with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the particles of Compound 1 are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.

[0135] Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.

[0136] The pharmaceutical solid dosage forms described herein can include Compound 1, and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersingWSGR Docket No. 56756-709.601 agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of Compound 1 . In one embodiment, some or all of the particles of the Compound 1 are coated. In another embodiment, some or all of the particles of the Compound 1 are microencapsulated. In still another embodiment, the particles of the Compound 1 are not microencapsulated and are uncoated.

[0137] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0138] Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0139] In order to release the Compound 1 from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as com starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® Pl 00, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a crosslinked starch such as sodium starch glycolate, a cross -linked polymer such as crospovidone, aWSGR Docket No. 56756-709.601 cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation -exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like. In some embodiments provided herein, the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, crosslinked carb oxy methylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum. In some embodiments provided herein, the disintegrating agent is croscarmellose sodium.

[0140] Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxy ethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

[0141] In general, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.WSGR Docket No. 56756-709.601

[0142] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, com starch, sodium stearyl fumarate, alkali-metal and alkaline earth metal salts, such as calcium, magnesium, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmito stearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like. In some embodiments provided herein, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments provided herein, the lubricant is magnesium stearate.

[0143] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like. In some embodiments provided herein, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

[0144] The term “non water-soluble diluent” represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose (e.g., having a density of about 0.45 g / cm3, e.g. Avicel, powdered cellulose), and talc.

[0145] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0146] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like. In some embodiments provided herein, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glycerylWSGR Docket No. 56756-709.601 monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

[0147] Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy -propylmethylcellulose, polysorbate- 80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, poly ethoxylated sorbitan monolaurate, poly ethoxylated sorbitan monolaurate, povidone, and the like.

[0148] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0149] It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.

[0150] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[0151] Compressed tablets are solid dosage forms preparedby compacting the bulk blend of the formulations described above. In various embodiments, compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide a delayed release of Compound 1 from the formulation. In other embodiments, the film coating aids in patient compliance (e.g., Opadry® coatings or sugar coating). Film coatings including Opadry® typically range from about 1% toWSGR Docket No. 56756-709.601 about 3% of the tablet weight. In other embodiments, the compressed tablets include one or more excipients.

[0152] A capsule may be prepared, for example, by placing the bulk blend of the formulation of Compound 1 inside of a capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule. In some embodiments, the formulations (non-aqueous suspensionsand solutions) are placed in a hard shell gelatin capsule. In other embodiments, the formulations are placed in standard gelatin capsules or non -gelatin capsules such as capsules comprising HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule may be swallowed whole or the capsule may be opened and the contents sprinkled on food prior to eating. In some embodiments, the therapeutic dose is split into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the formulation is delivered in a capsule form.

[0153] In various embodiments, the particles of Compound 1 and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[0154] In another aspect, dosage forms may include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0155] Materials useful for the microencapsulation described herein include materials compatible with Compound 1 which sufficiently isolate the Compound 1 from other noncompatible excipients. Materials compatible with Compound 1 are those that delay the release of the compounds of Compound 1 in vivo.

[0156] Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds described herein, include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,WSGR Docket No. 56756-709.601 hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxy ethylcelluloses such as Natrosol®, carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aquaion ®-CMC, polyvinyl alcohol and polyethylene glycol co -polymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[0157] In still other embodiments, plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.

[0158] Microencapsulated Compound 1 may be formulated by several methods, illustrative examples of which include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, several chemical techniques, e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used. Furthermore, other methods such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating may also be used.

[0159] In one embodiment, the particles of Compound 1 are microencapsulated prior to being formulated into one of the above forms. In still another embodiment, some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[0160] In other embodiments, the solid dosage formulations of the Compound 1 are plasticized (coated) with one or more layers. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate,WSGR Docket No. 56756-709.601 citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[0161] In other embodiments, a powder including the formulations with Compound 1 may be formulated to include one or more pharmaceutical excipients and flavors. Such a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and / or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multidosage packaging units.

[0162] In still other embodiments, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and / or tartaric acid. When salts of the compositions described herein are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing “effervescence.” Examples of effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[0163] In some embodiments, the solid dosage forms described herein can be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to affect release in the small intestine of the gastrointestinal tract. The enteric coated dosage form may be a compressed or molded or extruded tablet / mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and / or other composition components, which are themselves coated or uncoated. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.

[0164] The term “delayed release” as used herein refers to the delivery so that the release can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations. In some embodiments the method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids atWSGR Docket No. 56756-709.601 pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments the polymers described herein are anionic carboxylic polymers. In other embodiments, the polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to:

[0165] Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7.

[0166] Acrylic polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting. The Eudragit series E dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in the stomach and dissolve in the intestine;

[0167] Cellulose Derivatives. Examples of suitable cellulose derivatives are ethyl cellulose; and reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH >6. Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles <1 pm. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). The performance can vary based on the degree and type of substitution. For example, HPMCP such as, HP-50, HP- 55, HP-55S, orHP-55F grades are suitable. The performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules, or as fine powders for aqueous dispersions; Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids.WSGR Docket No. 56756-709.601

[0168] In some embodiments, the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.

[0169] Colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., carnuba wax or PEG) may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.

[0170] In other embodiments, the formulations described herein, which include Compound 1 are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. Other types of controlled release systems maybe used. Examples of such delivery systems include, e.g., polymer-based systems, such as polylactic and polygly colic acid, polyanhydrides and poly caprolactone; porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209- 214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology , 2ndEd., pp. 751 -753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977, 175, 6,465,014 and 6,932,983, each of which is specifically incorporated by reference.

[0171] In some embodiments, pharmaceutical formulations are provided that include particles of Compound 1 and at least one dispersing agent or suspending agent for oral administration to a subject. The formulations may be a powder and / or granules for suspension and, upon admixture with water, a substantially uniform suspension is obtained.

[0172] It is to be appreciated that there is overlap between the above-listed additives used in the aqueous dispersions or suspensions described herein, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several differentWSGR Docket No. 56756-709.601 functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in formulations described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.Methods

[0173] In some embodiments, described herein is a method for treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3 -yl)-5 -(triflu oromethyl)phenol hydrochloride, or solvate thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity and gout.

[0174] In some embodiments, described herein is a method for treating a liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3 -yl)-5 -(triflu oromethyl)phenol hydrochloride, or solvate thereof, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis.

[0175] In some embodiments, described herein is a method for treating a lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3 -yl)-5 -(triflu oromethyl)phenol hydrochloride, or solvate thereof, wherein the lung disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and pulmonary idiopathic fibrosis.WSGR Docket No. 56756-709.601

[0176] In some embodiments, described herein is a method for treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)- 4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)- 4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington’s disease, traumatic brain injury, ischemic stroke and reperfusion, haemorrhagic stroke, epilepsy, and depression.

[0177] In some embodiments, described herein is a method for treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)- hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammatory bowel disease, Crohn’s disease, and ulcerative colitis.

[0178] In some embodiments, described herein is a method for treating a cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride, or solvate thereof, described herein. In some embodiments, described herein is a method for treating a cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3 -yl)-5 -(triflu oromethyljphenol hydrochloride, or solvate thereof, wherein the cardiovascular disease is atherosclerosis or stroke.Methods of Dosing and Treatment Regimens

[0179] In some embodiments, crystalline Compound 1 is used in the preparation of medicaments for the treatment of diseases or conditions that would benefit from NLRP3WSGR Docket No. 56756-709.601 modulation. In addition, a method for treating any of the diseases or conditions described herein in an individual in need of such treatment, involves administration of pharmaceutical compositions containing crystalline Compound 1, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said individual.

[0180] In some embodiments, compositions containing crystalline Compound 1 are administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, compositions containing Compound 1 are administered for therapeutic applications. In some embodiments, compositions containing Compound 1 are administered for prophylactic applications.

[0181] In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0182] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0183] In some embodiments, crystalline Compound 1 is administered daily. In some embodiments, crystalline Compound 1 is administered every other day.

[0184] In some embodiments, crystalline Compound 1 is administered once per day. In some embodiments, crystalline Compound 1 is administered twice per day. In some embodiments, crystalline Compound 1 is administered three times per day. In some embodiments, crystalline Compound 1 is administered four times per day.

[0185] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0186] Once improvement of the patient's conditions has occurred, a maintenance dose is administered, if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder,WSGR Docket No. 56756-709.601 or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0187] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 - about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub -doses per day.

[0188] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non -limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non -reclosable containers. Alternatively, multipledose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[0189] The daily dosages appropriate for the compounds described herein are from about 0.01 mg / kg to about 20 mg / kg. In one embodiment, the daily dosages are from about 0.1 mg / kg to about 10 mg / kg. An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 1000 mg, conveniently administered in a single dose or in divided doses, including, but not limited to, up to four times a day or in extended release form. Suitable unit dosage forms for oral administration include from about 1 to about 500 mg active ingredient. In one embodiment, the unit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are notuncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated,WSGR Docket No. 56756-709.601 the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0190] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50and ED50. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.Kits / Articles of Manufacture

[0191] For use in the therapeutic methods of use described herein, kits and articles of manufacture are also described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be usedin a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[0192] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include, e.g., U.S. Patent No. 5,323,907. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.

[0193] In some embodiments, the compounds or compositions described herein, are presented in a package or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The compound or composition described herein is packaged alone, or packaged with another compound or another ingredient or additive. In some embodiments, the package contains one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. In some embodiments, the package comprises metal or plastic foil, such as a blister pack. In some embodiments, the package or dispenser device is accompanied by instructions for administration, such as instructions for administering the compounds or compositions for treating a neoplastic disease. In some embodiments, the package or dispenser is accompanied with a notice associated with the container in form prescribed by a governmentalWSGR Docket No. 56756-709.601 agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. In some embodiments, such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions include a compound described herein formulated in a compatible pharmaceutical carrier are prepared, placedin an appropriate container, and lab eled for treatment of an indicated condition.

[0194] For example, the container(s) include crystalline Compound 1, optionally in a composition or in combination with another agent as disclosed herein. Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.

[0195] A kit typically includes labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[0196] In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[0197] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.WSGR Docket No. 56756-709.601EXAMPLESList of abbreviations

[0198] As used throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:ACN or MeCN acetonitrileBn benzylBOC or Boc tert-butyl carbamate t-Bu tert-butylCy cyclohexylDCE dichloroethane (C1CH2CH2C1)DCM dichloromethane (CH2C12)DIPEA or DIEA diisopropylethylamineDMAP 4-(A,A-dimethylamino)pyridineDMF dimethylformamideDMA A,A-dimethylacetamideDMSO dimethylsulfoxide eq or equiv equivalent(s)Et ethylEt2O diethyl etherEtOH ethanolEtOAc ethyl acetateHPLC high performance liquid chromatographyIPA isopropanolMe methylMeOH methanolMS mass spectroscopyGC gas chromatography h hour(s)KF Karl Fischer min minutesMsOH methanesulfonic acidNMP N-methylpyrrolidineWSGR Docket No. 56756-709.601NMR nuclear magnetic resonanceRP-HPLC reverse phase-high performance liquid chromatography rt room temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographyV volumesI. Synthesis of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol (Compound 1)Example 1A: Synthesis of Compound 1, Method ACompound 1

[0199] Step 1 : Charged 3-methylfuran (1.75 Kg, 21.32 mol, 1.0 eq) and2-MeTHF (8.98L, 5 V) into flask 1 and stir. Cooled the mixture to 0 to 10 °C. Charged NBS (4 Kg, 22.47 mol, 1.1 eq) in portions into flask at 0 to 20 °C. Stirred the resulting mixture at 15 to 25 °C for 1 -2 h. Charged 10% aq. Na2CC>3 solution (8.75 L, 5 V) dropwise into flask at 10 to 30 °C and stirred at 10 to 30 °C for 10-30 min. Separated the layers and collect the organic layer. Obtained 2-bromo-3- methylfuran as a solution in 2-MeTHF (LC / MS: m / z, MH+257.13).

[0200] Step 2: Charged 2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (3.85 Kg, 17.5 mol, 1.0 eq), pinacol (2.068 Kg, 17.5 mol, 1.0 eq), and toluene (61.6 L, 16 V) into flask 2. Charged 2- bromo-3 -methylfuran (2.82 Kg, 17.5 mol, 1.0 eq) solution in 2-MeTHF into flask 2 and stirred for 10 min. Charged aq. K3PO4(11.14 Kg, 52.5 mol, 3.0 eq, dissolved with 30.8 L of H2O (8 V)) and S-Phos (144 g, 0.35 mol, 2 mol %) into flask 3 at 20 to 25 °C. Purged flask 2 with N2.WSGR Docket No. 56756-709.601Charged Pd(OAc)2(39.6 g, 0. 175 mol, 1 mol%) into flask 3 under N2. Heated flask to 70 to 80 °C and charged the solution in flask 2 into flask 3 at 70 to 80 °C over 1 h under N2. Agitated the mixture at 70 to 80 °C for 2-3 h under N2. Separated the layers, obtained the organic layer, and extract aqueous layer with toluene (19.3 L x 2, 5 V x 2) twice. Charged activated carbon (385 g,10 wt %) into the combined organic layer and stir at 70 to 80 °C for 2-3 h. Filtered the slurry and washed the cake with toluene (5 L,l-2 V). Charged water (19.3 L, 5 V) into the filtrate and stirred the mixture at 50 to 60 °C for 30-60 min. Separated the layers and obtained organic layer. Charged water (19.3 L, 5 V) into the filtrate and stirred the mixture at 50 to 60 °C for 30-60 min. Separated the layers and obtained organic layer. Concentrated the organic layer in vacuo at 50 to 60 °C to dryness. Dissolved the residue with THF (3.8 L,1-2V). Obtained a solution of arylfuran in THF (77% assay yield). !HNMR (400 MHz, MeOD, isolated sample) 87.55 (d, 1H), 7.53 (s, 1H), 7.37 (d, 1H), 7.35 (d, 1H), 6.39 (s, 1H), 3.87 (s, 3H), 2.05 (s, 3H).

[0201] Step 3 : Charged arylfuran (3.6 Kg, 14.05 mol, 1.0 eq) in THF (7.2 L, 2 V) into flask under N2. Purged the flask with N2three time and cooled the mixture to -50 to -40 °C under N2. Charged dropwise 2.5 mol / L n-BuLi in n-hexane (5.9 L, 14.75 mol, 1.05 eq) at -50 to -40 °C then stirred at -50 to -40 °C for 40-50 min under N2. Charged dropwise Weinreb amide (3.01 Kg, 16.16 mol, 1.15 eq) solution in THF at -50 to -40 °C within 1.5 h under N2. Held the reaction mixture at -50 to -40 °C for 2-3 h. Adjusted the temperature to -10 to 0 °C and stirred at -10 to 0 °C for 1-2 h. Quenched the reaction with 20% aq NH4Cl (25.2 L, 7 V) slowly. Separated the layers and extracted the water phase with ethyl acetate (25.2 L, 7 V). Combined the organic layers, and washed with sat. aq. NaCl solution (36 L,10 V). Concentrated the organic layer to dryness. Charged n-heptane (36 L, 7 V) to produce a yellow slurry. Stirred the slurry at room temperature for 2-3 h. Filtered the slurry and wash the cake with n-heptane (4 L, 1-2 V). Dried the cake at 40 to 45 °C in vacuum. Obtained furanyl ketone intermediate as a pale-yellow solid (77% assay yield). Tf NMR QOO MHz, CDC13) 67.55 (m, 1H), 7.28 (m, 1H), 7.15 (m 2H), 4.89 (s, 3H), 3.37 (m, 1H), 3.00 (m, 1H), 2.85 (m, 1H), 2.28 (s, 3H), 2.15 (t, 1H), 2.08 (s, 3H), 1.95 (m, 2H), 1.75 (m 2H), 1.45 (m, 1H).

[0202] Step 4: Charged ketone intermediate (5.94 Kg, 15.57 mol,1.0 eq) and DCM (30 L, 5 V) into a flask and stir to dissolve the solid under N2. Cooled the mixture to -10-0 °C under N2. Charged formic acid (4.3 Kg, 93.4 mol, 6 eq) into the flask at -10-10 °C under N2. Cooled the mixture to -10-0 °C under N2. Charged dropwise TEA (9.45 Kg, 93.4 mol, 6 eq) into the flask at -10-10 °C under N2. Purged the mixture with N2at 0-10 °C for 20-30 min. Charged (R,R)-Teth- TsDpen RuCl (193 g, 0.31 mol, 2% mol) into the flask at 0-10 °C under N2. Agitated the mixture at 15-25 °C for 12-14 h under N2. Cooled the mixture to -5-5 °C under N2. Quenched theWSGR Docket No. 56756-709.601 reaction with sat. NaHCO3aq. (30 L, 5 V) purged with N2at -5—10 °C and stir 15-25 °C for 0.5~lh under N2. Separated the layers and extracted the water phase with DCM (24 L, 4V) purged with nitrogen. Washed the combined organic layer with water (30 L x 3, 5V x 3) purged with nitrogen three times under N2. Concentrated the combined organic layer in vacuo below 26 °C to 2-3 V. Exchanged DCM with MTBE (24 L x 3, 4 V x 3) by concentration to 2-3 V three times. Charged n-heptane (72 L, 12 V) dropwise into the concentrated residue at 20-30 °C and stir at 20-30 °C for 2-3 hrs under N2. Filtered the resulting slurry and washed the cake with the mixed solvent of MTBE (4.5 L, 0.75 V) and n-heptane (13.5 L, 2.25 V). Concentrated the combined filtrates in vacuo below 45 °C to 2-2.5 V. Charged MTBE (12 L, 2 V) and SNFT-01 amino silica gel (3 Kg, 50 % wt) into the concentrated residue and stir 20-25 °C for 10-12 hrs under N2. Filtered the resulting slurry and wash the cake with MTBE (36 L, 6 V). Concentrated the combined filtrates in vacuo below 35 °C to 2-3 V. Exchanged MTBE with THF (30 L x 3, 5 V x 3)by concentrating in vacuo below 40 °C to 3-4 V three times. Obtained the hydroxyfuranyl intermediate as a solution in THF (92% assay yield). 'H NMR (400 MHz, MeOD, isolated sample) 87.53 (d, lH), 7.29 (d, 1H), 7.28 (s, lH), 6.24(s, 1H), 4.35 (d, 1H), 3.89 (s, 3H), 3.10 (d, 1H), 2.80 (d, 1H), 2.28 (s, 3H), 2.13 (m, 1H), 2.02 (s, 3H), 1.92 (t, 1H), 1.83 (t, 1H), 1.68 (m,lH), 1.58 (m, 1H), 1.55 (m, 1H), 1.00 (m, 1H).

[0203] Steps 5 and 6: Charged hydroxyfuranyl intermediate (5.67 Kg, 14.8 mol, 1.0 eq), THF (58 L, 10 V), H2O (5.7 L, 1 V) into a flask at 20-30 °C under N2. Adjusted the temperature to 0~5°C. Charged 4NHC1 aq. solution (4.1 L, 16.3 mol, 1.1 eq) into the flask at 0-10 °C under N2. Adjusted the temperature to -5~0°C. ChargedNBS (3.42 Kg, 19.24 mol, 1.3 eq) into the flask in portions at -5-0 °C. Stirred the reaction mixture at -5-0 °C for 1-1.5 h. Charged 50% of NH2NH2.H2O (15 Kg, 148 mol, 10 eq) dropwise into the flask at -5-0 °C under N2. Stirred the resulting mixture at -5-0 °C for 0.5-1 h, then at 15-20 °C for 0.5-1 h. Quenched the reaction with sat. NaHCO3(56.7 L, 10 V) at 10-20 °C. Extracted the separated aqueous layer with EtOAc (40 L x 2, 7 V x 2) twice. Washed the combined organic layer with 10% brine (40 L, 7 V). Concentrated the organic layer in vacuo at 35-40 °C to 1-2 V. Charged MTBE (28.5 L, 5 V) and continued to concentrate in vacuo at 35-40 °C to 1-2 V. Charged MTBE (28.5 L, 5 V) and continued to concentrate in vacuo at 35-40 °C to 1-2 V resulting in a slurry. Charged n-heptane (68 L, 12 V) dropwise into the slurry at 20-30 °C. Stirred the slurry at 20-30 °C for 2-3 h.Filtered the slurry and rinsed the cake with MTBE (2.8 L, 0.5 V). Dried the cake under vacuum at 40-45 °C for 24 h. Obtained the hydroxypyridazinyl intermediate as a light brown solid THF (90% assay yield). 'HNMR (400 MHz, MeOD) 67.72 (s 1H), 7.48 (d, 1H), 7.42 (d, 1H), 7.40 (s,WSGR Docket No. 56756-709.6011H), 4.68 (d, 1H), 3.84 (s, 3H), 3.14 (d, 1H), 2.82 (d, 1H), 2.29 (s, 3H), 2.20 (s, 3H), 2.10 (tm, 1H),1.95 (t, 2H), 1.70 (m, 1H), 1.55 (m, 1H), 1.35 (d, 1H), 1.11 (m, 1H).

[0204] Step 7: Charged hydroxypyridazinyl intermediate (4.5 Kg, 11.38 mol, 1 eq) and DCM (68 L, 15 V) into a flask and stir at 20-30 °C under N2. Adjusted the temperature to -8~0°C.Charged Imol / L BBr3(56.9 L, 56.9 mol, 5.0 eq) solution in DCM dropwise into the flask at - 8-0 °C under N2. Stirred the resulting mixture at -5-0 °C for 30- 35 h. Warmed the mixture to 11-16 °C and stirred at 11-16 °C for 0.5-3 h until the mixture became a homogeneous solution. Cooled the mixture down to -5-0 °C, sampled to determine reaction completion, then cooled the mixture down to -10-0 °C. Charged iso-propyl alcohol (18 L, 4 V) dropwise into the flask at - 10-0 °C under N2. Stirred the mixture for 1-3 h until all the materials sticking on the wall of the flask dissolved. Concentrated the resulting mixture in vacuo at 20-40 °C to 5-7 V. Charged water (36 L, 8 V) into the residue, and continued to concentrate in vacuo at 50-70 °C to 5-7 V. Charged water (18 L, 4 V) into the residue, and continued to concentrate in vacuo at 50-70 °C to 5-7 V. Cooled the mixture down to 20-30 °C. Charged water (171 L, 38 V) into the residue at 20-30 °C, and stirred at 20-30 °C for 3-5 hrs. Filtered the slurry and washed the cake with water (4.5 L x 2, 1 V x 2) twice. Basified the obtained filtrates with sat. NaHCO3aq. solution till pH was 7-8. Stirred the resulting slurry at 20-30 °C for 15-18 hrs. Filtered the slurry and washed the cake with purified water (9 L x 2, 2 V x 2). Slurried the cake with purified water (81 L, 18 V) at 20-30 °C for 6-8 hrs. Filtered the slurry and washed the cake with purified water (9 Lx 2, 2 Vx 2) twice. Dried the cake at 65-70 °C for 10-12 h. Charged the crude compound and iso-propyl alcohol (18 L, 4 V) into a flask and stir under N2. Heated the mixture to 55-60 °C and stirred at 55-60 °C for 1-4 h until the solid dissolved. Charged water (45 L, 10 V) dropwise at 55-60 °C for3~5 h. Cooled the mixture to 18-25 °C at cooling rate 5-10 °C / h. Stirred the slurry at 18-25 °C for 15-18 h. Filtered the slurry and washed the cake with purified water (9 Lx 2, 2 V x 2) twice. Dried the cake at 65-70 °C for 25-30 h. Collected 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) monohydrate as an off-white solid to light brown solid (63% assay yield). 'H NMR (400 MHz, MeOD) 6 7.67 (s, lH), 7.37 (d, lH), 7.18 (d, 1H), 7.14 (s, 1H), 4.65 (d, 1H), 3.10 (d, 1H), 2.80 (d, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.08 (tm, 1H), 1.95 (t, 2H), 1.66 (m, 1H), 1.50 (m, 1H), 1.35 (d, 1H), 1.10 (m, 1H).Example IB: Synthesis of Compound 1, Method BWSGR Docket No. 56756-709.601

[0205] Step 1 : Charged EtOH (13.0 L, 2.0 V), H2O (13.0 L ,2.0 V), chloropyridazine (6.5 kg ,1.0 eq.) and 2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (13.3 kg, 1.2 eq.) successively into reactor and stirred at 25±5 °C. Charge K2CO3(4.9 kg, 0.7 eq.) to the flask while maintaining the temperature at 25±10 °C. Rinsed the flask with H2O (3.3 L ,0.5 V). Purged with nitrogen and stir for 10 min. Charged Pd(PPh3)2Cl2(0.35 kg, 0.01 eq.) andrinsedthe reactor with EtOH (3.3 L ,0.5 V). Purged with nitrogen again. Heated the mixture to 80±5 °C and stirred for 6 h. Sampled forHPLC. Cooled the reaction mixture to 25±5 °C. Charged aq. HC1 solution (32.5 L, 5 V, 6 M) drop wise into reactor. Filtered and washed the filtrate with toluene (32.5 L, 5 V) twice and collected the aqueous phase. Charged N-acetyl cysteine (0.65 kg, 0.1 w / w) into the aqueous phase and stirred at25±5 °C for 1 h. Charged aq. NaOH (39.0 L, 6 V, 20 %w / w) slowly to the reactor and stirred at25±5 °C for 2 h. Filtered and washed the solid with H2O (6.5 L,1 V) twice. Dried the wet cake at 50±5 °C in vacuo. Obtained ary Ipyridazine as a light brown solid (11.6 kg, 90.1% isolated yield). 1HNMR(4OO MHz, DMSO-t / 6) 69.11 (d, J= 5.2 Hz, 1H), 7.64 (dd, J = 5.2, 1.0 Hz, 1H), 7.53 (d, = 8.2 Hz, 1H), 7.48 (dd, J= 5.5, 1.7 Hz, 2H), 3.85 (s, 3H), 2.11 (s, 3H).

[0206] Step 2: Charged toluene (4.0 L, 8 V) and arylpyridazine (500 g ,1.0 eq.) to reactor A at 25±5 °C. Charged morpholine amide (475 g ,1.2 eq.) to reactor A at 25±5 °C. Purged the flask withN23 times and cooled to -40±10 °C. Charged LDA (1.2 L,1.3 eq., 2.0 M in THF / Hexane) slowly to the reaction mixture over 1 h while maintaining the temperature below -30 °C. Stirred the reaction mixture for another 1 h. Sampled forHPLC. To reactor B was charged aq. HC1 (3.5 L, 7 V, 3 M) and MeOH (2.5 L ,5 V). Adjusted the temperature of reactor B to 20±l 0 °C. Added the reaction mixture in reactor A into reactor B via a cannula under N2pressure. Stirred the resulting mixture for 1 h. Stopped stirring and allowed the reaction mixture to stand for 1 h. Separated and charged the aqueous phase to reactor B. Charged 20% aq. NaOH (0.9 L, ~1.8 V) to reactor B until pH> 9 and stirred at20±10 °C for 2 h. Filtered and washed the solid with H2O (1.0 L ,2 V x2) to give the wet cake 1 , sample for HPLC. Dissolved the wet solid in DMAc (5.0 L ,10 V) at 60±5 °C and stirred until the solid was fully dissolved. Charged H2O (5.0 L ,10 V) toWSGR Docket No. 56756-709.601 the reactor B dropwise and stirred for at least 2 h. Cooled to 20±10 °C. Filtered and washed the solid with H2O (1.0 L ,2 V x 2) to give the wet cake 2. Sampled for HPLC. Dried the wet cake 2 in vacuum at 50±5 °C for 16 h. Obtained pyridazinyl ketone intermediate as a beige solid (610 g, 83.1% isolated yield). !HNMR(400 MHz, CDC13) 87.98 (d, J= 0.9 Hz, 1H), 7.54 (dd, J = 7.9, 1.0 Hz, 1H), 7.41 (ddd, = 7.9, 1.6, 0.8 Hz, 1H), 7.25 - 7.20 (m, 1H), 4.32 (tt, J= 10.7, 3.7 Hz, 1H), 3.85 (s, 3 H), 3.07 (ddd, J= 11.3, 3.6, 1.7Hz, 1H), 2.82 (dt, J= 10.8, 3.9 Hz, lH), 2.37 (d, J = 10.9 Hz, 1H), 2.33 (s, 4H), 2.26 (d, J= 0.9 Hz, 3H), 2.21 - 2.14 (m, 1H), 2.12 - 2.00 (m, 1H), 1.88 - 1.74 (m, 2H), 1.55 - 1.38 (m, 1H).

[0207] Step 3 : Charged H2O (5 L, 25 V) to reactor A and stirred and adjust temperature to 35±5 °C. Added Tween 40 (100 g, 0.5 w / w) to reactor A and stirred for at least 1 h at 35±5 °C.Charged H3PO4 (70.3 g , 1.2 eq., 85% w / w) and stirred for at least 0.5 h. Charged pyridazinyl ketone intermediate (200 g,1.0 eq.) to the reactor. Adjusted pH to 5.70±0.20 with 0.5 M Na3PO4and stirred for at least 0.5 h at 30±5 °C. Charged glucose (183.2 g ,2.0 eq.), NADP2Na (7.6 g, 0.02 eq.), glucose dehydrogenase GDH-108b (1.0 g ,0.5 wt%), ketoreductase enzyme KRD- MB027 (50.0 g , 25 wt%, supplied by Pharmaron) to reactor A at 28±4 °C. The reaction was stirred at 28±4 °C for at least 20 h while controlling pH at 6.0±0.4 in real time with 0.5 M Na3PC>4. Sampled for HPLC. Adjusted the temperature to 50±5 °C. Charged 30% w / w K3PC>4 (1.2 L, 6 V) solution dropwise into reactor A and adjusted pH >10. Stirred for at least 1 h at 50±5 °C. Filtered and washed the filter cake with soften water (0.2 L ,1.0 V) twice. Charged zPrOH (1.5 L, 7.5 V) to reactor B and stirred. Charged the crude cake to reactor B. Stirred for at least 4 h at 30±5 °C. Filtered and washed the cake with iPrOH (0.2 L ,1 V) twice, collected the filtrate. The filtrate was combined with the filtrate of another 200 g batch. Added the filtrate to the reactor B. Adjusted the temperature to 40±5 °C and concentrate the solution to 4-5 V. Cooled the reaction solution to 25±5 °C. Charged water (0.8 L, 2 V) to the reactor B and stir for 0.5 h. Charged water (5.6 L,14 V) to reactor A. Adjusted the temperature of reactor A to 40±5 °C. Charged the solution in reactor B to reactor A dropwise over at least 4 h. Adjusted the temperature of flask A to 50±5 °C. Concentrated the solution to 14-16 V. Cooled reactor A to 30±5 °C and stirred for atleast2 h. Filtered and washed the filter cake with soften water (0.8 L ,2.0 V) twice. Dried the wet cake in vacuum for at least 16 h at 50±5 °C. Obtained the hydroxypyridazinyl intermediate as a beige solid (350 g solid, >99.9% ee, d.r. >500, 87.0% isolated yield).1HNMR(400 MHz, DMSO-d6) 6 7.64 (d, J= 1.0 Hz, 1H), 7.54 (d, J= 8.1 Hz, 1H), 7.47 (dd, J=4.3, 2.6 Hz, 2H), 5.71 (s, 1H), 4.64 (d, J= 7.6 Hz, 1H), 3.85 (s, 3H), 2.88 (dd, J= 11.1, 3.3 Hz, 1H), 2.68 - 2.58 (m, 1H), 2.15 (s, 3H), 2.13 (s, 3H), 1.98 (ddt, J= 14.0, 10.0,WSGR Docket No. 56756-709.6015.3 Hz, 1H), 1.90 - 1.76 (m, 2H), 1.59 (dt, J= 13.1, 3.4 Hz, 1H), 1.47 - 1.31 (m, 1H), 1.30 - 1.19 (m, 1H), 0.98 (qd, J= 12.0, 4.0 Hz, 1H).

[0208] Step 4: Charged DMAc (2.43 L, 5.4 V) and NaOH (72.9 g ,1.6 eq.) to the flask at 25±5 °C. Charged water (45 mL, 0.1 V) to the flask at 25±5 °C. Charged 1 -dodecanethiol (391 g ,1.7 eq.) to the flask at 25±5 °C. Purged the flask with N23 times and stirred for 1 h. Charged hydroxypyridazinyl intermediate (450 g , 1.0 eq.) to the flask at 25±5 °C. Purged the reactor with N23 times. Heated the reaction mixture to 80±5 °C and stir for 6 h. Sampled for HPLC. Cooled the reaction mixture to 20±5 °C. Charged H2O (2.7 L, 6 V) to the reactor while maintaining the temperature at 20±15 °C. Charged 12M HC1 (292.5 g, 2.6 eq.) to the reactor at 20 ±15 °C. Washed the mixture with MTBE (1.8 L , 4.0 V) three times and collected the aqueous phase. Charged H2O (3.6 L, 8 V) and 27% aq. NH3H2O (184 g, 2.6 eq.) to the reactor at 20±5 °C. Charged the aqueous phase dropwise to the diluted NH3H2O solution over 2 h and stirred for 2 h. Filtered and washed with H2O (0.9 L ,2 V) twice. Collected wet cake and dried the wet cake at 50 ± 5 °C in vacuo until KF < 10%. The crude solid was suspended in the EtOH (2.25 L, 5 V ) and stirred at40±5 °C until fully dissolved. Charged H2O (0.9 L, 2 V) dropwise into the reactor in over 4 h. Charged H2O (3.6 L, 8 V) drop wise into the reactor in over 1 h. Filtered and washed the cake with H2O (0.9 L ,2 V) twice. Collected cake and dry at 60±5 °C in vacuo. Obtained 2- (6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol (Compound 1) monohydrate as a solid (415 g, 92% isolated yield). 'H NMR (400 MHz, DMSO-t / 6) 67.61 (s, 1H), 7.46 (d, = 7.8 Hz, 1H), 7.31 - 7.21 (m, 2H), 4.61 (d, = 7.5 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.63 (d, J= 11.0 Hz, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 1.96 (dd, J= 10.8, 7.4 Hz, 1H), 1.84 (q, J= 10.0 Hz, 2H), 1.65 - 1.53 (m, 1H), 1.38 (q, J= 12.1 Hz, 1H), 1.29 - 1.22 (m, 1H), 0.97 (qd, J= 12.0, 4.0 Hz, 1H).Alternative reaction conditions for Method B, step 3:

[0209] Step 3 : Charged H2O (18 mL) to the reactor and started stirring, adjusted temperature to 26 ± 4 °C. Charged H3PC>4 (85 wt%, 1.05 g, 1.2 eq.) to the reactor. Charged the pyridazinyl ketone (3 00 g, 1.0 eq.) to the reactor and stirred until the solution was clear. Rinsed the reactor with H2O (3 mL). Adjusted pH to 5.7 with 0.5 M Na3PO4. Charged glucose (2.74 g, 2.0 eq.) to the reactor. Charged NADP+ (117 mg, 0.02 eq.) to the reactor. Charged glucose dehydrogenase GDH-108b (15 mg, 0.5 wt%) to the reactor. Charged ketoreductase enzyme KRD-A17 (60 mg,WSGR Docket No. 56756-709.6012.0 wt%, supplied by Pharmaron) to the reactor. Rinse the reactor with H2O (6.0 mL). Adjusted temperature to 26 ± 4 °C. Controlled pH 6.0±0.4 at real time with 0.5 M Na3PO4and stirred for at least 18 h at 26 ± 4 °C. Sampled the crude product mixture and analyzed by HPLC. The crude product solution showed 98.5% product.

[0210] Step 3 : Charged H2O (500 mL) to the reactor and started stirring, adjusted temperature to 35 ± 5. Charged Tween 80 or Tween 40 (15 g, 30 wt%) to the reactor and stirred until the solution was clear. Adjusted the temperature of the reactor to 30± 5 °C. Charged H3PO4 (85 wt%, 17.6 g, 1.2 eq.) to the reactor. Charged the pyridazinyl ketone (50 0 g, 1.0 eq.) to the reactor and stirred until the solution is clear. Rinsed the reactor with H2O (50 mL). Adjusted pH to 6.00±0.10 with 0.5 M Na3PO4. Charged glucose (45.8 g, 2.0 eq.) to the reactor. Charged NADP+ (1.95 g, 0.02 eq.) to the reactor. Charged glucose dehydrogenase GDH-108b (250 mg, 0.5 wt%) to the reactor. Charged ketoreductase enzyme KRD-V01 (2.5 g, 5 wt% supplied by Pharmaron) to the reactor. Rinsed the reactor with H2O (100 mL). Adjusted temperature to 28 °C. Controlled pH 6.20 ± 0.30 at real time with 0.5 MNa3PO4and stirred for at least 20 h at 26 ± 4 °C. Sampled the crude product mixture and analyzed by HPLC. Heated the reaction mixture to 50 ± 5 °C.Charged 30% aq. K3PO4(-300 mL) dropwise over 1 h until pH > 10.0 and stirred for 2 h. Filtered and washed with H2O (100 mL *2) twice. Charged IPA (400 mL) and wet cake into the reactor at 25±5 °C. Heated to 30±5 °C and stirred for 4 h at 30±5 °C. Filtered and washed the cake with IPA (50 mL * 2) twice. Charged the filtrate to reactor and concentrated the solution to 200-250 V at 40 ± 5 °C. Cooled to 25±5 °C. Charged H2O (100 mL) into the reactor and stirred for 1 h. Placed the solution into drum ready for use. ChargedH2O (700 mL) into reactor at 25±5 °C. Heated to 40 ±5 °C. Charged the IPA / H2O solution dropwise into the H2O (700 mL) at 40±5 °C over 4 h. Concentrated the solution to 700-800 mL at 50 ± 5 °C. Cooled to 30 ± 5 °C and stirred for 1 h. Filtered and washed with H2O (100 mL*2) twice. Dried the wet cake under vacuum at 50±5 °C for 24 h. The product was obtained as a solid, 44.4 g, 88.2% isolated yield.Example 1C: Synthesis of 3-chloro-4-methylpyridazineWSGR Docket No. 56756-709.601

[0211] Under N2protection, charged DCM (30.0 L, 5 V) into the reactor at 25±5 °C. Charged TiCl4(10.8 kg , 1.1 eq.) to the reactor. The solution was cooled to -5±5 °C and stirred for 30 min. A solution of ethyl pyruvate (6.0 kg , 1.0 eq.) and vinyl acetate (5.8 kg ,1.3 eq.) in DCM (12.0 L ,2 V) was added dropwise into the reactor while maintaining the temperature below 10 °C. The resulting yellow slurry was stirred for 3 h, Sampled for HPLC. Charged H2O (30.0 L ,5 V) dropwise into the flask at -5±5 °C and stirred for 1 h. Separated the organic phase and washed the aqueous phase with DCM (12.0 L ,2.0 V). The organic phase was combined and concentrated under reduced pressure to ~2 V. Charged the crude intermediate and H2O (12.0 L, 2 V) into the reactor and the mixture was cooled to 0±5 °C. Charged N2H4-H2O (12.9 kg, 4.0 eq., 80 %w / w in H2O) dropwise into the reactor at 0±5 °C. Heated the reaction mixture to 70±5 °C and stirred for 16 hr at 70±5 °C. Sampled for HPLC. The reaction was cooled to 25±5 °C. Charged Na2SO4(3.0 kg, 0.5 w / w) into the reactor. Stirred until the solid is fully dissolved. Extracted the aqueous solution with DCM (30.0 L, 5.0 V x 3). Combined the organic phase and concentrated under reduced pressure to ~2 V. Charged MEK (12.0 L ,2 V) to the reactor at 25 ± 5 °C and stirred for 30 min. Concentrated the reaction mixture at 30 ± 5 °C to ~2 V. Charged n-Heptane (30.0 L ,5 V) to the reactor at 25 ± 5 °C and stirred for at least 1 hr. Filtered and washed the cake with n- heptane (6.0 L ,1 V) twice. Dried at 50±5 °C for 16 hr. Obtained pyridazinone as a light yellow to off-white solid (2.7 kg, 47.5% isolated yield).JH NMR (400 MHz, DMSO-t / 6) 8 12.94 (s, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.30 - 7.19 (m, 1H), 2.06 (d, J = 1.4 Hz, 3H).

[0212] Charged CH3CN (20.0 L, 4 V) and pyridazinone (5.0 kg ,1.0 eq.) into the reactor A at 25±5 °C. The reaction was backfilled with N2for three times. Charged POC13(9. 1 kg, 1 .3 eq.) dropwise into the reactor A over 0.5 h at25±5 °C. Heated the reaction to 80±5 °C and stirred for 3 h. Sampled for HPLC. The reaction mixture was cooled to 30±5 °C and concentrated under reduced pressure to ~ 2 V. Charged the concentrated reaction mixture dropwise into the H2O (10.0 L, 2 V) in reactor B at 30±5 °C. Charged 20 wt% Na2CO3(35.0 L, 7 V) dropwise into the reactor B at 10±5 °C until pH 5~6. The resulting aqueous phase was extracted with ethyl acetate (25.0 L, 5.0 V) twice. The organic phase was combined and charged activated charcoal (0.5 kg, 0.1 w / w). The mixture was stirred for 3 h at 25±5 °C. Filtered and washed with ethyl acetate (2.5 L ,0.5 V). Concentrated the filtrate under reduced pressure to ~ 2 V. Charged the concentrated filtrate dropwise into n-heptane (35.0 L, 7 V) at 15±5 °C in a flask. The resulting mixture was further concentrated to 3~4 V at 35±5 °C. Cooled the mixture to 15±5 °C and stirred for 2 h. Filtered and washed with heptane (5.0 L, 1 V) twice. Dried the cake with N2flush at 25±5 °C for 16 h. Obtained chloropyridazine as brown solid (5.0 kg, 85% isolated yield). 1H NMR (400 MHz, DMSO-t / 6) 6 9.10 (d, J = 4.9 Hz, 1H), 7.75 (d, J = 4.9 Hz, 1H), 2.38 (s, 3H).WSGR Docket No. 56756-709.601IL Synthesis Compound 1, Hydrochloride PolymorphsCompound 1 Compound 1 HCI saltExample 2 A: Synthesis of Crystalline Compound 1, Hydrochloride Form 1

[0213] Compound 1, free form (about 6.0g, synthesized as describedin US2023 / 0295113) was weighed into a 400 mL glass reaction kettle. Acetone (78 mL) was added under stirring at 50°C for about 5 min. To this suspension was added an HCI solution (18.86 mL, -1.05 equivalents by molar ratio, diluted by acetone) and Compound 1, hydrochloride Form 1 seed crystals (5 mg) (seed crystals were prepared by crystallizing the HCI salt from an isopropanol solution at 40 °C and slowly coolingto 5 °C over 7 hours). After stirring at 50°C for 2 hours, the suspension was cooled to 25°C and kept stirring at 25 °C for about 1 day. Solids were collected by centrifugation and then dried at 40°C under vacuum for about 16 hours. Then, the sample was dried at 50°C under vacuum for 2 hours and dried at 60°C under vacuum for 3 hours to afford 5.9 g of Compound 1, hydrochloride Form 1 (5.9 g, 87.7% yield). 'H NMR (400 MHz, DMSO-t / e) 8 10.71 (s, 1H), 10.03 (br s, lH), 7.64 (s, 1H), 7.45 (d, 1H), 7.33 (m, 2H), 6.12 (br s, 1H), 4.72 (d, 1H), 2.90 - 2.75 (m, 5H), 2.23 (s, 3H), 1.82 - 1.73 (m, 2H), 1.50 - 1.30 (m, 2H).Example 2B: Synthesis of Crystalline Compound 1, Hydrochloride Form 2

[0214] Compound 1, hydrochloride Form 1 (about 200 mg) was dissolved in ethanol (40 mL). The clear solution was purged by N2at room temperature and the resultant solids were collected to afford Compound 1, hydrochloride Form 2. 'H NMR (400 MHz, DMSO-<6) 8 10.64 (s, 1H), 9.54 (br s, 1H), 7.63 (s, 1H), 7.45 (d, 1H), 7.32 (m, 2H), 6.12 (d, 1H), 4.72 (m, 1H), 2.88 - 2.78 (m, 5H), 2.23 (s, 3H), 1.84 (m, 1H), 1.68 (m, 1H), 1.55 (m, 1H), 1.36 (m, 1H).III. Characterization of PolymorphsExample 3 : X-ray Powder Diffraction (XRPD)

[0215] XRPD patterns were collected using a Bruker D8 Advance diffractometer with the following parameters in either Method 1 or Method 2: Method 1WSGR Docket No. 56756-709.601Method 2

[0216] XRPD analysis of Compound 1, hydrochloride Form 1 (Figure 1) showed it to be crystalline with characteristic peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2- Theta.

[0217] XRPD analysis of Compound 1, hydrochloride Form 2 (Figure 4) showed it to be crystalline with characteristic peaks at 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2- Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta.Example 4: Thermogravimetric Analysis (TGA)

[0218] TGA was carried out using the following parameters:WSGR Docket No. 56756-709.601

[0219] TGA of Compound 1, hydrochloride Form 1 (Figure 2) showed about 0.8% weight loss at about 120°C.

[0220] TGA of Compound 1, hydrochloride Form 2 (Figure 5) showed about 1.0% weight loss at about 100°C.Example 5: Differential Scanning Calorimetry (DSC)

[0221] DSC was performed using the following parameters:

[0222] DSC analysis of Compound 1, hydrochloride Form 1 (Figure 3) showed no melting point before 250°C.

[0223] DSC analysis of Compound 1, hydrochloride Form 2 (Figure 6) showed no melting point before 250°C.IV. Polymorph ScreenExample 6: Slow Evaporation Method

[0224] About 25 mg of Compound 1, hydrochloride Form 1 was dissolved in 0.15-19 mL of selected solvents. Obtained solutions were filtered through a 0.45pm syringe nylon membrane filter. The clear solutions were slowly evaporated at ambient conditions (about 23 -24°C, 70%- 77%RH). XRPD characterization was directly conducted for obtained solid samples. Results are shown in Table 1.Table 1WSGR Docket No. 56756-709.601Example 7: Fast Evaporation Method

[0225] About 25 mg of Compound 1, hydrochloride Form 1 was dissolved in 0.15-19 mL of selected solvents. Obtained solutions were filtered through a 0.45pm syringe nylon membrane filter. The clear solutions were fast evaporated at room temperature (about 23 -24°C) under a dry nitrogen flow. XRPD characterization was directly conducted for obtained solid samples. Results are shown in Table 2.Table 2Example 8: Crystallization by Addition of Anti-solvent

[0226] About 40 mg of Compound 1, hydrochloride Form 1 was dissolved in 0.28-2.3 mL of selected solvents at ambient temperature. Obtained solutions were filtered through a 0.45pm syringe membrane filter. 4 folds of anti -solvent were added into the clear solutions slowly until a large amount of solids precipitated out. Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000 rpm. XRPD characterization was directly conducted for obtained solid samples. Results are shown in Table 3.Table 3WSGR Docket No. 56756-709.601Example 9: Crystallization by Reverse Addition of Anti-solvent

[0227] About 40 mg of Compound 1, hydrochloride Form 1 was dissolved in 0.28-2.3 mL of selected solvents at ambient temperature. Obtained solutions were filtered through a 0.45pm syringe membrane filter. The clear solutions were added into 4 folds of anti -solvent quickly.Precipitates were collected by centrifugation filtration through a 0.45 pm nylon membrane filter at 14,000 rpm. XRPD characterization was directly conducted for obtained solid samples. Results are shown in Table 4.Table 4WSGR Docket No. 56756-709.601Example 10: Crystallization by Vapor Diffusion

[0228] About 40 mg of Compound 1 , hydrochloride Form 1 was dissolved in a minimal amount of selected solvents at ambient temperature. Obtained solutions were filtered through a 0.45pm syringe membrane filter. The clear solutions were transferred into 2 mL or 4 mL glass vials without lids. Then these lidless vials were placed in 40 mL or 20 mL glass vials. Anti-solvents were added to the 40 mL or 20 mL vials. Then these 40 mL or 20 mL vials were capped tightly and placed at ambient temperature. Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000 rpm. XRPD characterization was directly conducted for obtained solid samples. Results are shown in Table 5.Table 5V. Crystalline Salt FormsExample 11 : Competitive Equilibrium Experiments

[0229] To determine relative stability of Compound 1 HC1 salt Form 1 and HC1 salt Form 2, competitive equilibration experiments were conducted in different solvent systems. About 7 mg of Compound 1, hydrochloride Form 1 and about? mg of Compound 1, hydrochloride Form 2 were added to 0.3-1 mL saturated solutions of selected solvents. Obtained suspensions wereWSGR Docket No. 56756-709.601 stirred at 50°C for 3 -5 days. Solid parts (wet cakes) were isolated by centrifugation filtration and investigated by XRPD. Results are shown in Table 6.Table 6

[0230] From the competitive equilibrium experiments, Compound 1, hydrochloride Form 1 is the most stable form.Example 12: Stability Test of Compound 1, Hydrochloride Form 1

[0231] Compound 1, hydrochloride Form 1 (purity 99.3%) was placed at 25°C / 92% RH in an open container, at 40°C / 75% RH in an open container and at 60°C in a closed container for 4 weeks. The results are summarized in Table 7. In another stability test, at25°C and 60%RH for 24 months Compound 1, hydrochloride Form 1, showed no form change, no loss of purity, and no color change.Table 7Example 13 : Single Crystal X-Ray Diffraction

[0232] A single crystal structure of Compound 1, hydrochloride Form 1 was collected using crystals grown in Example 9 (Methanol 0.8 mL / ACN 3.2 mL). Data were collected using a B inker D8 VENTURE diffractometer. A crystal structure of Compound 1, hydrochloride Form 1 was determined at 170(2) K with single crystal obtained in MeOH / ACN by vapor diffusion (Example 9). This crystalline form is crystallized in orthorhombic system, P212121 with Rint= 8.7% and the final Rl= [I>2o(I)]= 8.7% at 170(2) K. No solvent molecule is contained in the asymmetric unit. The Ortep image of Compound 1, hydrochloride Form 1 is shown in Figure 7.WSGR Docket No. 56756-709.601Crystal data:Data collection:Refinement:VI. Biological DataExample 14: Human Monocyte IL- lb AssayWSGR Docket No. 56756-709.601

[0233] Serially diluted testing compounds were incubated with 200 mL of fresh human whole blood for 0.5 hours. Cells were primed with 100 ng / mL lipopolysaccharide (LPS) for 3.5 hours at 37°C followed by stimulation with 5 mM ATP for an additional 45 minutes. The concentration of IL-lb concentration in the supernatant was determined with commercially available ELISA kits. Negative controls are wells without stimulation, while positive controls are wells with stimulation but only DMSO without compounds added. After background subtraction, compound treatment wells were then normalized to the positive controls for IC50 calculations. Compound 1 IL-lb IC50 is less than 500 11M.

Claims

WSGR Docket No. 56756-709.601CLAIMSWhat Is Claimed:

1. A crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt or solvate thereof.

2. The crystalline form of claim 1, wherein the crystalline form of 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol is a hydrochloride salt and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride is Form 1 with an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2- Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta.

3. The crystalline form of claim 1 or claim 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1.

4. The crystalline form of claim 1 or claim 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta.

5. The crystalline form of claim 1 or claim 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least eight characteristic peaks selected from peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta.

6. The crystalline form of claim 1 or claim 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at about 13.3° 2-Theta, 13.8° 2-Theta, 14.5° 2-Theta, 15.7° 2-Theta, 16.4° 2-Theta, 19.5° 2-Theta, 20.0° 2-Theta, 22.1° 2-Theta, 22.7° 2-Theta, and 28.8° 2-Theta.

7. The crystalline form of any one of claims 1 -6, wherein the crystalline form has a thermo- gravimetric analysis (TGA) substantially similar to the one set forth in Figure 2.

8. The crystalline form of any one of claims 1-7, wherein the crystalline form has a DSC thermogram substantially similar to the one set forth in Figure 3.

9. The crystalline form of any one of claims 1-8, wherein the crystalline form has a DSC thermogram that shows no melting point before 250°C.

10. The crystalline form of any one of claims 1-9, wherein the crystalline formis obtained from acetone.WSGR Docket No. 56756-709.60111. The crystalline form of any one of claims 1-10, wherein the crystalline form is an anhydrate.

12. The crystalline form of claim 1, wherein the crystalline form of 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol is a hydrochloride salt and the crystalline form of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3- yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride is Form 2 with an X-ray powder diffraction (XRPD) pattern with at least four characteristic peaks selected from peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2- Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta.

13. The crystalline form of claim 1 or claim 12, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 4.

14. The crystalline form of claim 1 or claim 12, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with at least six characteristic peaks selected from peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta.

15. The crystalline form of claim 1 or claim 12, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at about 11.6° 2-Theta, 13.9° 2-Theta, 17.7° 2-Theta, 19.6° 2-Theta, 19.8° 2-Theta, 20.9° 2-Theta, 22.4° 2-Theta, and 23.2° 2-Theta.

16. The crystalline form of any one of claims 1 and 12-15, wherein the crystalline form has a thermo-gravimetric analysis (TGA) substantially similar to the one set forth in Figure 5.

17. The crystalline form of any one of claims 1 and 12-16, wherein the crystalline form has a DSC thermogram substantially similar to the one set forth in Figure 6.

18. The crystalline form of any one of claims 1 and 12-17, wherein the crystalline form has a DSC thermogram that shows no melting point before 250°C.

19. The crystalline form of any one of claims 1 and 12-18, wherein the crystalline form is obtained from ethanol.

20. The crystalline form of any one of claims 1 and 12-19, wherein the crystalline form is an anhydrate.

21. The crystalline form of any one of claims 1 -20 for use in medicine.

22. A pharmaceutical composition comprisingthe crystalline form of any one of claims 1 -20, and a pharmaceutically acceptable excipient.WSGR Docket No. 56756-709.60123. A method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of claims 1 -20, or a pharmaceutically acceptable salt or solvate thereof.

24. The method of claim 23, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity and gout.

25. A method of treating a liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of claims 1 -20, or a pharmaceutically acceptable salt or solvate thereof.

26. The method of claim 25, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis.

27. A method of treating a lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of claims 1 -20, or a pharmaceutically acceptable salt or solvate thereof.

28. The method of claim 27, wherein the lung disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and pulmonary idiopathic fibrosis.

29. A method of treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of claims 1 -20, or a pharmaceutically acceptable salt or solvate thereof.

30. The method of claim 29, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington’s disease, traumatic brain injury, ischemic stroke and reperfusion, haemorrhagic stroke, epilepsy, and depression.31 . A method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of claims 1 -20, or a pharmaceutically acceptable salt or solvate thereof.

32. The method of claim 31, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammatory bowel disease, Crohn’s disease, and ulcerative colitis.

33. A method of treating a cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a crystalline form of any one of claims 1 -20, or a pharmaceutically acceptable salt or solvate thereof.

34. The method of claim 33, wherein the cardiovascular disease is atherosclerosis or stroke.WSGR Docket No. 56756-709.60135. A process for the preparation of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1), comprising:A) the reaction of compound with the structure:with N-bromosuccinimide, followed by reaction with the compound with the structure:OMewith dicyclohexyl(2',6'-dimethoxy[l,l'-biphenyl]-2-yl)phosphane(SPhos), palladium acetate, and tripotassium phosphate to produce a compound with the structure:B) followed by the reaction of the compounds with the structures:C) the reaction of the compound with the structure:chlororuthenium(l+);[(lR,2R)-l,2-diphenyl-2-(3- phenylpropylamino)ethyl]-(4-methylphenyl)sulfonylazanide, tri ethylamine, and formic acid to produce a compound with the structure:WSGR Docket No. 56756-709.601D) followed by the reaction of the compound with the structure:hydrochloric acid and N-bromosuccinimide followed by hydrazine hydrate to produce a compound with the structure:E) followed by the reaction of the compound with the structure:boron tribromide to produce 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) having the structure:(Compound 1).

36. The process of claim 35, further comprising the reaction of 2-(6-((R)-hydroxy((R)-l- methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) with hydrochloric acid to produce 2-(6-((R)-hydroxy((R)-l -methylpiperidin-3-yl)methyl)- 4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloric acid salt (Compound 1, HC1 salt).

37. A process for the preparation of 2-(6-((R)-hydroxy((R)-l-methylpiperidin-3-yl)methyl)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1):WSGR Docket No. 56756-709.601(Compound 1), comprising contacting the compound with the structure:boron tribromide in the presence of a solvent.

38. The process of claim 37, wherein the solvent is selected from dichloromethane, 1,2- dichloroethane, 1,4-dioxane, tetrahydrofuran, dimethoxy ethane, chlorobenzene, and trifluorotoluene.

39. The process of claim 37 or claim 38, wherein the solvent is dichloromethane.

40. The process of any one of claims 37-39, wherein the compound with the structure:prepared by a process comprising contacting the compound with the structure:hydrochloric acid and N-bromosuccinimide followed by hydrazine hydrate in the presence of a solvent.

41. The process of claim 40, wherein the solvent is selected from dimethylformamide, dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,4-dioxane, tetrahydrofuran (THF), and 2-methyltetrahydrofuran.

42. The process of claim 40 or claim 41, wherein the solvent is 2-methyltetrahydrofuran.

43. The process of any one of claims 37-42, wherein the compound with the structure:WSGR Docket No. 56756-709.601, , phenylpropylamino)ethyl]-(4-methylphenyl)sulfonylazanide, tri ethylamine, and formic acid in the presence of a solvent.

44. The process of claim 43, wherein the solvent is methanol.

45. The process of any one of claims 37-44, wherein the compound with the structure:prepared by a process comprising contacting the compounds with the structures:with a base in the presence of a solvent.

46. The process of claim 45, wherein the base is n-BuLi.

47. The process of claim 45 or claim 46, wherein the solvent is selected from 1,4-dioxane, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), 2-methyltetrahydrofuran, and acetonitrile.

48. The process of any one of claims 45-47, wherein the solvent is tetrahydrofuran (THF).

49. The process of any one of claims 37-48, wherein the compound with the structure:prepared by a process comprising contacting the compound with the structure:WSGR Docket No. 56756-709.601with N-bromosuccinimide in the presence of a solvent, followed by reaction of the compound with the structure:OMe with dicyclohexyl(2',6'-dimethoxy[l,l'-biphenyl]-2-yl)phosphane (SPhos), palladium acetate, and tripotassium phosphate.

50. The process of claim 49, wherein the solvent is selected from tetrahydrofuran (THF), 2- m ethyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy ethane, dimethylacetamide (DMA), and N-methyl pyrrolidone (NMP).

51. The process of claim 49 or claim 50, wherein the solvent is tetrahydrofuran (THF).

52. A compound having a structure selected from:pharmaceutically acceptable salt thereof.

53. A compound having a structure selected from:pharmaceutically acceptable salt thereof.

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