Synthetic methods for preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-n-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-n-prop-2-ynyl-1,3-thiazol-2-amine

Abstract

The present disclosure relates to the fields of chemistry and medicine, more particularly to processes for making 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), pharmaceutically acceptable salts, and crystalline forms thereof, for the treatment of congenital adrenal hyperplasia (CAH).

Description

SYNTHETIC METHODS FOR PREPARATION OF 4-(2-CHLORO-4-METHOXY-5- METHYLPHENYL)-N-[(1S)-2-CYCLOPROPYL-1-(3-FLUORO-4- METHYLPHENYL)ETHYL]-5-METHYL-N-PROP-2-YNYL-1,3-THIAZOL-2-AMINEFIELD OF THE INVENTIONThe present disclosure relates to the fields of chemistry and medicine, more particularly to processes for making 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), pharmaceutically acceptable salts, and crystalline forms thereof, for the treatment of congenital adrenal hyperplasia (CAH).BACKGROUND OF THE INVENTIONClassic congenital adrenal hyperplasia (CAH) is a disease that includes a group of autosomal recessive disorders that result in an enzyme deficiency that alters the production of adrenal steroids due to 21-hydroxylase deficiency, a condition that results in little or no cortisol biosynthesis. One clinical manifestation of the absence of cortisol is the lack of feedback inhibition of pituitary adrenocorticotropic hormone (ACTH) secretion. Increased ACTH levels cause adrenal hyperplasia and the enzyme mutation causes a shunting of cortisol precursor steroids to alternate pathways. Most notably, the shunting of androgens leads to virilization and other developmental complications in females and the over-accumulation of ACTH is associated with the formation of testicular adrenal rest tumors in males. In addition, since the same enzyme (21-hydroxylase) is used in the pathway for the biosynthesis of the mineralocorticoids, a number of these patients suffer from aldosterone deficiency which can result in dehydration and death due to salt-wasting. The prevalence of classic 21-hydroxylase deficiency CAH in the US general population, based on newborn screening, has been documented as 1:10,000 to 1:20,800 (Trakakis et al., “An update to 21-hydroxylase deficient congenital adrenal hyperplasia,” Gynecol. Endocrinol. (2010) 26(1):63-71; Hertzberg et al., “Birth prevalence rates of newborn screening disorders in relation to screening practices in the United States,” J. Pediatr. (2011) 159(4):555-560).Pediatric patients from birth through adolescence, and females in particular, appear to be the most vulnerable population of CAH sufferers and represent the subgroup of patients with the greatest unmet medical need (Cheng and Speiser, “Treatment outcomes in congenital adrenal hyperplasia,” Adv. Pediatr. (2012) 59(1):269-281; Merke and Poppas, “Management of adolescents with congenital adrenal hyperplasia,” Lancet Diabetes Endocrinol. (2013) 1(4):341-352). Excessive androgenproduction in these younger patients results in early onset puberty and adrenarche, changes in skeletal maturation patterns, short stature caused by premature growth plate fusion, as well as significant hirsutism and acne problems. While survival is properly ensured through steroid replacement strategies based on physiologic dosing of glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone), these doses are often inadequate to suppress the accumulating ACTH and overproduction of progestogens and androgens (e.g., 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone). The uncontrolled symptoms of androgen excess, indeed, have a substantial impact on the day-to-day functioning and development of these patients.Currently, exogenous corticosteroids are the standard of care for treating patients with classic CAH. This treatment is used to correct the cortisol deficiency and reduce the excessive ACTH levels and androgen excess. However, the dose and duration of steroid use required to suppress ACTH are typically well above the normal physiological level used for cortisol replacement alone (as in patients with Addison’s disease). This increased exposure to glucocorticoids can lead to iatrogenic Cushing’s syndrome, increased cardiovascular risk factors, glucose intolerance, reduced growth velocity, and decreased bone mineral density in CAH patients (Elnecave et al., “Bone mineral density in girls with classical congenital adrenal hyperplasia due to CYP21 deficiency,” J. Pediatr. Endocrinol. Metab. (2008) 21(12):1155-1162; King et al., “Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia,” J. Clin. Endocrinol. Metab. (2006) 91(3):865-869; and Migeon and Wisniewski, “Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Growth, development, and therapeutic considerations,” Endocrinol. Metab. Clin. North Am. (2001) 30(1):193-206).It has been demonstrated in clinical trials that orally active compounds that block CRF1, such as 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), provide a reduction from baseline in 17-hydroxyprogesterone (17-OHP) and androstenedione levels in amounts believed to allow use of lower, more physiologic doses of glucocorticoid (e.g. hydrocortisone) in patients with CAH. The structure of Compound 1 is shown below:Accordingly, a significant need exists for efficient methods for the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) to support further clinical trials and commercial efforts.SUMMARY OF THE INVENTIONThe present invention provides, inter alia, processes for the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) and intermediates related thereto.The processes and intermediates of the present invention are useful in preparing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), pharmaceutical salts, crystalline forms, and pharmaceutical compositions that are useful in the treatment of corticotropin releasing factor 1 (CRF1) receptor-mediated disorders.One aspect of the present invention pertains to processes for preparing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof:comprising: alkylating (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:with a Compound of Formula (Ii):wherein: LG is a leaving group;in the presence of an alkylating-step solvent, a phase-transfer catalyst, an alkylating-step base, and water to form 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof.One aspect of the present invention pertains to processes for preparing (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:comprising:cyclizing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof:with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) or a tautomeric form thereof:in the presence of a cyclizing-step solvent to form (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof.One aspect of the present invention pertains to processes for preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof:comprising:deprotecting a Compound of Formula (Ig), or a salt thereof,wherein:R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen;in the presence of a deprotecting-catalyst, hydrogen, and a deprotecting-step solvent to form (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof.One aspect of the present invention pertains to processes for preparing a Compound of Formula (Ig), or a salt thereof,wherein: R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen;comprising:reducing a Compound of Formula (Ie):in the presence of a reducing-catalyst, hydrogen, and a reducing-step solvent to form a Compound of Formula (Ig), or a salt thereof.One aspect of the present invention pertains to processes for preparing a Compound of Formula (Ie):wherein:R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen;comprising:condensing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A):with a Compound of Formula (Ic), or a salt thereof:in the presence of a condensing-step acid and a condensing-step solvent to a Compound of Formula (Ie).One aspect of the present invention pertains to processes for preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A):comprising: reacting 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A):with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a reacting-step solvent to form 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).One aspect of the present invention pertains an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base).One aspect of the present invention pertains to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt).One aspect of the present invention pertains to pharmaceutical compositions comprising a crystalline form (Compound 1, free base) as described herein, and a pharmaceutically acceptable carrier.One aspect of the present invention pertains to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form (Compound 1, free base) as described herein.One aspect of the present invention pertains to pharmaceutical compositions comprising a crystalline form (Compound 1, tosylate salt) as described herein, and a pharmaceutically acceptable carrier.One aspect of the present invention pertains to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form (Compound 1, tosylate salt) as described herein.One aspect of the present invention pertains to compositions comprising:a. 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof; andb. at least one compound selected from:(S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A);(S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa);(S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb);4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine (Compound IIc);ethanol; andpropargyl bromide.One aspect of the present invention pertains to methods of treating a disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; wherein the subject has abnormal levels of CRF1.One aspect of the present invention pertains to methods of treating a Corticotropin Releasing Factor 1 (CRF1) disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein.One aspect of the present invention pertains to methods of treating congenital adrenal hyperplasia (CAH), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein.One aspect of the present invention pertains to uses of an anhydrous crystalline form (Compound 1, free base) as described herein; or the crystalline form (Compound 1, tosylate base) as described herein; for the manufacture of a medicament for the treatment of a subject wherein the subject has abnormal levels of CRF1.One aspect of the present invention pertains to uses of an anhydrous crystalline form (Compound 1, free base) as described herein; or the crystalline form (Compound 1, tosylate base) as described herein; for the manufacture of a medicament for the treatment of a Corticotropin Releasing Factor 1 (CRF1) disorder.One aspect of the present invention pertains to uses of an anhydrous crystalline form (Compound 1, free base) as described herein; or the crystalline form (Compound 1, tosylate base) as described herein; for the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH).One aspect of the present invention pertains to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treatment of the human or animal body by therapy.One aspect of the present invention pertains to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treatment of a disorder in a subject wherein the subject has abnormal levels of CRF1.One aspect of the present invention pertains to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treatment of a Corticotropin Releasing Factor 1 (CRF1) disorder.One aspect of the present invention pertains to an anhydrous crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; a pharmaceutical composition as described herein; a pharmaceutical product as described herein; or a composition as described herein; for use in a method of treating congenital adrenal hyperplasia (CAH).One aspect of the present invention pertains to Compounds of Formula (Ie):wherein:R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen.One aspect of the present invention pertains to Compounds of Formula (Ig) or a salt thereof:wherein:R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen.One aspect of the present invention pertains to processes for preparing a pharmaceutical composition comprising admixing a crystalline form (Compound 1, free base) as described herein; a crystalline form (Compound 1, tosylate base) as described herein; or a composition according as described herein; and a pharmaceutically acceptable carrier.These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.BRIEF DESCRIPTION OF THE FIGURES FIG.1 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) prepared according to Example 3.FIG.2 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) prepared according to Example 3.FIG.3 shows an exemplary Gravimetric Vapor Sorption (GVS) for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) as described in Example 4.FIG.4 shows general synthetic schemes for the preparation of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), 4-Chloro-2-(methoxy-13C-d3)-1-methylbenzene (Compound 7A’), and 1-(2-Chloro-4-(methoxy-13C-d3)-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A’). The synthesis of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) has previously been described in International Publication Number WO2010 / 125414 by Sanofi-Aventis.FIG.5 shows a general scheme for the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1).FIG.6 shows a general scheme for the preparation of (S)-4-(2-chloro-4-(methoxy-13C-d3)-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound 3).FIG.7 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1).FIG.8 shows an overlay of the exemplary X-ray powder diffraction (XRPD) patterns from Figure 1 and Figure 7 for crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), and although the intensities for certain peaks are rather dramatic, the overlay clearly shows substantially the same peak positioning.FIG.9 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A).FIG.10 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A).FIG.11 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A).FIG.12 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A).FIG.13 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt).FIG.14 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt).FIG.15 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).FIG.16 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).FIG.17 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt).FIG.18 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt).FIG.19 shows the dissolution performance of several spray-dried dispersion formulations in 0.5 wt% simulated intestinal fluid (SIF) in phosphate buffered saline (PBS), pH 6.5.FIG.20 shows the vertical membrane flux cell integrated in the µDiss ProfilerTM used for the membrane flux assay.FIG.21 shows non-sink dissolution data for several spray-dried dispersion formulations and the compound of Formula (I) in 0.5 wt% SIF in PBS, pH 6.5.FIG.22 is a graph showing membrane flux of 1 mg / mL GB / IB 0.5 wt% SIF doses of Compound 1 and various spray-dried dispersion formulations over time. The solid lines indicate flux (µg min-1 cm-2) and the broken lines indicate concentration (µg / mL) in 0.5% SIF.FIG.23 is a flow diagram of the spray drying manufacturing process used to prepare a 1000 g batch of an SDD containing 25% of Compound 1 and 75% PVP / VA 64.FIG.24 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt).FIG.25 shows an exemplary Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermograms for a sample of crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt).DETAILED DESCRIPTION OF THE INVENTIONDEFINITIONSUnless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.The term “about” preceding a temperature have an allowable variability of ±5°C. In all other instances, unless otherwise specified, the term “about” preceding a stated value includes the stated value and also includes ±20% of the stated value, and includes more specifically values of ±10%, ±5%, ±2%, and ±1% of the stated value.To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that when a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any range therein.As used herein, “room temperature”, or “RT”, refers to the ambient temperature of a typical laboratory, which is generally around 25ºC.As used herein, “administration”, or “administering”, refers to a method of giving a dosage of a compound or pharmaceutical formulation to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.The term “C6-C10 aryl” refers to a saturated ring system containing 6 to 10 carbon atoms that can contain a single ring or two fused rings and is aromatic, such as phenyl and naphthalenyl. When one or more substituents are present on the “aryl” ring, the substituent(s) can be bonded at any available ring carbon.The term “C1-C6 alkyl” and “C1-C4 alkyl” refers to a saturated straight or branched carbon radical containing 1 to 6 carbons (i.e., “C1-C6 alkyl”) or 1 to 4 carbons (i.e., “C1-C4 alkyl”). Some embodiments are 1 to 5 carbons (i.e., C1-C5 alkyl), some embodiments are 1 to 3 carbons (i.e., C1-C3 alkyl), and some embodiments are 1 or 2 carbons. Examples of an alkyl group include: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neo-pentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl and the like.The term “C1-C4 alkylsulphonyloxy” refers to a radical consisting of a C1-C4 alkyl group attached directly to the sulfur of an SO3 group. The “C1-C4 alkylsulphonyloxy” group can be represented by the formula: C1-C4 alkylS(=O)2O- or the following:The term C1-C4 alkyl has the same definition as found herein. Examples include: methanesulfonate [CH3S(=O)2O-, or (methylsulfonyl)oxy], ethanesulfonate, propanesulfonate, isopropylsulfonate, butanesulfonate, and the like.The term “C1-C6 alkoxy” refers to a radical consisting of a C1-C6 alkyl group attached directly to an oxygen atom, wherein C1-C6 alkyl has the same definition as found herein. Some embodiments contain 1 to 5 carbons (i.e., C1-C5 alkoxy). Some embodiments contain 1 to 4 carbons (i.e., C1-C4 alkoxy). Some embodiments contain 1 to 3 carbons (i.e., C1-C3 alkoxy). Some embodiments contain 1 or 2 carbons. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, sec-butoxy, and the like.The term “amorphous” means a solid that is in a non-crystalline state. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long-range ordering. The solid-state form of a solid can be determined by polarized light microscopy, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or other standard techniques known to those of skill in the art.The term “C6-C10 arylsulfonyloxy” refers to a radical consisting of an aryl group attached directly to the sulfur atom of an SO3 group and can be represented by the formula aryl-S(=O)2O- or the following:The term aryl has the same definition as found herein. Examples include: benzenesulfonate [PhS(=O)2O-, or (phenylsulfonyl)oxy, besylate], (naphthalen-1-ylsulfonyl)oxy, and (naphthalen-2-ylsulfonyl)oxy.The term “composition” refers to a compound or crystalline form thereof, including but not limited to, salts, solvates, and hydrates of a compound of the present invention, in combination with at least one additional component, such as, a composition obtained / prepared during synthesis, preformulation, in-process testing / control (e.g., TLC, HPLC, NMR samples), and the like.The term “% crystallinity” or “crystalline purity” refers to the percentage of a crystalline form in a preparation or sample. It is understood that the preparation or sample may contain other forms, such as, an amorphous form of the same compound, or different crystalline form(s) of the same compound, or mixtures thereof. In some embodiments, the crystalline form can be isolated as the desired form (i.e., the crystalline form as described herein) with a crystalline purity of at least about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight, about 95% by weight, about 96% by weight, about 97% by weight, about 98% by weight, or about 99% by weight. In some embodiments, the crystalline form can be isolated with a purity of about 90% or greater by weight. In some embodiments, the crystalline form can be isolated with a purity of about 95% or greater by weight. In some embodiments, the crystalline form can be isolated with a purity of about 99% or greater by weight.When describing particle size for a sample, “D10” , “D50” , “D90” are used and have the following definitions: the term “D10” as used herein means that 10% of the particles (based on volume) are smaller than or equal to the indicated size; the term “D50” as used herein means that 50% of the particles (based on volume) are smaller than or equal to the indicated size; and the term “D90” as used herein means that 90% of the particles (based on volume) are smaller than or equal to the indicated size. As an example, when a sample as a D10 of 21 µM, then 10% of the particles in that sample are smaller than or equal to 21 µM based on volume.The term “in need of treatment” and the term “in need thereof” when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit, or ameliorate the disease, condition, or disorder.The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo. In some embodiments, halogen is chloro, bromo, or iodo. In some embodiments, halogen is fluoro, chloro, or bromo. In some embodiments, halogen is fluoro. In some embodiments, halogen is chloro. In some embodiments, halogen is bromo. In some embodiments, halogen is iodo.The term “C1-C6 haloalkyl” refers to a radical consisting of a C1-C6 alkyl group substituted with one or more halogens, wherein C1-C6 alkyl has the same definition as found herein. The C1-C6 haloalkyl may be fully substituted in which case it can be represented by the formula CnL2n+1, wherein L is a halogen and “n” is 1, 2, 3, 4, 5, or 6. When more than one halogen is present then they may be the same or different and selected from: fluorine, chlorine, bromine, and iodine. In some embodiments, haloalkyl contains 1 to 5 carbons (i.e., C1-C5 haloalkyl). In some embodiments, haloalkyl contains 1 to 4 carbons (i.e., C1-C4 haloalkyl). In some embodiments, haloalkyl contains 1 to 3 carbons (i.e., C1-C3 haloalkyl). In some embodiments, haloalkyl contains 1 or 2 carbons. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, and the like.The term “hydroxyl” refers to the group -OH.The term “individual” or “subject” refers to any animal, including mammals, such as, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiment “individual” refers to humans. In the context of a clinical trial or screening or activity experiment the subject may be a healthy volunteer or healthy participant without an underlying CFR-mediated disorder or condition or a volunteer or participant that has received a diagnosis for a disorder or condition in need of medical treatment as determined by a health care professional. In the context outside of a clinical trial a subject under the care of a health care professional who has received a diagnosis for a disorder or condition is typically described as a patient.The term “inorganic base” refers to a base that does not include at least one C-H bond and includes at least one alkali metal or alkaline earth metal. Examples of an inorganic base include, but are not limited to, barium carbonate, calcium carbonate, cesium carbonate, lithium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, cesium hydrogen carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, barium hydroxide, calcium hydroxide, cesium hydroxide, lithium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, and the like.As used herein, “leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as a stable species. Suitable leaving groups are well known in the art, e.g., see, March’s Advanced Organic Chemistry, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001 and T. W. Greene, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, 1999. Such leaving groups include, but are not limited to, halogen, optionally substituted alkylsulphonyloxy, and optionally substituted arylsulfonyloxy. Examples of some leaving groups include chloro, bromo, iodo, mesylate, tosylate, triflate, nosylate, and brosylate.The term “nitro” refers to the group -NO2.The term “pediatric subject” refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)) see e.g., Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph et al., Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.In some embodiments, a “pediatric subject” is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.The phrase “pharmaceutically acceptable” refers to compounds (and salts thereof), compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulations. In addition, various excipients, such as are commonly used in the art, can be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.The term “pharmaceutical composition” refers to a specific composition comprising at least one active ingredient; including but not limited to, salts, solvates, and hydrates of compounds of the present invention, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.The term “phase-transfer catalyst” is any ionic catalyst, such as quaternary ammonium salts, that can enable the migration of a reactant from one phase into another phase where the reaction occurs. Suitable leaving groups are well known in the art. Examples include, acetylcholine chloride, (2-aminoethyl)trimethylammonium chloride hydrochloride, benzalkonium chloride, benzyldimethyldecylammonium chloride, benzyldimethyldodecylammonium chloride, benzyldimethylhexadecylammonium chloride, benzyldimethylhexylammonium chloride, benzyldimethyloctylammonium chloride, benzyldimethyltetradecylammonium chloride, benzyldodecyldimethylammonium bromide, benzyltributylammonium bromide, benzyltributylammonium chloride, benzyltributylammonium iodide, benzyltriethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, (3-carboxypropyl)trimethylammonium chloride, cetyltrimethylammonium chloride, cetyltrimethylammonium hydrogensulfate, choline chloride, decyltrimethylammonium bromide, diallyldimethylammonium chloride, didecyldimethylammonium bromide, didodecyldimethylammonium bromide, dihexadecyldimethylammonium bromide, dimethyldioctadecylammonium bromide, dimethylditetradecylammonium bromide, dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, dodecylethyldimethylammonium bromide, dodecyltrimethylammonium chloride, domiphen bromide, heptadecafluorooctanesulfonic acid tetraethylammonium salt, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, hexyltrimethylammonium bromide, malondialdehyde tetrabutylammonium salt, methyltrioctylammonium bromide, methyltrioctylammonium chloride, methyltrioctylammonium hydrogen sulfate, methyltrioctylammonium thiosalicylate, myristyltrimethylammonium bromide, tetrabutylammonium acetate, tetrabutylammonium benzoate, tetrabutylammonium bisulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium cyanide, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogensulfate, tetrabutylammonium iodide, tetrabutylammonium methanesulfonate, tetrabutylammonium methoxide,tetrabutylammonium nonafluorobutanesulfonate, tetrabutylammonium perchlorate, tetrabutylammonium phosphate monobasic, tetrabutylammonium succinimide, tetrabutylammonium sulfate, tetrabutylammonium tetrabutylborate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium tetraphenylborate, tetrabutylammonium thiocyanate, tetrabutylammonium p-toluenesulfonate, tetrabutylammonium trifluoromethanesulfonate, tetradodecylammonium bromide, tetradodecylammonium chloride, tetraethylammonium acetate tetrahydrate, tetraethylammonium benzoate, tetraethylammonium bicarbonate, tetraethylammonium bromide, tetraethylammonium chloride, tetraethylammonium cyanide, tetraethylammonium hexafluorophosphate, tetraethylammonium iodide, tetraethylammonium tetrafluoroborate, tetraethylammonium p-toluenesulfonate, tetraethylammonium trifluoromethanesulfonate, tetraheptylammonium bromide, tetrahexadecylammonium bromide, tetrahexylammonium bromide, tetrahexylammonium chloride, tetrahexylammonium hexafluorophosphate, tetrahexylammonium hydrogensulfate, tetrahexylammonium iodide, tetrahexylammonium tetrafluoroborate, tetrakis(decyl)ammonium bromide, tetramethylammonium acetate, tetramethylammonium bis(trifluoromethanesulfonyl)imide, tetramethylammoniumbisulfate, tetramethylammonium bromide, tetramethylammonium chloride, tetramethylammonium chloride, tetramethylammonium hexafluorophosphate, tetramethylammonium hydrogen sulfate, tetramethylammonium hydrogensulfate, tetramethylammonium iodide, tetramethylammonium silicate, tetramethylammonium sulfate, tetramethylammonium tetrafluoroborate, tetraoctadecylammonium bromide, tetraoctylammonium bromide, tetraoctylammonium chloride, tetrapentylammonium bromide, tetrapentylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium iodide, tetrapropylammonium tetrafluoroborate, tributylammonium pyrophosphate, tributylmethylammonium bromide, tributylmethylammonium chloride, tridodecylmethylammonium chloride, tridodecylmethylammonium iodide, triethylhexylammonium bromide, triethylmethylammonium chloride, trihexyltetradecylammonium bromide, trimethyloctadecylammonium bromide, trimethyloctylammonium bromide, trimethyloctylammonium chloride, trimethylphenylammonium bromide, trimethylphenylammonium chloride, trimethyl-tetradecylammonium chloride, and the like.The term “prescribing” refers to order, authorize, or recommend the use of a drug or other therapy, remedy, or treatment. In some embodiments, a health care provider orally advises, recommends, or authorizes the use of a compound, dosage regimen, or other treatment to an individual. The health care provider may or may not provide a written prescription for the compound, dosage regimen, or treatment. Further, the health care provider may or may not provide the compound or treatment to the individual. For example, the health care provider can advise the individual where to obtain the compound without providing the compound. In some embodiments, a health care provider can provide a written prescription for the compound, dosage regimen, or treatment to the individual. A prescription can be written on paper or recorded on electronic media. In addition, a prescription can be called in (oral) or faxed in (written) to a pharmacy or a dispensary. In some embodiments, a sample of the compound or treatment is given to the individual. As used herein, giving a sample of a compound constitutes an implicit prescription for the compound. Different health care systems around the world use different methods for prescribing and administering compounds or treatments, and these methods are encompassed by the disclosure herein. A health care provider can include, for example, a physician, nurse, nurse practitioner, or other health care professional who can prescribe or administer compounds (drugs) for the disorders disclosed herein. In addition, a health care provider can include anyone who can recommend, prescribe, administer, or prevent an individual from receiving a compound or drug, including, for example, an insurance provider.The terms “prevent”, “preventing”, and “prevention” refer to the elimination or reduction of the occurrence or onset of one or more symptoms associated with a specific disorder. For example, the terms “prevent”, “preventing”, and “prevention” can refer to the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disorder but who has not yet done so. Such individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease, such as the presence of a biomarker. Alternatively, prevention therapy can be administered as a prophylactic measure without prior identification of a risk factor. Delaying the onset of the at least one episode and / or symptom of a disorder can also be considered prevention or prophylaxis.As used herein, the term “reacting”, “contacting”, or “treating” when describing a certain chemical reaction or process is used as known in the art and generally refers to the bringing together chemical reagents and / or intermediates in such a manner so as to allow their interaction at the molecular level to achieve a chemical or physical transformation. In some embodiments, the reacting involves two reagents, wherein one or more equivalents of second reagent are used with respect to the first reagent. The reacting steps of the processes described herein can be conducted for a time and under conditions suitable for preparing the identified product. Additional terms are also used herein solely to provide descriptive clarity between the different process steps and each of these terms have the same definition as described above. These additional terms include, “alkylating”, “cyclizing”, “deprotecting”, “reducing”, and “condensing”.The term “solvate” as used herein refers to a solid-state form of a compound of the present invention or a pharmaceutically acceptable salt thereof which includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.The term “subject”, as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the subject is a human.In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having congenital adrenal hyperplasia (CAH). In some embodiments, the subject is suspected of having CAH. In some embodiments, the subject has a clinical record indicating that the subject has CAH (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject.As used herein, the term “substituted” refers to the replacement of at least one of hydrogen atom of a chemical group with a non-hydrogen substituent or group, the non-hydrogen substituent can be monovalent or divalent. When the chemical group or substituent is divalent, then it is understood that this group is further substituted with another substituent or group. When a chemical group herein is “substituted” it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and the like. Likewise, “substituted with one or more substituents” refers to the substitution of a group substituted with one substituent up to the total number of substituents physically allowed by the group. It is understood that “optionally substituted” as used herein refers to the group being either “unsubstituted” or “substituted” with a group. Accordingly, when a group is “optionally substituted with one or more substituents”, it is understood that the group is either “unsubstituted” or “substituted” and when substituted, the group is substituted with one substituent up to the total number of substituents physically allowed by the group as described above. In some embodiments, a group can be “optionally substituted with one, two, three, or four substituents”. In some embodiments, a group can be “optionally substituted with one, two, or three substituents”. In some embodiments, a group can be “optionally substituted with one or two substituents”. In some embodiments, a group can be “optionally substituted with one substituent”. Further, when a group is substituted with more than one substituent, then the substituents can be identical, or they can be different. Examples of substituents include, without limitation, halogen, alkoxy, alkyl, haloalkyl, hydroxy, nitro.As used herein, “treat”, or “treatment”, refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.The term “therapeutically effective amount” refers to the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising the compound of the invention or a pharmaceutically acceptable salt thereof, that elicits the biological or medicinal response in a tissue, system, animal, or human that is being sought by an individual, researcher, veterinarian, medical doctor, or other clinician or caregiver, which can include one or more of the following:(1) preventing the disorder, for example, preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but does not yet experience or display the relevant pathology or symptomatology;(2) inhibiting the disorder, for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the relevant pathology or symptomatology (i.e., arresting further development of the pathology and / or symptomatology); and(3) ameliorating the disorder, for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the relevant pathology or symptomatology (i.e., reversing the pathology and / or symptomatology).CRYSTALLINE FORMSThe crystalline forms of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) and intermediates related thereto can be identified by their unique solid state signatures with respect to, for example, Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD), and other solid state methods. Further characterization with respect to water or solvent content of the crystalline forms can be gauged by any of the following methods for example, Thermogravimetric Analysis (TGA), DSC and the like.For DSC, it is known that the temperatures observed for thermal events will depend upon sample purity and may also depend on the rate of temperature change, as well as sample preparationtechnique, and the instrument employed. Thus, the values reported herein relating to DSC thermograms can vary by plus or minus about 5°C (i.e., ± about 5°C). The values reported herein relating to DSC thermograms can also vary by plus or minus about 20 joules per gram (i.e., ± about 20 joules per gram).For XRPD, the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the instrument employed. Moreover, instrument variation and other factors can often affect the 2θ values. Therefore, the peak assignments of diffraction patterns can vary by plus or minus about 0.2° (i.e., ± about 0.2°). For TGA, the temperature features reported herein can vary by plus or minus about 5°C (i.e., ± about 5°C). The TGA % weight changes reported herein over a specified temperature range can vary by plus or minus about 2% weight change (i.e., ± about 2% weight change) due to, for example, variations in sample quality and sample size. All X-ray powder diffraction patterns (diffractograms) were obtained using Cu-Kα radiation.Further characterization with respect to hygroscopicity of the crystalline form can be gauged by, for example, Gravimetric Vapor Sorption (GVS). The GVS features reported herein can vary by plus or minus about 5% relative humidity (i.e., ± about 5% relative humidity). The GVS features reported herein can also vary by plus or minus about 2% weight change (i.e., ± about 2% weight change).A. 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, Anhydrous Crystalline Form I).One aspect of the present invention relates to a novel anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) and processes related thereto.A summary of representative physical properties for the anhydrous crystalline form are provided in Table 1 and Table 2.Table 1Certain other XRPD peaks for the anhydrous form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) are shown in Table 2 below.Table 2The GVS profile (adsorption / desorption isotherm) for the anhydrous crystalline Form I of Compound 1 (free base) is shown in Figure 3. The corresponding data in tabular form is provided in Table 3, where there was substantially no weight change after a cycle from 10% RH to 90% RH and back to 10% RH.Table 3One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base). Anhydrous crystalline Form I of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) refers to anhydrous crystalline form that contains 2% or less of water. In some embodiments, the anhydrous crystalline form contains 1% or less water. In some embodiments, the water content is determined by Karl Fischer (KF) analysis.One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2 θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least four peaks, in terms of 2 θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least five peaks, in terms of 2 θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystallineform (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least six peaks, in terms of 2 θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least seven peaks, in terms of 2 θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least eight peaks, in terms of 2 θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least nine peaks, in terms of 2 θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least ten peaks, in terms of 2 θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°.One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 θ, at 14.3° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) an X-ray powder diffraction pattern comprising a peak, in terms of 2 θ, at 19.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising a peak, in terms of 2 θ, at 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1,free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, and 19.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 19.7° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, and 25.7° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, and 29.6° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, and 29.6° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern substantially as shown in Figure 1, wherein by “substantially” is meant that the reported peaks can vary by about ± 0.2 °2 θ.It is understood that peak intensities can vary from one diffractogram to another for the same crystalline form based on any number of factors that are known to those skilled in the art, such as, preferred orientation effects, preparation technique, the sample mounting procedure, the instrumentemployed, etc. In some instances, peak intensities can be rather dramatical. Accordingly, the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not necessarily required. One example is the XRPD for Form I shown in Figure 7 showing substantially the same peak positions but dramatic peak intensity differences. One skilled in the art would understand that Figure 1 and Figure 7 are the XRPD’s for Form I, despite the differences in the peak intensities. Similarly, those skilled in the art would readily be capable of comparing the diffractograms provided herein with a diffractogram generated for an unknown crystal form and confirm whether the diffractogram is characterizing the same crystal form as provided herein or a different form.One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 81°C to about 89.5°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82°C to about 88°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82.5°C to about 88.5°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83°C to about 88°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83.5°C to about 87.5°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram substantially as shown in Figure 2, wherein by “substantially” is meant that the reported DSC features can vary by about ± 5°C and the reported DSC features can vary by about ± 20 joules per gram.One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 1.0% or less weight loss out to about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.9% or less weight loss out to about 125°C. Insome embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.6% or less weight loss out to about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.5% or less weight loss out to about 125°C.One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing about 0.05% to about 1.0% weight loss out to about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.1% to about 0.9% weight loss out to about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.1% to about 0.7% weight loss out to about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.1% to about 0.6% weight loss out to about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing about 0.1% to about 0.4% weight loss out to about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile substantially as shown in Figure 2, wherein by “substantially” is meant that the reported TGA features can vary by about ± 5°C, and the reported TGA features can vary by about ± 2% weight change (i.e., ± about 2% weight change).One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.015% or less weight change after an adsorption / desorption cycle from 10% relative humidity (RH) to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.01% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.008% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.005% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.003% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing substantially no weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.1% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.015% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.08% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.01% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.05% or less weight change from about 10% relative humidity (RH) to about 90% RH; and about 0.008% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.04% or less weight change from about 10% RH to about 90% RH; and about 0.005% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.03% or less weight change from about 10% RH to about 90% RH; and about 0.003% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile showing about 0.2% or less weight change from about 10% RH to about 90% RH; and substantially no weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile substantially as shown in Figure 3, wherein “substantially” is meant that the reported GVS features can vary by plus or minus about 5% relative humidity (i.e., ± about 5% relative humidity) and also vary by plus or minus about 2% weight change (i.e., ± about 2% weight change).One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has:an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2 θ, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 81°C to about 89.5°C;a thermogravimetric analysis profile showing about 0.05% to about 1.0% weight loss out to about 125°C; and / ora gravimetric vapor sorption profile showing about 0.015% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has:an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, and 25.7° ± 0.2°;a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82.5°C to about 88.5°C;a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 125°C; and / ora gravimetric vapor sorption profile showing about 0.005% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has:an X-ray powder diffraction pattern comprising peaks, in terms of 2 θ, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°;a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83°C to about 88°C;a thermogravimetric analysis profile showing about 0.5% or less weight loss out to about 125°C; and / ora gravimetric vapor sorption profile showing about 0.003% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.One aspect of the present invention relates to an anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has:an X-ray powder diffraction pattern substantially as shown in Figure 1;a differential scanning calorimetry thermogram substantially as shown in Figure 2;a thermogravimetric analysis profile substantially as shown in Figure 2; and / ora gravimetric vapor sorption profile substantially as shown in Figure 3.In some embodiments, the anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) can be isolated as the crystalline form described herein, with a crystalline purity of at least about 75% by weight. In some embodiments, about 80% by weight. In some embodiments, about 85% by weight. In some embodiments, about 90% by weight. In some embodiments, about 95% by weight. In some embodiments, about 96% by weight. In some embodiments, about 97% by weight. In some embodiments, about 98% by weight. In some embodiments, about 99% by weight.The manufacturing batches of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) have been prepared with the following particle size distribution characterization, as shown in Table 4.Table 4In some embodiments, the anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) has a particle size D10 of about 8 µM to about 35 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of about 10 µM to about 30 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of about 10 µM to about 27 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of about 12 µM to about 25 µM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of about 12 µM to about 23 µM.

Claims

CLAIMS1. A process for preparing 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1) or a pharmaceutical^ acceptable salt thereof:comprising:alkylating (5)-4-(2-chloro-4-methoxy-5-methylphenyl)-A^-(2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:K Fwith a Compound of Formula (Ii):LG(H)wherein: LG is a leaving group; in the presence of an alkylating-step solvent, a phase-transfer catalyst, an alkylating-step base, and water to form 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof.

2. The process according to claim 1, wherein the Compound of Formula (Ii) and Compound 9Aare present in substantially equal molar quantities.

3. The process according to claim 1, wherein the Compound of Formula (Ii) is present in a molar excess compared to Compound 9A.

4. The process according to claim 1, wherein the Compound of Formula (Ii) is present in about 30% molar excess compared to Compound 9A.

5. The process according to claim 1, wherein the Compound of Formula (Ii) is present in about 25% molar excess compared to Compound 9A.

6. The process according to claim 1, wherein the Compound of Formula (Ii) is present in about 20%> molar excess compared to Compound 9A.

7. The process according to any one of claims 1 to 6, wherein Compound 9A and the phase-transfer catalyst are present in substantially equal molar quantities.

8. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.9.

9. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.8.

10. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.7.

11. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.6.

12. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.5.

13. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.4.

14. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.1 to about 1.3:0.2.

15. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.15.

16. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.05:5 to about 1:0.4:25.

17. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.1:10 to about 1:0.2:20.

18. The process according to any one of claims 1 to 6, wherein the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.15:16.

19. The process according to any one of claims 1 to 18, wherein the alkylating-step solvent is selected from a halogenated solvent, an ether solvent, an aprotic solvent, and mixtures thereof.

20. The process according to any one of claims 1 to 18, wherein the alkylating-step solvent is selected from: dichloromethane, tefrachloroethylene, 1,1-dichloroethane, 1,2-dichloroethane, 1,2-dichlorobenzene, chlorobenzene, 1,2-dimethoxy ethane (DME), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, ethylene glycol diethyl ether, tert-amyl methyl ether (TAME, also referred to as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), benzene, cyclohexane, hexane, toluene, cycloheptane, methylcyclohexane, heptanes, «-heptane, ethylbenzene, o-xylene, m-xylene, p-xylene, mixtures of xylenes, octane, and mixtures thereof.

21. The process according to any one of claims 1 to 18, wherein the alkylating-step solvent is selected from: 1,2-dimethoxy ethane (DME), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, ethylene glycol diethyl ether, tert-sunylmethyl ether (TAME, also referred to as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), benzene, toluene, and mixtures thereof.

22. The process according to any one of claims 1 to 18, wherein the alkylating-step solvent is selected from: methyl tert-butyl ether (MTBE), toluene, and mixtures thereof.

23. The process according to any one of claims 1 to 22, wherein the phase-transfer catalyst is a quaternary ammonium salt.

24. The process according to any one of claims 1 to 22, wherein the phase-transfer catalyst is a quaternary ammonium salt selected from: tricaprylyl methyl ammonium chloride (Aliquat 336), tetra-«-butylammonium bromide (TBAB), benzyltriethylammonium chloride (BTEAC), cetyltrimethylammonium bromide (CTAB), tetra-«-butylammonium chloride (TBAC), tetra-«-butylammonium hydroxide, terra-«-butylammonium iodide, tetraethylammonium chloride (TEAC), benzyltributylammonium chloride (BTBAC), cetyltrimethylammonium chloride (CTAC), tetramethylammonium chloride, cetyltrimethylammonium chloride (CTAC), octyltrimethylammonium chloride, and combinations thereof.

25. The process according to any one of claims 1 to 22, wherein the phase-transfer catalyst is tetra-«-butylammonium bromide (TBAB).

26. The process according to any one of claims 1 to 25, wherein the alkylating-step base is an alkali metal hydroxide.

27. The process according to any one of claims 1 to 25, wherein the alkylating-step base is an alkali metal hydroxide selected from: lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide.

28. The process according to any one of claims 1 to 25, wherein the alkylating-step base is an alkali metal hydroxide selected from: sodium hydroxide and potassium hydroxide.

29. The process according to any one of claims 1 to 25, wherein the alkylating-step base is potassium hydroxide.

30. The process according to any one of claims 1 to 29, wherein alkylating further comprises thesteps of:forming a first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A at a first-alkylating temperature; andadding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture at the first-alkylating temperature to form an alkylating-biphasic mixture at a second-alkylating temperature.

31. The process according to claim 30, further comprising heating the first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 40 °C to about 75 °C and subsequently cooling to the first-alkylating temperature.

32. The process according to claim 30, further comprising heating first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 55 °C to about 65 °C and subsequently cooling to the first-alkylating temperature.

33. The process according to claim 30, further comprising heating first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 60 °C and subsequently cooling to the first-alkylating temperature.

34. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water.

35. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight / weight (% w / w) of the alkylating-step base and water is about 40 to about 60.

36. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in waterand the concentration in terms of percent weight / weight (% w / w) of the alkylating-step base and water is about 45 to about 55.

37. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight / weight (% w / w) of the alkylating-step base and water is about 52 to about 53.

38. The process according to any one of claims 30 to 33, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight / weight (% w / w) of the alkylating-step base and water is about 52.4.

39. The process according to any one of claims 30 to 38, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent.

40. The process according to any one of claims 30 to 38, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percent weight / weight (% w / w) of the Compound of Formula (Ii) in the alkylating-step solvent is about 65 to about 90.

41. The process according to any one of claims 30 to 38, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percent weight / weight (% w / w) of the Compound of Formula (Ii) in the alkylating-step solvent is about 75 to about 85.

42. The process according to any one of claims 30 to 38, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percentweight / weight (% w / w) of the Compound of Formula (Ii) in the alkylating-step solvent is about 80.

43. The process according to any one of claims 30 to 42, wherein adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture is conducted concurrently at a rate to maintain the first-alkylating temperature.

44. The process according to any one of claims 30 to 42, wherein adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture is conducted serially at a rate to maintain the first-alkylating temperature.

45. The process according to claim 44, wherein serially is conducted by adding the alkylating-step base followed by adding the Compound of Formula (Ii) to the first-alkylating mixture at a rate to maintain the first-alkylating temperature during each addition.

46. The process according to any one of claims 30 to 45, wherein the first-alkylating temperature is about -15 °C to about 15 °C.

47. The process according to any one of claims 30 to 45, wherein the first-alkylating temperature is about -10 °C to about 10 °C.

48. The process according to any one of claims 30 to 45, wherein the first-alkylating temperature is about -5 °C to about 7 °C.

49. The process according to any one of claims 30 to 45, wherein the first-alkylating temperature is about 0 °C to about 5 °C.

50. The process according to any one of claims 30 to 49, wherein the second-alkylating temperature is about -10 °C to about 20 °C.

51. The process according to any one of claims 30 to 49, wherein the second-alkylating temperature is about -5 °C to about 15 °C.

52. The process according to any one of claims 30 to 49, wherein the second-alkylating temperature is about 0 °C to about 10 °C.

53. The process according to any one of claims 30 to 49, wherein the second-alkylating temperature is about 4 °C to about 6 °C.

54. The process according to any one of claims 1 to 53, wherein the LG is selected from the group: C1-C4 alkylsulphonyloxy, C6-Ci0 arylsulfonyloxy, halogen, and hydroxy; wherein Cr C4 alkylsulphonyloxy and C6-Ci0 arylsulfonyloxy are each optionally substituted with one or more groups selected from the group: C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, Q-C4 haloalkoxy, and nitro.

55. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is a compound of the following Formula:^ S ^T O" "CrC4alkyl(Ii-A)wherein the alkyl group is optionally substituted with one or more groups selected from the group: C1-C4 alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, and nitro.

56. The process according to claim 55, wherein the alkyl group is optionally substituted with one or more fluoro groups.

57. The process according to claim 55, wherein the alkyl group is optionally substituted with three fluoro groups.

58. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is a compound of the following Formula:(Ii-B)R3awherein: Rla, R2a, and R3a are each selected independently from the group consisting of: H, C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, and nitro.

59. The process according to claim 58, wherein Rla, R2a, and R3a are each selected independently from the group consisting of: H, methyl, methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, trifluoromethoxy, and nitro.

60. The process according to claim 58, wherein Rla, R2a, and R3a are each selected independently from the group consisting of: H, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, and nitro.

61. The process according to claim 58, wherein Rla, R2a, and R3a are each selected independently from the group consisting of: H, methyl, fluoro, trifluoromethyl, trifluoromethoxy, and nitro.

62. The process according to claim 58, wherein R a, R a, and R a are each selected independently from the group consisting of: H and methyl.

63. The process according to any one of claims 1 to 53, wherein LG is halogen.

64. The process according to any one of claims 1 to 53, wherein LG is CI, Br, or I.

65. The process according to any one of claims 1 to 53, wherein LG is Br.

66. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is selected from the group consisting of: propargyl bromide, propargyl chloride, propargyl alcohol, propargyl methanesulfonate, propargyl trifluoromethanesulfonate, propargyl benzenesulfonate, and propargyl / >-toluenesulfonate.

67. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is selected from the group consisting of: propargyl bromide, propargyl methanesulfonate, propargyl trifluoromethanesulfonate, propargyl benzenesulfonate, and propargyl p-toluenesulfonate.

68. The process according to any one of claims 1 to 53, wherein the Compound of Formula (Ii) is propargyl bromide.

69. The process according to any one of claims 1 to 68, wherein alkylating is conducted with stirring.

70. The process according to any one of claims 1 to 68, wherein alkylating is conducted with vigorous stirring.

71. The process according to any one of claims 1 to 70, further comprising preparing (5)-4-(2-chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof, by the step of:cyclizing (5*)-2-cyclopropyl-1 -(3-fluoro-4-methylphenyl)ethan-1 -amine (Compound 6A) or a salt thereof:H7Nwith l-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-l-one (Compound 8A) or a tautomeric form thereof:SCNin the presence of a cyclizing-step solvent to form (5)-4-(2-chloro-4-methoxy-5-methylphenyl)-A^-(2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof.

72. The process according to claim 71, further comprising preparing (5)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethan-l-amine (Compound 6A) or a salt thereof, comprising:deprotecting a Compound of Formula (Ig), or a salt thereof:R1cR2<4R3cy us)Rlc, R2c, and R3c are each independently selected from: H, Ci-C6 alkoxy, Ci-C6 alkyl, Ci-C6 haloalkyl, and halogen;in the presence of a deprotecting-catalyst, hydrogen, and a deprotecting-step solvent to form (5)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethan-l-amine (Compound 6A) or a salt thereof.

73. The process according to claim 72, further comprising preparing a Compound of Formula (Ig), or a salt thereof,reducing a Compound of Formula (le):in the presence of a reducing-catalyst, hydrogen, and a reducing-step solvent to form the Compound of Formula (Ig), or a salt thereof.

74. The process according to claim 73, further comprising preparing a Compound of Formula (le), comprising: condensing 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethan-l-one (Compound 3A):with a Compound of Formula (Ic), or salt thereof:R (Ic)in the presence of a condensing-step acid and a condensing-step solvent to form the Compound of Formula (Ie).

75. The process according to claim 74, further comprising preparing 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethan-l-one (Compound 3A), by the step of:reacting 2-cyclopropyl-7V-methoxy-7V-methylacetamide (Compound 2A):*KJ^with an organomagnesium reagent of 4-bromo-2-fluoro-l-methylbenzene in the presence of a reacting-step solvent to form 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethan-l-one (Compound 3A).

76. The process according to any one of claims 1 to 75, further comprising the step of isolating 4-(2-chloro-4-methoxy-5-methylphenyl)-Af-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1), or a pharmaceutical^ acceptable salt thereof.

77. The process according to any one of claims 1 to 76, further comprising the step of formulating 4-(2-chloro-4-methoxy-5-methylphenyl)-Af-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof, to form a pharmaceutical composition.

78. The process according to claim 77, wherein the step of formulating comprises admixing 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, with a pharmaceutical excipient.

79. The process according to any one of claims 1 to 78, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-Af-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1) is the free base.

80. The process according to any one of claims 1 to 79, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-Af-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1) is crystalline.

81. The process according to any one of claims 1 to 80, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-Af-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1) is anhydrous crystalline Form I.

82. A process for preparing (5)-4-(2-chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof:

83. The process according to claim 82, wherein the cyclizing-step solvent is an aprotic solvent.

84. The process according to claim 82, wherein the cyclizing-step solvent is an aprotic solvent selected from: benzene, cyclohexane, pentane, hexane, acetonitrile, toluene, o-xylene, m-xylene, / (-xylene, a mixture of xylenes, heptanes, «-heptane, octanes, «-octanes, ethylbenzene, and mixtures thereof.

85. The process according to claim 82, wherein the cyclizing-step solvent is an aprotic solvent selected from: benzene, cyclohexane, hexane, toluene, cycloheptane, o-xylene, m-xylene,p-xylene, a mixture of xylenes, heptanes, «-heptane, octanes, «-octane, ethylbenzene, and mixtures thereof.

86. The process according to claim 82, wherein the cyclizing-step solvent comprises a mixture of heptanes.

87. The process according to claim 82, wherein the cyclizing-step solvent is «-heptane.

88. The process according to any one of claims 82 to 87, wherein Compound 6A and Compound 8A are present in substantially equal molar quantities.

89. The process according to any one of claims 82 to 87, wherein Compound 6A is present in a molar excess compared to Compound 8A.

90. The process according to any one of claims 82 to 87, wherein Compound 6A is present in about 5% molar excess compared to Compound 8A.

91. The process according to any one of claims 82 to 87, wherein Compound 6A is present in about 2% molar excess compared to Compound 8A.

92. The process according to any one of claims 82 to 87, wherein Compound 6A is present in about 1 % molar excess compared to Compound 8A.

93. The process according to any one of claims 82 to 92, wherein cyclizing further comprises the step of adding Compound 6A to a first-cyclizing mixture comprising Compound 8A and the cyclizing-step solvent at a first-cyclizing temperature.

94. The process according to claim 93, wherein the first-cyclizing temperature is about 50°C to about 110°C.

95. The process according to claim 93, wherein the first-cyclizing temperature is about 60°C to about 95°C.

96. The process according to claim 93, wherein the first-cyclizing temperature is about 70°C to about 90°C.

97. The process according to claim 93, wherein the first-cyclizing temperature is about 80°C to about 87°C.

98. The process according to claim 93, wherein the first-cyclizing temperature is about 85°C.

99. The process according to any one of claims 82 to 98, wherein cyclizing is conducted with stirring.

100. A process for preparing (5*)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethan-1 -amine (Compound 6A) or a salt thereof:H,N101. The process according to claim 100, wherein the deprotecting-catalyst comprises palladium.

102. The process according to claim 100, wherein the deprotecting-catalyst comprises palladium on carbon.

103. The process according to claim 100, wherein the deprotecting-catalyst comprises about 2% palladium on carbon to about 20% palladium on carbon.

104. The process according to claim 100, wherein the deprotecting-catalyst comprises about 5% palladium on carbon to about 15% palladium on carbon.

105. The process according to claim 100, wherein the deprotecting-catalyst comprises about 10% palladium on carbon.

106. The process according to any one of claims 100 to 105, wherein the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.01 to about 1:0.15.

107. The process according to any one of claims 100 to 105, wherein the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.02 to about 1:0.1.

108. The process according to any one of claims 100 to 105, wherein the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.03 to about 1:0.07.

109. The process according to any one of claims 100 to 105, wherein the weight ratio between the Compound of Formula (Ig) and the deprotecting-catalyst is about 1:0.05.

110. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent comprises an alcohol solvent.

111. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, 2-ethoxyethanol, 1-pentanol, 2-pentanol, 3-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof.

112. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof.

113. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, and mixtures thereof.

114. The process according to any one of claims 100 to 109, wherein the deprotecting-step solvent is methanol.

115. The process according to any one of claims 100 to 114, wherein deprotecting further comprises the steps of:forming a first-deprotecting mixture comprising the Compound of Formula (Ig), the deprotecting-catalyst, and the deprotecting-step solvent;pressurizing the first-deprotecting mixture with hydrogen to form a second-deprotecting mixture; andheating the second-deprotecting mixture to a first-deprotecting temperature.

116. The process according to claim 115, wherein pressurizing the first-deprotecting mixture with hydrogen is conducted at about 5 to about 12 bar.

117. The process according to claim 115, wherein pressurizing the first-deprotecting mixture with hydrogen is conducted at about 9 to about 11 bar.

118. The process according to claim 115, wherein pressurizing the first-deprotecting mixture with hydrogen is conducted at about 9.8 to about 10.2 bar.

119. The process according to any one of claims 115 to 118, wherein the first-deprotecting temperature is about 40°C to about 80°C.

120. The process according to any one of claims 115 to 118, wherein the first-deprotecting temperature is about 50°C to about 70°C.

121. The process according to any one of claims 115 to 118, wherein the first-deprotecting temperature is about 58°C to about 62°C.

122. The process according to any one of claims 100 to 121, wherein Rlc, R2c, and R3c are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.

123. The process according to any one of claims 100 to 121, wherein Rlc, R2c, and R3c are each H.

124. The process according to any one of claims 100 to 123, wherein deprotecting is conducted with stirring.

125. A process for preparing a Compound of Formula (Ig), or a salt thereof:(Ig) wherein:Rlc, R2c, and R3c are each independently selected from: H, Ci-C6 alkoxy, Ci-C6 alkyl, Ci-C6 haloalkyl, and halogen; comprising: reducing a Compound of Formula (Ie):

126. The process according to claim 125, wherein the reducing-catalyst is sponge nickel or Pd / Cu-C.

127. The process according to claim 125, wherein the reducing-catalyst is sponge nickel.

128. The process according to claim 125, wherein the reducing-catalyst is Pd / Cu-C.

129. The process according to claim 128, wherein the Pd / Cu-C catalyst comprises about 1% to about 10% Pd and about 0.2% to about 4% Cu.

130. The process according to claim 128, wherein the Pd / Cu-C catalyst comprises about 2% to about 6% Pd and about 0.5% to about 2% Cu.

131. The process according to claim 128, wherein the Pd / Cu-C catalyst comprises about 4% Pd and 1% Cu.

132. The process according to claim 127, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.5 to about 1:0.9.

133. The process according to claim 127, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.6 to about 1:0.8.

134. The process according to claim 127, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.65 to about 1:0.75.

135. The process according to claim 127, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.7.

136. The process according to any one of claims 128 to 131, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.01 to about 1:0.3.

137. The process according to any one of claims 128 to 131, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.015 to about 1:0.1.

138. The process according to any one of claims 128 to 131, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.02 to about 1:0.05.

139. The process according to any one of claims 128 to 131, wherein the weight ratio between the Compound of Formula (Ie) and the reducing-catalyst is about 1:0.03.

140. The process according to any one of claims 125 to 139, wherein the reducing-step solvent comprises an alcohol solvent.

141. The process according to any one of claims 125 to 139, wherein the reducing-step solvent comprises an alcohol solvent selected from: methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, 2-ethoxyethanol, 1-pentanol, 2-pentanol, 3-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof.

142. The process according to any one of claims 125 to 139, wherein the reducing-step solvent comprises an alcohol solvent selected from: methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof.

143. The process according to any one of claims 125 to 139, wherein the deprotecting-step solvent comprises an alcohol solvent selected from: methanol, ethanol, and mixtures thereof.

144. The process according to any one of claims 125 to 139, wherein the reducing-step solvent comprises ethanol.

145. The process according to any one of claims 125 to 144, wherein reducing further comprises the steps of: 6forming a first-reducing mixture comprising the reducing-catalyst and the reducing-step solvent;adding the Compound of Formula (le) to the first-reducing mixture to form a second-reducing mixture;pressurizing the second-reducing mixture with hydrogen to form a third-reducing mixture; andheating the third-reducing mixture to a first-reducing temperature.

146. The process according to claim 145, wherein adding the Compound of Formula (le) to the first-reducing mixture is conducted as a solution of the Compound of Formula (le) in toluene.

147. The process according to claim 145, wherein adding the Compound of Formula (le) to the first-reducing mixture is conducted as a solution of about 40% to about 80% of the Compound of Formula (le) in toluene.

148. The process according to claim 145, wherein adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of about 50% to about 70% of the Compound of Formula (Ie) in toluene.

149. The process according to claim 145, wherein adding the Compound of Formula (Ie) to the first-reducing mixture is conducted as a solution of about 60%> to about 65 % of the Compound of Formula (Ie) in toluene.

150. The process according to any one of claims 145 to 149, wherein pressurizing the second-reducing mixture with hydrogen is conducted at about 5 to about 12 bar.

151. The process according to any one of claims 145 to 149, wherein pressurizing the second-reducing mixture with hydrogen is conducted at about 9 to about 11 bar.

152. The process according to any one of claims 145 to 149, wherein pressurizing the second-reducing mixture with hydrogen is conducted at about 9.8 to about 10.2 bar.

153. The process according to any one of claims 145 to 152, wherein the first-reducing temperature is about 25°C to about 55°C.

154. The process according to any one of claims 145 to 152, wherein the first-reducing temperature is about 30°C to about 45°C.

155. The process according to any one of claims 145 to 152, wherein the first-reducing temperature is about 33°C to about 37°C.

156. The process according to any one of claims 125 to 155, wherein Rlc, R2c, and R3c are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.

157. The process according to any one of claims 125 to 155, wherein Rlc, R2c, and R3c are each H.

158. The process according to any one of claims 125 to 157, wherein reducing is conducted with stirring.

159. A process for preparing a Compound of Formula (Ie):.Fwith a Compound of Formula (Ic), or a salt thereof:p1C2cxN^r NH2R%160. The process according to claim 159, wherein the Compound of Formula (Ic) and Compound 3A are present in substantially equal molar quantities.

161. The process according to claim 159, wherein the Compound of Formula (Ic) is present in a molar excess compared to Compound 3A.

162. The process according to claim 159, wherein the molar ratio between Compound 3A and the Compound of Formula (Ic) is about 1:1 to about 1:1.5.

163. The process according to claim 159, wherein the molar ratio between Compound 3A and the Compound of Formula (Ic) is about 1:1.1 to about 1:1.3.

164. The process according to claim 159, wherein the molar ratio between Compound 3A and the Compound of Formula (Ic) is about 1:1.2.

165. The process according to claim 159, wherein the molar ratio between Compound 3A, the Compound of Formula (Ic), and the condensing-step acid is about 1:1:0.01 to about 1:1.5:0.2.

166. The process according to claim 159, wherein the molar ratio between Compound 3A, the Compound of Formula (Ic), and the condensing-step acid is about 1:1.1:0.03 to about 1:1.3:0.1167. The process according to claim 159, wherein the molar ratio between Compound 3A, the Compound of Formula (Ic), and the condensing-step acid is about 1:1.2:0.05.

168. The process according to any one of claims 159 to 167, wherein the condensing-step acid comprises a Bronsted acid.

169. The process according to any one of claims 159 to 167, wherein the condensing-step acid comprises a Bronsted acid selected from: acetic acid, trifluoroacetic acid (TFA),p-toluenesulfonic acid (pTSA), H3P04, H2S04, methanesulfonic acid (MSA), formic acid, and HC1.

170. The process according to any one of claims 159 to 167, wherein the condensing-step acid isp-toluenesulfonic acid (pTSA).

171. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is an aprotic solvent.

172. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is an aprotic solvent selected from: benzene, cyclohexane, pentane, hexane, acetonitrile, toluene, cycloheptane, o-xylene, m-xylene, / (-xylene, a mixture of xylenes, heptanes, «-heptane, octanes, «-octanes, ethylbenzene, and mixtures thereof.

173. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is acetonitrile or toluene.

174. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is acetonitrile.

175. The process according to any one of claims 159 to 170, wherein the condensing-step solvent is toluene.

176. The process according to any one of claims 159 to 175, wherein condensing is conducted at the boiling point of the condensing-step solvent.

177. The process according to any one of claims 159 to 176, wherein condensing further comprises the removal of water.

178. The process according to any one of claims 159 to 176, wherein condensing further comprises the removal of water using a Dean-Stark process, a desiccant, or a combination thereof.

179. The process according to any one of claims 159 to 176, wherein condensing further comprises the removal of water using a desiccant.

180. The process according to any one of claims 159 to 176, wherein condensing further comprises the removal of water using a Dean-Stark process.

181. The process according to any one of claims 159 to 180, wherein condensing further comprises the step of isolating the Compound of Formula (Ie) from a condensing-step mixture comprising the Compound of Formula (Ie) and the Compound of Formula (Ic).

182. The process according to claim 181, wherein isolating comprises substantially removing the Compound of Formula (Ic) from the condensing-step mixture using an isolating-step acid.

183. The process according to claim 182, wherein the isolating-step acid is a water-soluble acid.

184. The process according to claim 182, wherein the isolating-step acid is an ammonium halide.

185. The process according to claim 182, wherein the isolating-step acid is ammonium chloride.

186. The process according to any one of claims 159 to 185, wherein Rlc, R2c, and R3c are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.

187. The process according to any one of claims 159 to 185, wherein Rlc, R2c, and R3c are each H.

188. The process according to any one of claims 159 to 187, wherein condensing is conducted with stirring.

189. A process for preparing 2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethan-l-one (Compound190. The process according to claim 189, wherein the organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene is prepared by the process comprising the steps of:forming a first-reacting mixture comprising magnesium and the reacting-step solvent;adding a magnesium activator to the first-reacting mixture at a first-reacting temperature to form a second-reacting mixture; andadding 4-bromo-2-fluoro-l-methylbenzene to the second-reacting mixture at a second-reacting temperature to form the organomagnesium reagent of 4-bromo-2-fluoro-l-methylbenzene.

191. The process according to claim 190, wherein the first-reacting temperature is about 15°C to about 45°C.

192. The process according to claim 190, wherein the first-reacting temperature is about 25°C to about 40°C.

193. The process according to claim 190, wherein the first-reacting temperature is about 25°C to about35°C.

194. The process according to any one of claims 190 to 193, wherein the second-reacting temperature is about 20°C to about 65°C.

195. The process according to any one of claims 190 to 193, wherein the second-reacting temperature is about 25°C to about 60°C.

196. The process according to any one of claims 190 to 193, wherein the second-reacting temperature is about 30°C to about 50°C.

197. The process according to any one of claims 190 to 196, wherein the magnesium activator is h, 1,2-dibromoethane, diisobutylaluminium hydride (DIBAL-H), LiAlH4, NaBH4, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), and borane dimethyl sulfide complex (BH3-SMe2).

198. The process according to any one of claims 190 to 196, wherein the magnesium activator is diisobutylaluminium hydride (DIBAL-H).

199. The process according to any one of claims 189 to 198, wherein the reacting-step solvent is an ether solvent.

200. The process according to any one of claims 189 to 198, wherein the reacting-step solvent is selected from: diethyl ether, 1,2-dimethoxyethane (DME), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF).

201. The process according to any one of claims 189 to 198, wherein the reacting-step solvent is selected from: tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF).

202. The process according to any one of claims 189 to 198, wherein the reacting-step solvent is tetrahydrofuran (THF).

203. The process according to any one of claims 189 to 202, wherein the organomagnesium reagent of 4-bromo-2-fluoro-l-methylbenzene is:

204. The process according to any one of claims 189 to 203, wherein reacting is conducted with stirring.

205. A process for preparing 2-cyclopropyl-7V-methoxy-7V-methylacetamide (Compound 2A),^l,0.coupling 2-cyclopropylacetic acid (Compound 1A) with 7V,0-dimethylhydroxylamine or a salt thereof in the presence of a coupling-step reagent, a coupling-step base, and acoupling-step solvent to form 2-cyclopropyl-7V-methoxy-7V-methylacetamide (Compound2A).

206. The process according to claim 205, further comprising mixing 2-cyclopropylacetic acid (Compound 1A), the coupling-step reagent, and the coupling-step solvent together to form a first-coupling mixture.

207. The process according to claim 206, wherein the first-coupling mixture is at a first-coupling temperature of about -15°C to about 35°C.

208. The process according to claim 206, wherein the first-coupling mixture is at a first-coupling temperature of about -10°C to about 30°C.

209. The process according to claim 206, wherein the first-coupling mixture is at a first-coupling temperature of about -10°C to about 25°C.

210. The process according to claim 206, wherein the first-coupling mixture is at a first-coupling temperature of < 25 °C.

211. The process according to any one of claims 205 to 210, wherein coupling further comprising adding Af0-dimethylhydroxylamine or a salt thereof to the first-coupling mixture to form a second-coupling mixture at a second-coupling temperature.

212. The process according to claim 211, wherein the second-coupling temperature is < 30 °C.

213. The process according to claim 211, wherein the second-coupling temperature is about -15°C toabout30°C.

214. The process according to claim 211, wherein the second-coupling temperature is about -10°C to about 25°C.

215. The process according to claim 211, wherein the second-coupling temperature is about 20°C to about 25°C.

216. The process according to any one of claims 211 to 215, wherein A^,0-dimethylhydroxylamine or a salt thereof is added to the first-coupling mixture at a rate to maintain the temperature at the second-coupling temperature.

217. The process according to any one of claims 211 to 216, further comprising adding the coupling-step base to the second-coupling mixture.

218. The process according to any one of claims 211 to 216, further comprising adding the coupling-step base to the second-coupling mixture and maintaining a third-coupling temperature at about -10°C to about 25°C.

219. The process according to any one of claims 211 to 216, further comprising adding the coupling-step base to the second-coupling mixture and maintaining a third-coupling temperature at about 20°C to about 25°C.

220. The process according to any one of claims 205 to 219, wherein the coupling-step reagent is a tetramethyluronium-based coupling reagent.

221. The process according to any one of claims 205 to 219, wherein the coupling-step reagent is a tetramethyluronium-based coupling agent selected from: 2-(l / / -benzotriazole-l-yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(l / / -benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-l / / -benzotriazole-l-yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-(6-chloro-l / / -benzotriazole-l-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), and 7V,7V,7V,7V-tetramethyl-0-(3,4-dihydro-4-oxo-1,2,3 -benzotriazin-3 -yl)uranium tetrafluoroborate (TDBTU).

222. The process according to any one of claims 205 to 219, wherein the coupling-step reagent is l,l'-carbonyldiimidazole (CDI).

223. The process according to any one of claims 205 to 222, wherein the coupling-step solvent is an aprotic solvent.

224. The process according to any one of claims 205 to 222, wherein the coupling-step solvent is selected from a halogenated solvent, an ether solvent, and mixtures thereof.

225. The process according to any one of claims 205 to 222, wherein the coupling-step solvent comprises dichloromethane (DCM).

226. The process according to any one of claims 205 to 225, wherein the coupling-step base is a tertiary amine.

227. The process according to any one of claims 205 to 225, wherein the coupling-step base is selected from: 7V,7V-diisopropylethylamine (DIEA), triethylamine (TEA), 7V-methylmorpholine (NMM), 4-dimethylaminopyridine (DMAP), 2,4,6-trimethylpyridine (collidine), 2,3,5,6-tetramethylpyridine (TEMP), and 2,6-di-?er?-butyl-4-(dimethylamino)pyridine (DBDMAP).

228. The process according to any one of claims 205 to 225, wherein the coupling-step base is triethylamine.

229. The process according to any one of claims 205 to 228, wherein coupling is conducted with stirring.

230. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl] -5 -methyl-7V-prop-2-ynyl-1,3 -thiazol-2-amine (Compound 1, free base).

231. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl] -5 -methyl-7V-prop-2-ynyl-1,3 -thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2 8, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ± 0.2°, and 43.5° ± 0.2°.

232. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl] -5 -methyl-7V-prop-2-ynyl-1,3 -thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 25.7° ± 0.2°.

233. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl] -5 -methyl-7V-prop-2-ynyl-1,3 -thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 14.3° ± 0.2°.

234. The anhydrous crystalline form (Compound 1, free base) according to claim 233, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20 at 14.3° ± 0.2°, and 25.7° ± 0.2°.

235. The anhydrous crystalline form (Compound 1, free base) according to claim 233, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 14.3° ± 0.2°, and 19.7° ± 0.2°.

236. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl] -5 -methyl-7V-prop-2-ynyl-1,3 -thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 19.7° ± 0.2°.

237. The anhydrous crystalline form (Compound 1, free base) according to claim 236, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 19.7° ± 0.2°, and 25.7° ± 0.2°.

238. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl] -5 -methyl-7V-prop-2-ynyl-1,3 -thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 14.3° ± 0.2°, 19.7° ± 0.2°, and 25.7° ± 0.2°.

239. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, and 25.7° ± 0.2°.

240. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, and 29.6° ± 0.2°.

241. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, and 29.6° ±0.2°.

242. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 29.6° ±0.2°, and 43.5° ±0.2°.

243. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°.

244. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°.

245. The anhydrous crystalline form (Compound 1, free base) according to claim 238, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 26, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 24.2° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°.

246. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 223, wherein the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 1.

247. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 81°C to about 89.5°C.

248. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82°C to about 88°C.

249. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82.5°C to about 88.5°C.

250. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83°C to about 88°C.

251. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83.5°C to about 87.5°C.

252. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 246, wherein the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure 2.

253. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 1.0% or less weight loss out to about 125°C.

254. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.9% or less weight loss out to about 125°C.

255. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.7%> or less weight loss out to about 125°C.

256. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.6%o or less weight loss out to about 125°C.

257. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.5%o or less weight loss out to about 125°C.

258. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.05%o to about 1.0% weight loss out to about 125°C.

259. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1%> to about 0.9%o weight loss out to about 125°C.

260. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1 %> to about 0.7%o weight loss out to about 125°C.

261. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1% to about 0.6% weight loss out to about 125°C.

262. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.1%> to about 0.4%> weight loss out to about 125°C.

263. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 252, wherein the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in Figure 2.

264. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.015%o or less weight change after an adsorption / desorption cycle from 10%o RH to 90% RH and back to 10% RH.

265. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.01%> or less weight change after an adsorption / desorption cycle from 10%o RH to 90% RH and back to 10% RH.

266. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.008%> or less weight change after an adsorption / desorption cycle from 10%o RH to 90% RH and back to 10% RH.

267. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.005%o or less weight change after an adsorption / desorption cycle from 10%o RH to 90% RH and back to 10% RH.

268. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.003% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

269. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing substantially no weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

270. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.1 %> or less weight change from about 10%o relative humidity (RH) to about 90%o RH; and about 0.015%> or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

271. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.08%o or less weight change from about 10%o relative humidity (RH) to about 90%o RH; and about 0.01%> or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

272. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.05%> or less weight change from about 10%o relative humidity (RH) to about 90%o RH; and about 0.008%o or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

273. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.04%> or less weight change from about 10%o relative humidity (RH) to about 90%o RH; and about 0.005%> or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

274. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.03% or less weight change from about 10% relative humidity (RH) to about 90%> RH; and about 0.003%o or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

275. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile showing about 0.2%> or less weight change from about 10%o relative humidity (RH) to about 90% RH; and substantially no weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

276. The anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 263, wherein the anhydrous crystalline form has a gravimetric vapor sorption profile substantially as shown in Figure 3.

277. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl] -5 -methyl-7V-prop-2-ynyl-1,3 -thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has:an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2 8, selected from the group consisting of: 6.0° ± 0.2°, 11.9° ± 0.2°, 13.9° ± 0.2°, 14.3° ± 0.2°, 16.8° ± 0.2°, 17.9° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 21.8° ± 0.2°, 22.3° ± 0.2°, 23.2° ± 0.2°, 23.9° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 28.7° ± 0.2°, 29.6° ± 0.2°, 36.1° ±0.2°, and 43.5° ±0.2°;a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 81°C to about 89.5°C;a thermogravimetric analysis profile showing about 0.05%> to about 1.0% weight loss out to about 125°C; and / ora gravimetric vapor sorption profile showing about 0.015% or less weight change after an adsorption / desorption cycle from 10%o RH to 90%o RH and back to 10%o RH.

278. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 14.3° ± 0.2°, 19.7° ±0.2°, and 25.7° ±0.2°;a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 82.5°C to about 88.5°C;a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 125°C; and / ora gravimetric vapor sorption profile showing about 0.005% or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

279. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 14.3° ± 0.2°, 19.7° ± 0.2°, 20.2° ± 0.2°, 22.3° ± 0.2°, 25.7° ± 0.2°, 26.8° ± 0.2°, 29.6° ± 0.2°, and 43.5° ± 0.2°;a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 83°C to about 88°C;a thermogravimetric analysis profile showing about 0.5%> or less weight loss out to about 125°C; and / ora gravimetric vapor sorption profile showing about 0.003%o or less weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH.

280. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-an X-ray powder diffraction pattern substantially as shown in Figure 1; a differential scanning calorimetry thermogram substantially as shown in Figure 2; a thermogravimetric analysis profile substantially as shown in Figure 2; and / or a gravimetric vapor sorption profile substantially as shown in Figure 3.

281. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(lS)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl] -5 -methyl-7V-prop-2-ynyl-1,3 -thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline is prepared by the process according to Claim 81.

282. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1, tosylate salt).

283. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising at least three peaks, in terms of 20, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.

284. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 9.1° ± 0.2°.

285. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 21.1° ± 0.2°.

286. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 20, at 23.3° ± 0.2°.

287. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1,tosylate salt), wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 21.1° ± 0.2°, and 23.3° ± 0.2°.

288. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, and 23.3° ± 0.2°.

289. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, and 23.3° ± 0.2°.

290. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, and 21.1° ± 0.2°.

291. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.

292. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 11.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.

293. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ± 0.2°.

294. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 19.0° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ±0.2°.

295. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° ±0.2°.

296. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ±0.2°.

297. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 19.0° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ±0.2°, and 23.8° ±0.2°.

298. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ±0.2°, and 23.8° ±0.2°.

299. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ±0.2°, and 28.5° ±0.2°.

300. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ±0.2°, and 23.8° ±0.2°.

301. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 16.3° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ±0.2°, and 23.8° ±0.2°.

302. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 16.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ±0.2°, and 28.5° ±0.2°.

303. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.

304. The crystalline form (Compound 1, tosylate salt) according to claim 287, wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 20, at 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, 23.8° ± 0.2°, and 28.5° ± 0.2°.

305. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 304, wherein the crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 24.

306. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 154°C to about 159°C.

307. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 154.5°C to about 158.5°C.

308. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155°C to about 158°C.

309. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155°C to about 158°C.

310. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155.5°C to about 157.5°C.

311. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 305, wherein the crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure 25.

312. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 1.0% or less weight loss out to about 125°C.

313. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.9% or less weight loss out to about 125°C.

314. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.7% or less weight loss out to about 125°C.

315. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.6% or less weight loss out to about 125°C.

316. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.5% or less weight loss out to about 125°C.

317. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.05% to about 1.0% weight loss out to about 125°C.

318. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.1% to about 0.9%> weight loss out to about 125°C.

319. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.2% to about 0.7%> weight loss out to about 125°C.

320. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.3% to about 0.6%> weight loss out to about 125°C.

321. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile showing about 0.4% to about 0.5%> weight loss out to about 125°C.

322. The crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 311, wherein the crystalline form has a thermogravimetric analysis profile substantially as shown in Figure 25.

323. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1, tosylate salt), wherein the crystalline form has:an X-ray powder diffraction pattern comprising at least three peaks, in terms of 2 8, selected from the group consisting of: 9.1° ± 0.2°, 10.5° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, 19.0° ± 0.2°, 19.3° ± 0.2°, 20.4° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, 23.3° ± 0.2°, 23.8° ±0.2°, and 28.5° ±0.2°;a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 154°C to about 159°C; and / ora thermogravimetric analysis profile showing about 0.05% to about 1.0% weight loss out to about125°C.

324. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, and 23.3° ± 0.2°;a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155°C to about 158°C; and / ora thermogravimetric analysis profile showing about 0.9%> or less weight loss out to about125°C.

325. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-an X-ray powder diffraction pattern comprising peaks, in terms of 28, at 9.1° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, and 21.1° ± 0.2°;a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155.5°C to about 157.5°C; and / ora thermogravimetric analysis profile showing about 0.6%> or less weight loss out to about125°C.

326. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-an X-ray powder diffraction pattern substantially as shown in Figure 24; a differential scanning calorimetry thermogram substantially as shown in Figure 25; and / or327. A pharmaceutical composition comprising a crystalline form (Compound 1, free base)according to any one of claims 230 to 281, and a pharmaceutically acceptable carrier.

328. The pharmaceutical composition according to claim 327, wherein the composition is adapted for oral administration.

329. The pharmaceutical composition according to claim 327 or 328, wherein the composition is in the form of a tablet or capsule.

330. A pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form (Compound 1, free base) according to any one of claims 230 to 281.

331. A pharmaceutical composition comprising a crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 326, and a pharmaceutically acceptable carrier.

332. The pharmaceutical composition according to claim 331, wherein the composition is adapted for oral administration.

333. The pharmaceutical composition according to claim 331 or 332, wherein the composition is in the form of a tablet or capsule.

334. A pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a crystalline form (Compound 1, tosylate salt) according to any one of claims 282 to 326.

335. A composition comprising:a. 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(15)-2-cyclopropyl-l-(3-fluoro-4-pharmaceutically acceptable salt thereof; andb. at least one compound selected from:(5)-4-(2-Chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A);(5)-4-(2-chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(p-tolyl)ethyl)-5-methyl-7V-(prop-2-yn-l-yl)thiazol-2-amine (Compound Ha);(5)-4-(2-chloro-5-methyl-4-(prop-2-yn-l-yloxy)phenyl)-7V-(2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-7V-(prop-2-yn-1 -yl)thiazol-2-amine (Compound lib);4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(17?)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-(2-propyn-l-yl)-2-thiazolamine (Compound He);ethanol; and336. The composition according to claim 335, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl] -5 -methyl-7V-prop-2-ynyl-1,3 -thiazol-2-amine (Compound 1) is the free base.

337. The composition according to claim 335 or 336, wherein the composition contains at least 97% of 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1) as determined by HPLC.

338. The composition according to claim 335 or 336, wherein the composition contains at least 98%of4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1) as determined by HPLC.

339. The composition according to claim 335 or 336, wherein the composition contains at least 99%of4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1) as determined by HPLC.

340. The composition according to any one of claims 335 to 339, wherein the composition contains no more than 0.3% of (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC.

341. The composition according to any one of claims 335 to 339, wherein the composition contains no more than 0.2%> of (5)-4-(2-Chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(3-342. The composition according to any one of claims 335 to 339, wherein the composition contains no more than 0.1% of (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC.

343. The composition according to any one of claims 335 to 342, wherein the composition contains no more than 0.8% of (5)-4-(2-chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(p-tolyl)ethyl)-5-methyl-7V-(prop-2-yn-l-yl)thiazol-2-amine (Compound Ha) as determined by HPLC.

344. The composition according to any one of claims 335 to 342, wherein the composition contains no more than 0.7%> of (5)-4-(2-chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(p-tolyl)ethyl)-5-methyl-7V-(prop-2-yn-l-yl)thiazol-2-amine (Compound Ha) as determined by HPLC.

345. The composition according to any one of claims 335 to 342, wherein the composition contains no more than 0.6%> of (5)-4-(2-chloro-4-methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(p-tolyl)ethyl)-5-methyl-7V-(prop-2-yn-l-yl)thiazol-2-amine (Compound Ha) as determined by HPLC.

346. The composition according to any one of claims 335 to 345, wherein the composition contains no more than 0.15%o of (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-l-yloxy)phenyl)-7V-(2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl)-5 -methyl-7V-(prop-2-yn-1 -yl)thiazol-2-amine (Compound lib) as determined by HPLC.

347. The composition according to any one of claims 335 to 345, wherein the composition contains no more than 0.1 % of (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-l-yloxy)phenyl)-7V-(2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl)-5 -methyl-7V-(prop-2-yn-1 -yl)thiazol-2-amine (Compound lib) as determined by HPLC.

348. The composition according to any one of claims 335 to 345, wherein the composition contains no more than 0.05% of (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-l-yloxy)phenyl)-7V-(2-cyclopropyl-1 -(3 -fluoro-4-methylphenyl)ethyl)-5 -methyl-7V-(prop-2-yn-1 -yl)thiazol-2-amine (Compound lib) as determined by HPLC.

349. The composition according to any one of claims 335 to 348, wherein the composition contains no more than 0.3% of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(17?)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-(2-propyn-l-yl)-2-thiazolamine (Compound He) as determined by chiral HPLC.

350. The composition according to any one of claims 335 to 348, wherein the composition contains no more than 0.2% of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(17?)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-(2-propyn-l-yl)-2-thiazolamine (Compound He) as determined by chiral HPLC.

351. The composition according to any one of claims 335 to 348, wherein the composition contains no more than 0.1% of 4-(2-chloro-4-methoxy-5-methylphenyl)-A^-[(17?)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-(2-propyn-l-yl)-2-thiazolamine (Compound He) as determined by chiral HPLC.

352. The composition according to any one of claims 335 to 351, wherein the composition contains no more than 5000 ppm of ethanol as determined by gas chromatography.

353. The composition according to any one of claims 335 to 351, wherein the composition contains no more than 3000 ppm of ethanol as determined by gas chromatography.

354. The composition according to any one of claims 335 to 351, wherein the composition contains no more than 1000 ppm of ethanol as determined by gas chromatography.

355. The composition according to any one of claims 335 to 354, wherein the composition contains no more than 200 ppm of propargyl bromide as determined by gas chromatography.

356. The composition according to any one of claims 335 to 354, wherein the composition contains no more than 100 ppm of propargyl bromide as determined by gas chromatography.

357. The composition according to any one of claims 335 to 354, wherein the composition contains no more than 30 ppm of propargyl bromide as determined by gas chromatography.

358. The composition according to any one of claims 335 to 357, wherein 4-(2-chloro-4-methoxy-5-methylphenyl)-7V-[(15)-2-cyclopropyl-l-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-7V-prop-2-ynyl-l,3-thiazol-2-amine (Compound 1, free base) is anhydrous crystalline Form I.

359. The composition according to any one of claims 335 to 359, further comprising a pharmaceutically acceptable excipient.

360. A method of treating a disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; wherein the subject has abnormal levels of CRFi.

361. A method of treating a Corticotropin Releasing Factor 1 (CRFi) disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359.

362. A method of treating congenital adrenal hyperplasia (CAH), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceuticalcomposition of any one of claims 327 to 329 and 331to333;a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359.

363. The use of an anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; or the crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; for the manufacture of a medicament for the treatment of a subject wherein the subject has abnormal levels of CRF^364. The use of an anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; or the crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; for the manufacture of a medicament for the treatment of a Corticotropin Releasing Factor 1 (CRFi) disorder.

365. The use of an anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; or the crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; for the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH).

366. An anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; for use in a method of treatment of the human or animal body by therapy.

367. An anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; for use in a method of treatment of a disorder in a subject wherein the subject has abnormal levels of CRFi.

368. An anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; for use in a method of treatment of a Corticotropin Releasing Factor 1 (CRFO disorder.

369. An anhydrous crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; a pharmaceutical composition according to any one of claims 327 to 329 and 331 to 333; a pharmaceutical product according to claim 330 or 334; or a composition according to any one of claims 335 to 359; for use in a method of treating congenital adrenal hyperplasia (CAH).

370. A Compound of Formula (Ie):Rlc, R2c, and R3c are each independently selected from: H, Ci-C6 alkoxy, Ci-C6 alkyl, Ci-C6 haloalkyl, and halogen.

371. The compound according to claim 370, wherein Rlc, R2c, and R3c are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.

372. The compound according to claim 370, wherein Rlc, R2c, and R3c are each H.373.A Compound of Formula (Ig) or a salt thereof:

374. The compound according to claim 373, wherein Rlc, R2c, and R3c are each independently selected from: H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo.

375. The compound according to claim 373, wherein Rlc, R2c, and R3c are each H.

376. The compound according to any one of claims 373 to 375, wherein the compound is an HCl salt.

377. The compound according to claim 376, wherein the HCl salt is crystalline.

378. A process for preparing a pharmaceutical composition comprising admixing a crystalline form (Compound 1, free base) according to any one of claims 230 to 281; a crystalline form (Compound 1, tosylate base) according to any one of claims 282 to 326; or a composition according to any one of claims 335 to 359; and a pharmaceutically acceptable carrier.