Synthetic method 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

Abstract

A synthetic method 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 is provided. [Solution] The present disclosure relates to the fields of chemistry and medicine, and more specifically to methods 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

[Technical Field]

[0001] FIELD OF THE INVENTION The present disclosure relates to the fields of chemistry and medicine, and more particularly to methods 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 technology]

[0002] Background of the Invention Classic congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders resulting in 21-hydroxylase deficiency, an enzyme that alters adrenal steroidogenesis, resulting 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 enzyme mutations lead to the shunting of cortisol precursor steroids to alternative pathways. Most notably, androgen shunting leads to virilization and other developmental complications in females, and excessive ACTH accumulation in males is associated with the formation of testicular adrenal rest tumors. Additionally, because the same enzyme (21-hydroxylase) is used in the pathway for mineralocorticoid biosynthesis, some of these patients develop aldosterone deficiency, which can lead to salt-loss-related dehydration and death. Based on newborn screening, the prevalence of classic 21-hydroxylase deficiency CAH in the US population has been documented to be 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).

[0003] Pediatric patients from birth to adolescence and women, in particular, appear to be the most vulnerable populations affected by CAH and the subgroups with the most unmet medical needs (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). Excess androgen production in these young patients results in precocious puberty and signs of adrenocortical puberty, altered patterns of skeletal maturation, short stature caused by premature growth plate fusion, and significant hirsutism and acne problems. Although steroid replacement strategies based on physiological dosing of glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone) are reasonably life-saving, these dosings are often inadequate to suppress the accumulation of ACTH and the overproduction of progestogens and androgens (e.g., 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone). Uncontrolled symptoms of androgen excess indeed have a substantial impact on the daily functioning and development of these patients.

[0004] Exogenous corticosteroids are currently the standard of care for treating patients with classic CAH. This treatment is used to correct cortisol deficiency and reduce excess ACTH levels and androgen excess. However, the dose and duration of steroid use required to suppress ACTH typically far exceeds the normal physiological levels used for cortisol replacement alone (as in patients with Addison's disease). This increased exposure to glucocorticoids may lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, impaired glucose tolerance, reduced growth rate, and decreased bone mineral density in patients with CAH (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).

[0005] 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), have been demonstrated in clinical trials to reduce 17-hydroxyprogesterone (17-OHP) and androstenedione levels from baseline in patients with CAH at amounts that are believed to allow the use of lower, more physiological doses of glucocorticoids (e.g., hydrocortisone). The structure of Compound 1 is shown below. [ka]

[0006] Therefore, there is a significant need for an efficient method 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. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Trakakis et al., "An update to 21-hydroxylase deficient congenital adrenal hyperplasia," Gynecol. Endocrinol. (2010) 26(1):63-71 [Non-patent document 2] 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 Non-Patent Document 3 Cheng and Speiser, "Treatment outcomes in congenital adrenal hyperplasia," Adv. Pediatr. (2012) 59(1):269-281 Non-Patent Document 4 Merke and Poppas, "Management of adolescents with congenital adrenal hyperplasia," Lancet Diabetes Endocrinol. (2013) 1(4):341-352). Non-Patent Document 5 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 Non-Patent Document 6 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):8--869 Non-Patent Document 7 Note: There seems to be a small error in the original text where "865-869" is written as "8--869" in the translation of line . I've corrected it to the proper range in the translation.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 Summary of the Invention [Means for solving the problem]

[0008] Summary of the Invention The present invention provides, inter alia, 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) and intermediates related thereto.

[0009] The methods and intermediates of the present invention are useful 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), pharmaceutical salts, crystalline forms, and pharmaceutical compositions useful in the treatment of corticotropin-releasing factor type 1 (CRF1) receptor-mediated disorders.

[0010] One aspect of the present invention is 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. [ka] 1. A method 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 [ka] with a compound of formula (Ii) [ka] wherein LG is a leaving group. in the presence of an alkylation step solvent, a phase transfer catalyst, an alkylation 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.

[0011] One aspect of the present invention is (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. [ka] 1. A method for preparing (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof [ka] with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (compound 8A) or its tautomeric form [ka] and cyclizing the compound in the presence of a solvent for the cyclization step 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.

[0012] One aspect of the present invention is (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof. [ka] 1. A method for preparing A compound of formula (Ig) or a salt thereof [ka] [In the formula, R 1c , R 2c , and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. in the presence of a deprotection catalyst, hydrogen, and a solvent for the deprotection step to form (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof.

[0013] One aspect of the present invention is a compound of formula (Ig) or a salt thereof [ka] [In the formula, R 1c , R 2c , and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. 1. A method for preparing Compounds of formula (Ie) [ka] in the presence of a reduction catalyst, hydrogen, and a solvent for the reduction step to form a compound of formula (Ig) or a salt thereof.

[0014] One aspect of the present invention is a compound of formula (Ie) [ka] [In the formula, R 1c , R 2c , and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. 1. A method for preparing 2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A) [ka] a compound of formula (Ic) or a salt thereof [ka] in the presence of a condensation step acid and a condensation step solvent to form a compound of formula (Ie).

[0015] One aspect of the present invention is 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A). [ka] 1. A method for preparing 2-Cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A) [ka] with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a solvent for the reaction step to form 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).

[0016] 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).

[0017] 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, tosylate salt).

[0018] One aspect of the present invention pertains to a pharmaceutical composition comprising a crystalline form described herein (Compound 1, free base) and a pharmaceutically acceptable carrier.

[0019] One aspect of the present invention pertains to pharmaceutical products selected from pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising the crystalline form (Compound 1, free base) described herein.

[0020] One aspect of the present invention pertains to a pharmaceutical composition comprising a crystalline form described herein (Compound 1, tosylate salt) and a pharmaceutically acceptable carrier.

[0021] One aspect of the present invention pertains to pharmaceutical products selected from pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a crystalline form (Compound 1, tosylate salt) described herein.

[0022] One aspect of the present invention is 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, and b. (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) at least one compound selected from Ethanol, and Propargyl bromide The present invention relates to a composition comprising:

[0023] One aspect of the present invention relates to a method of treating a disorder in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein, wherein the subject has an abnormal level of CRF1.

[0024] One aspect of the present invention relates to a method of treating a corticotropin-releasing factor type 1 (CRF1) disorder in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein.

[0025] One aspect of the present invention relates to a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein.

[0026] One aspect of the present invention relates to the use of an anhydrous crystalline form described herein (Compound 1, free base), or a crystalline form described herein (Compound 1, tosylate base), for the manufacture of a medicament for the treatment of a subject, wherein the subject has an abnormal level of CRF1.

[0027] One aspect of the present invention relates to the use of an anhydrous crystalline form described herein (Compound 1, free base), or a crystalline form described herein (Compound 1, tosylate base), for the manufacture of a medicament for the treatment of corticotropin-releasing factor type 1 (CRF1) disorders.

[0028] One aspect of the present invention relates to the use of an anhydrous crystalline form described herein (Compound 1, free base), or a crystalline form described herein (Compound 1, tosylate base), for the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH).

[0029] One aspect of the present invention pertains to an anhydrous crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein for use in a method of treatment of the human or animal body by therapy.

[0030] One aspect of the present invention pertains to an anhydrous crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein for use in a method of treating a disorder in a subject having an abnormal level of CRF1.

[0031] One aspect of the present invention pertains to an anhydrous crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein for use in a method of treating a corticotropin-releasing factor type 1 (CRF1) disorder.

[0032] One aspect of the present invention pertains to an anhydrous crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein for use in a method of treating congenital adrenal hyperplasia (CAH).

[0033] One aspect of the present invention is a compound of formula (Ie) [ka] [In the formula, R 1c , R 2c , and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. Regarding.

[0034] One aspect of the present invention is a compound of formula (Ig) or a salt thereof [ka] [In the formula, R 1c , R 2c , and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. Regarding.

[0035] One aspect of the present invention relates to a method for preparing a pharmaceutical composition, the method comprising combining a crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), or a composition described herein, and a pharmaceutically acceptable carrier.

[0036] These and other aspects of the invention disclosed herein will be described in more detail as the disclosure proceeds. [Brief explanation of the drawings]

[0037] [Figure 1] FIG. 1 shows an illustrative 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.

[0038] [Figure 2]FIG. 2 shows 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.

[0039] [Figure 3] FIG. 3 shows an exemplary gravimetric vapor sorption (GVS) spectrum 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.

[0040] [Figure 4] Figure 4 shows a general synthetic scheme 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 been previously described by Sanofi-Aventis in International Publication No. WO 2010 / 125414.

[0041] [Figure 5] 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).

[0042] [Figure 6] 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).

[0043] [Figure 7] 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).

[0044] [Figure 8] FIG. 8 shows an overlay of exemplary X-ray powder diffraction (XRPD) patterns from FIGS. 1 and 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 of certain peaks are rather pronounced, the overlay clearly shows substantially the same peak positions.

[0045] [Figure 9] 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).

[0046] [Figure 10]FIG. 10 shows 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).

[0047] [Figure 11] 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).

[0048] [Figure 12] FIG. 12 shows 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).

[0049] [Figure 13] 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).

[0050] [Figure 14] FIG. 14 shows 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).

[0051] [Figure 15] 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).

[0052] [Figure 16] FIG. 16 shows 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).

[0053] [Figure 17] 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).

[0054] [Figure 18] FIG. 18 shows 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).

[0055] [Figure 19] 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).

[0056] [Figure 20] FIG. 20 shows a vertical membrane flux cell integrated into a μDiss Profiler™ for use in membrane flux assays.

[0057] [Figure 21] FIG. 21 shows non-settling dissolution data for several spray-dried dispersion formulations and the compound of formula (I) in 0.5 wt % SIF in PBS (pH 6.5).

[0058] [Figure 22]Figure 22 is a graph showing the membrane flux of Compound 1 and various spray-dried dispersion formulations at a 1 mg / mL GB / IB 0.5 wt% SIF dose over time. The solid line shows the flux (μg min-1cm-2) and the dotted line shows the concentration (μg / mL) in 0.5% SIF.

[0059] [Figure 23] FIG. 23 is a flow diagram of the spray drying manufacturing process used to prepare 1000 g batches of SDD containing 25% Compound 1 and 75% PVP / VA64.

[0060] [Figure 24] 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).

[0061] [Figure 25] FIG. 25 shows 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 INVENTION

[0062] Detailed Description of the Invention definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.Methods and materials are disclosed herein for use in this disclosure, and other suitable methods and materials known in the art can also be used.Materials, methods, and examples are merely illustrative and are 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 the event of any discrepancy, the present specification, including definitions, will prevail.

[0063] The term "about" preceding a temperature has an acceptable variability of ±5° C. In all other cases, unless otherwise specified, the term "about" preceding a stated value is inclusive of the stated value and includes ±20% of the stated value, and more specifically includes values ​​of ±10%, ±5%, ±2%, and ±1% of the stated value.

[0064] To provide a more concise description, some quantitative expressions herein are described as a range from about the amount of X to about the amount of Y. When a range is described, it is understood that the range is not limited to the stated upper and lower limits, but rather includes the entire range from about the amount of X to about the amount of Y, or any range therebetween.

[0065] As used herein, "room temperature" or "RT" refers to the ambient temperature in a typical laboratory, which is generally about 25°C.

[0066] 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, bird, fish, or amphibian. The preferred method of administration may vary depending on various factors, such as the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

[0067] "C6~C 10The term "aryl" refers to a saturated ring system containing 6 to 10 carbon atoms, e.g., phenyl and naphthalenyl, which contains a single ring or two fused rings and is aromatic. When one or more substituents are present on an "aryl" ring, the substituents may be attached at any available ring carbon.

[0068] The terms "C1-C6 alkyl" and "C1-C4 alkyl" refer to saturated, straight-chain or branched carbon radicals 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 alkyl groups 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.

[0069] The term "C1-C4 alkylsulfonyloxy" refers to a radical consisting of a C1-C4 alkyl group directly attached to the sulfur of an SO3 group. A "C1-C4 alkylsulfonyloxy" group is a radical of the formula C1-C4 alkylS(=O)2O- or [ka] It can be expressed as:

[0070] 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.

[0071] The term "C1-C6 alkoxy" refers to a radical consisting of a C1-C6 alkyl group bonded directly to an oxygen atom, where 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.

[0072] The term "amorphous" refers to a solid in a non-crystalline state. Amorphous solids have disordered molecular arrangements and therefore lack a distinct crystal lattice or unit cell, and consequently lack a definable long-range order. The solid-state morphology 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 skilled in the art.

[0073] "C6~C 10 The term "arylsulfonyloxy" refers to a radical consisting of an aryl group attached directly to the sulfur atom of an SO group and has the formula aryl-S(=O)2O- or [ka] It can be expressed as:

[0074] 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.

[0075] 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, for example, a composition obtained / prepared during synthesis, preformulation, in-process testing / control (e.g., TLC, HPLC, NMR sample), etc.

[0076] The term "% crystallinity" or "crystalline purity" refers to the percentage of crystalline form in a preparation or sample. It is understood that a preparation or sample may contain other forms, such as amorphous form(s) of the same compound, or different crystalline forms of the same compound, or mixtures thereof. In some embodiments, a crystalline form can be isolated as the desired form (i.e., a crystalline form described herein) having a crystalline purity of at least about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% by weight. In some embodiments, a crystalline form can be isolated at a purity of about 90% or greater by weight. In some embodiments, a crystalline form can be isolated at a purity of about 95% or greater by weight. In some embodiments, a crystalline form can be isolated at a purity of about 99% or greater by weight.

[0077] When describing the particle size of a sample, "D10", "D50", and "D90" are used, and they have the following definitions. As used herein, the term "D10" means that 10% of the particles (based on volume) are smaller than or equal to the indicated size, and the term "D50" means that 50% of the particles (based on volume) are smaller than or equal to the indicated size, and the term "D90" means that 90% of the particles (based on volume) are smaller than or equal to the indicated size. For example, if a sample has a D10 of 21 μM, then 10% of the particles in the sample are smaller than or equal to 21 μM based on volume.

[0078] The terms "in need of treatment" and "in need thereof," when referring to treatment, are used interchangeably to mean the judgment made by a caregiver (e.g., a doctor, nurse, medical attendant, etc. in the case of humans, or a veterinarian in the case of animals, including non-human mammals), that an individual or animal needs or will benefit from treatment. This judgment is made based on a variety of factors within the caregiver's area of ​​expertise, including knowledge that the individual or animal is ill or at risk of becoming ill as a result of a disease, condition, or disorder treatable by the compounds of the invention. Thus, the compounds of the invention can be used protectively or prophylactically, or the compounds of the invention can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0079] The term "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo. In some embodiments, a halogen is chloro, bromo, or iodo. In some embodiments, a halogen is fluoro, chloro, or bromo. In some embodiments, a halogen is fluoro. In some embodiments, a halogen is chloro. In some embodiments, a halogen is bromo. In some embodiments, a halogen is iodo.

[0080] The term "C1-C6 haloalkyl" refers to a radical consisting of a C1-C6 alkyl group substituted with one or more halogens, where C1-C6 alkyl has the same definition as found herein. When C1-C6 haloalkyl can be fully substituted, it can be any group of the formula C n L 2n+1(L is a halogen and "n" is 1, 2, 3, 4, 5, or 6). When more than one halogen is present, they may be the same or different and may be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, a haloalkyl contains 1 to 5 carbons (i.e., a C1-C5 haloalkyl). In some embodiments, a haloalkyl contains 1 to 4 carbons (i.e., a C1-C4 haloalkyl). In some embodiments, a haloalkyl contains 1 to 3 carbons (i.e., a C1-C3 haloalkyl). In some embodiments, a 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.

[0081] The term "hydroxy" refers to the group --OH.

[0082] The term "individual" or "subject" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, "individual" refers to humans. In the context of clinical trials or screening or activity experiments, a subject can be a healthy volunteer or participant who does not have an underlying CFR-mediated disorder or condition, or a volunteer or participant who has been diagnosed with a disorder or condition that requires medical treatment, as determined by a medical professional. In the context of other than clinical trials, a subject who has been diagnosed with a disorder or condition and is under the care of a medical professional is typically referred to as a patient.

[0083] The term "inorganic base" refers to a base that does not contain at least one C-H bond and that contains at least one alkali metal or alkaline earth metal. Examples of inorganic bases include, but are not limited to, barium carbonate, calcium carbonate, cesium carbonate, lithium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, cesium bicarbonate, potassium bicarbonate, sodium bicarbonate, barium hydroxide, calcium hydroxide, cesium hydroxide, lithium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, and the like.

[0084] As used herein, "leaving group" refers to an atom or group of atoms that are displaced as a stable species in a chemical reaction. Suitable leaving groups are well known in the art, see, for example, March's Advanced Organic Chemistry, 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001 and TW Greene, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, 1999. Such leaving groups include, but are not limited to: Examples of leaving groups include halogen, optionally substituted alkylsulfonyloxy, and optionally substituted arylsulfonyloxy. Examples of some leaving groups include chloro, bromo, iodo, mesylate, tosylate, triflate, nosylate, and brosylate.

[0085] The term "nitro" refers to the group --NO.sub.2.

[0086] The term "pediatric subject" refers to a subject who is 21 years of age or younger at the time of diagnosis or treatment. The term "pediatric subject" can be further divided into various subpopulations, including neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years), and adolescents (12 to 21 years (up to, but not including, their 22nd birthday)). See, for example, Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: WB 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.

[0087] In some embodiments, a "pediatric subject" is a subject from birth to 28 days of age, 29 days to under 2 years of age, 2 years to under 12 years of age, or 12 years to 21 years of age (up to but not including the 22nd birthday). In some embodiments, a pediatric subject is a subject from birth to 28 days of age, 29 days to under 1 year of age, 1 month to under 4 months of age, 3 months to under 7 months of age, 6 months to under 1 year of age, 1 year to under 2 years of age, 2 years to under 3 years of age, 2 years to under 7 years of age, 3 years to under 5 years of age, 5 years to under 10 years of age, 6 years to under 13 years of age, 10 years to under 15 years of age, or 15 years to under 22 years of age.

[0088] The phrase "pharmaceutically acceptable" refers to compounds (and salts thereof), compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0089] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, cosolvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., that 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 formulation is contemplated. Supplementary active ingredients can also be incorporated into the formulation. In addition, various excipients, such as those commonly used in the art, may be included. These and other such compounds are described in the literature, e.g., 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), in Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0090] 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 the compounds of the present invention, whereby the composition is amenable to testing for a specified efficacious outcome in a mammal (e.g., but not limited to, a human). Those skilled in the art will understand and appreciate techniques appropriate for determining whether an active ingredient has a desired efficacious outcome, given the needs of the artisan.

[0091] The term "phase transfer catalyst" refers to any ionic catalyst, e.g., a quaternary ammonium salt, that is capable of transferring reactants from one phase to another when a 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 hydrogen sulfate, choline chloride, decyltrimethylammonium ammonium 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 bromideTetrabutylammonium 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 ammonium 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, tetramethylammonium bisulfate, tetramethylammonium bromide, tetramethylammonium chloride,Tetramethylammonium chloride, tetramethylammonium hexafluorophosphate, tetramethylammonium hydrogen sulfate, tetramethylammonium hydrogen sulfate, tetramethylammonium iodide, tetramethylammonium silicate, tetramethylammonium sulfate, tetramethylammonium tetrafluoroborate, tetraoctadecylammonium bromide, tetraoctylammonium bromide, tetraoctylammonium chloride, tetrapentylammonium bromide, tetrapentylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium iodide, tetrapropyl Examples of such ammonium tetrafluoroborate include ammonium 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, and trimethyl-tetradecylammonium chloride.

[0092] The term "prescribing" refers to directing, authorizing, or recommending the use of a drug or other treatment, therapy, or procedure. In some embodiments, a healthcare provider verbally advises, recommends, or authorizes the use of a compound, dosing regimen, or other treatment to an individual. The healthcare provider may or may not provide a written prescription for the compound, dosing regimen, or treatment. Additionally, the healthcare provider may or may not provide the compound or treatment to the individual. For example, the healthcare provider may advise the individual where to obtain the compound without providing the compound. In some embodiments, the healthcare provider may provide the individual with a written prescription for the compound, dosing regimen, or treatment. The prescription may be written on paper or recorded in an electronic medium. Additionally, the prescription may be telephoned (verbally) or faxed (written) to a pharmacy or clinic. 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. Various medical systems around the world use various methods for prescribing and administering compounds or treatments, and these methods are encompassed herein by the present disclosure. Healthcare providers may include, for example, doctors, nurses, nurse practitioners, or other medical professionals who can prescribe or administer compounds (drugs) for the disorders disclosed herein. In addition, healthcare providers may include those who can recommend, prescribe, administer, or prevent individuals from receiving compounds or drugs, including, for example, insurance providers.

[0093] The terms "prevent," "preventing," and "prevention" refer to eliminating or reducing the occurrence or onset of one or more symptoms associated with a particular disorder. For example, the terms "prevent," "preventing," and "prevention" can refer to administering a treatment on a prophylactic or preventative basis to an individual who may eventually, but has not yet, exhibited at least one symptom of a disorder. Such individuals can be identified based on the presence of risk factors, e.g., biomarkers, known to correlate with subsequent development of the disease. Alternatively, preventative treatment can be administered as a preventative measure without prior identification of risk factors. Delaying the onset of at least one episode and / or symptom of a disorder can also be considered prevention or prophylaxis.

[0094] As used herein, the terms "reacting," "contacting," or "treating," when describing a particular chemical reaction or method, are used as known in the art and generally refer to bringing together chemical reagents and / or intermediates in a manner such that interaction at the molecular level can achieve a chemical or physical transformation. In some embodiments, the reaction involves two reagents, where one or more equivalents of the second reagent are used relative to the first reagent. The reaction steps of the methods described herein can be carried out for a time and under conditions suitable to prepare the specified product. Additional terms are also used herein solely to provide descriptive clarity between the various method steps, and each of these terms has the same definition as previously described. These additional terms include "alkylation," "cyclization," "deprotection," "reduction," and "condensation."

[0095] 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 that contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0096] The term "subject," as used herein, means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the subject is a human.

[0097] In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed with congenital adrenal hyperplasia (CAH). In some embodiments, the subject is suspected of having CAH. In some embodiments, the subject has clinical records indicating that the subject has CAH (optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject.

[0098] As used herein, the term "substituted" refers to the replacement of at least one hydrogen atom of a chemical group with a non-hydrogen substituent or group, and the non-hydrogen substituent may be monovalent or divalent. If the chemical group or substituent is divalent, it is understood that the group is further substituted with another substituent or group. When a chemical group herein is "substituted," it may have up to the full substitution valence; for example, a methyl group may be substituted with 1, 2, or 3 substituents, a methylene group may be substituted with 1 or 2 substituents, a phenyl group may be substituted with 1, 2, 3, 4, or 5 substituents, a naphthyl group may be substituted with 1, 2, 3, 4, 5, 6, or 7 substituents, etc. Similarly, "substituted with one or more substituents" refers to the substitution of a group with from one substituent to the total number of substituents physically possible for that group. "Optionally substituted," as used herein, is understood to refer to a group that is "unsubstituted" or "substituted" with a group. Thus, 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 from one substituent, as described above, up to the total number of substituents physically possible for the group. In some embodiments, a group may be "optionally substituted with 1, 2, 3, or 4 substituents." In some embodiments, a group may be "optionally substituted with 1, 2, or 3 substituents." In some embodiments, a group may be "optionally substituted with 1 or 2 substituents." In some embodiments, a group may be "optionally substituted with 1 substituent." Furthermore, when a group is substituted with more than one substituent, these substituents may be the same or different. Examples of substituents include, but are not limited to, halogen, alkoxy, alkyl, haloalkyl, hydroxy, and nitro.

[0099] As used herein, "treat" or "treatment" refers to a curative or palliative measure. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, a decrease in the extent of the disease, stabilization of the disease state (i.e., not worsening), a delay or slowing of disease progression, alleviation or remission of the condition (e.g., one or more symptoms of the disease), and remission (whether partial or total). "Treatment" can also mean a prolongation of survival compared to the expected survival if not receiving treatment.

[0100] The term "therapeutically effective amount" refers to the amount of a compound of the invention or a pharmaceutically acceptable salt thereof, or the amount of a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof, that elicits a biological or medicinal response in a tissue, system, animal, or human as desired by an individual, researcher, veterinarian, physician, or other clinician or caregiver, which may include one or more of the following: (1) Prevention of a disorder, e.g., prevention of a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the associated pathology or symptoms; (2) Inhibition of a disorder, e.g., inhibition of a disease, condition, or disorder (i.e., arresting further development of the pathology and / or symptoms) in an individual experiencing or exhibiting the associated pathology or symptoms; and (3) Amelioration of the disorder, e.g., amelioration of a disease, condition, or disorder (i.e., reversal of pathology and / or symptoms) in an individual experiencing or exhibiting the associated pathology or symptoms. Crystalline morphology

[0101] 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 thereto can be characterized by their unique solid-state signatures, for example, with respect to differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and other solid-state methods. Further characterization of the water or solvent content of the crystalline form can be measured by any of the following methods, such as thermogravimetric analysis (TGA), DSC, etc.

[0102] For DSC, it is known that the temperatures observed for thermal events can vary depending on the purity of the sample and the rate of temperature change, as well as the sample preparation technique and instrumentation used. Thus, values ​​reported herein for DSC thermograms may vary by plus or minus about 5°C (i.e., ± about 5°C). Values ​​reported herein for DSC thermograms may also vary by plus or minus about 20 joules per gram (i.e., ± about 20 joules per gram).

[0103] For XRPD, the relative intensities of peaks may vary depending on the sample preparation technique, sample mounting procedure, and instrument used. Furthermore, instrumental variations and other factors can often affect 2θ values. Thus, peak assignments in a diffraction pattern may vary by plus or minus about 0.2° (i.e., ± about 0.2°). For TGA, temperature features reported herein may vary by plus or minus about 5°C (i.e., ± about 5°C). TGA % weight changes reported herein over a particular temperature range may vary by plus or minus about 2% weight change (i.e., ± about 2% weight change), for example, due to variations in sample quality and sample size. All X-ray powder diffraction patterns (diffractograms) were obtained using Cu-Kα radiation.

[0104] Further characterization of the hygroscopicity of the crystalline form can be measured, for example, by gravimetric vapor sorption (GVS). The GVS characteristics reported herein may vary by plus or minus about 5% relative humidity (i.e., ± about 5% relative humidity). The GVS characteristics reported herein may also vary by plus or minus about 2% weight change (i.e., ± about 2% weight change).

[0105] 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)

[0106] 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 methods related thereto.

[0107] A summary of representative physical properties for the anhydrous crystalline forms is provided in Tables 1 and 2. [Table 1]

[0108] Certain 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 2]

[0109] The GVS profile (adsorption / desorption isotherm) for the anhydrous crystalline Form I (free base) of Compound 1 is shown in Figure 3. The corresponding data in tabular form is provided in Table 3, where there was essentially no weight change after cycling from 10% RH to 90% RH and back to 10% RH. [Table 3-1] [Table 3-2]

[0110] 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). The 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 an anhydrous crystalline form containing 2% or less 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.

[0111] In one aspect of the invention, the anhydrous crystalline form has the following degrees of freedom in 2θ: 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°, 29.7°±0.2°, 30.2°±0.2°, 31.8°±0.2°, 32.3°±0.2°, 33.2°±0.2°, 34.2°±0.2°, 35.7°±0.2°, 36.8°±0.2°, 37.2°±0.2°, 38.2°±0.2°, 39.2°±0.2°, 40.2°±0.2°, 41.2°±0.2°, 42.2°±0.2°, 43.2°±0.2°, 44.2°±0.2°, 45.2°±0.2°, 46.2°±0.2°, 47.2°±0.2°, 48.2°±0.2°, 49.2°±0.2°, 50.2°±0.2°, 51.2°±0.2°, 52.2°± 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 an X-ray powder diffraction pattern containing at least three peaks selected from the group consisting of 29.6°±0.2°, 36.1°±0.2°, 43.5°±0.2°, 50.2°±0.2°, 60.2°±0.2°, 70.2°±0.2°, 80.2°±0.2°, 90.2°±0.2°, 100.2°±0.2°, 110.2°±0.2°, 120.2°±0.2°, 130.2°±0.2°, 140.2°±0.2°, 150.2°±0.2°, 160.2°±0.2°, 170.2°±0.2°, 180.2°±0.2°, 190.2°±0.2°, 200.2°±0.2°, 210.2°±0.2°, 220.2°±0.2°, 230.2°±0.2°, 240.2°±0.2°, 250.2°±0.2°, 260.2°±0.2°, 270.2°±0.2°, 280.2°±0.2°, 29.6°±0.2°, 36.1°±0.2°, and 300.2°±0.2°. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has the following angular degrees in degrees 2θ: 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°, 23.9°±0.2°, 24.3°±0.2°, 25.3°±0.2°, 26.3°±0.2°, 27.3°±0.2°, 28.3°±0.2°, 29.3°±0.2°, 30.3°±0.2°, 31.3°±0.2°, 32.3°±0.2°, 33.3°±0.2°, 34.3°±0.2°, 35.3°±0.2°, 36.3°±0.2°, 37.3°±0.2°, 38.3°±0.2°, 39.3°±0.2°, 40.3°±0.2°, 41.3°±0.2°, 42.3°±0.2°, 43.3°±0.2°, 44.3°±0.2°, 45.3°±0.2°, 46.3°±0.2°, 47.3°±0.2°, 48.3°±0.2°, 49.3°±0.2°, 50.3°±0.2°, 51.3°±0.2°, and 43.5°±0.2°, having an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 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 the following angular degrees in degrees 2θ: 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°, 23.9°±0.2°, 24.3°±0.2°, 25.3°±0.2°, 26.3°±0.2°, 27.3°±0.2°, 28.3°±0.2°, 29.3°±0.2°, 30.3°±0.2°, 31.3°±0.2°, 32.3°±0.2°, 33.3°±0.2°, 34.3°±0.2°, 35.3°±0.2°, 36.3°±0.2°, 37.3°±0.2°, 38.3°±0.2°, 39.3°±0.2°, 40.3°±0.2°, 41.3°±0.2°, 42.3°±0.2°, 43.3°±0.2°, 44.3°±0.2°, 45.3°±0.2°, 46.3°±0.2°, 47.3°±0.2°, 48.3°±0.2°, 49.3°±0.2°, 50.3°±0.2°, 51.3°±0.2°, and 43.5°±0.2°, having an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 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 the following angular degrees in degrees 2θ: 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°, 23.9°±0.2°, 24.3°±0.2°, 25.3°±0.2°, 26.3°±0.2°, 27.3°±0.2°, 28.3°±0.2°, 29.3°±0.2°, 30.3°±0.2°, 31.3°±0.2°, 32.3°±0.2°, 33.3°±0.2°, 34.3°±0.2°, 35.3°±0.2°, 36.3°±0.2°, 37.3°±0.2°, 38.3°±0.2°, 39.3°±0.2°, 40.3°±0.2°, 41.3°±0.2°, 42.3°±0.2°, 43.3°±0.2°, 44.3°±0.2°, 45.3°±0.2°, 46.3°±0.2°, 47.3°±0.2°, 48.3°±0.2°, 49.3°±0.2°, 50.3°±0.2°, 51.3°±0.2°, and 43.5°±0.2°, having an X-ray powder diffraction pattern comprising at least six peaks selected from the group consisting of 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 the following angular degrees in degrees 2θ: 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°, 23.9°±0.2°, 24.3°±0.2°, 25.3°±0.2°, 26.3°±0.2°, 27.3°±0.2°, 28.3°±0.2°, 29.3°±0.2°, 30.3°±0.2°, 31.3°±0.2°, 32.3°±0.2°, 33.3°±0.2°, 34.3°±0.2°, 35.3°±0.2°, 36.3°±0.2°, 37.3°±0.2°, 38.3°±0.2°, 39.3°±0.2°, 40.3°±0.2°, 41.3°±0.2°, 42.3°±0.2°, 43.3°±0.2°, 44.3°±0.2°, 45.3°±0.2°, 46.3°±0.2°, 47.3°±0.2°, 48.3°±0.2°, 49.3°±0.2°, 50.3°±0.2°, 51.3°±0.2°, and 43.5°±0.2°, having an X-ray powder diffraction pattern comprising at least seven peaks selected from the group consisting of 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 the following angular degrees in degrees 2θ: 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°, 23.9°±0.2°, 24.3°±0.2°, 25.3°±0.2°, 26.3°±0.2°, 27.3°±0.2°, 28.3°±0.2°, 29.3°±0.2°, 30.3°±0.2°, 31.3°±0.2°, 32.3°±0.2°, 33.3°±0.2°, 34.3°±0.2°, 35.3°±0.2°, 36.3°±0.2°, 37.3°±0.2°, 38.3°±0.2°, 39.3°±0.2°, 40.3°±0.2°, 41.3°±0.2°, 42.3°±0.2°, 43.3°±0.2°, 44.3°±0.2°, 45.3°±0.2°, 46.3°±0.2°, 47.3°±0.2°, 48.3°±0.2°, 49.3°±0.2°, 50.3°±0.2°, 51.3°±0.2°, and 43.5°±0.2°, having an X-ray powder diffraction pattern comprising at least eight peaks selected from the group consisting of 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 the following angular degrees in degrees 2θ: 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°, 23.9°±0.2°, 24.3°±0.2°, 25.3°±0.2°, 26.3°±0.2°, 27.3°±0.2°, 28.3°±0.2°, 29.3°±0.2°, 30.3°±0.2°, 31.3°±0.2°, 32.3°±0.2°, 33.3°±0.2°, 34.3°±0.2°, 35.3°±0.2°, 36.3°±0.2°, 37.3°±0.2°, 38.3°±0.2°, 39.3°±0.2°, 40.3°±0.2°, 41.3°±0.2°, 42.3°±0.2°, 43.3°±0.2°, 44.3°±0.2°, 45.3°±0.2°, 46.3°±0.2°, 47.3°±0.2°, 48.3°±0.2°, 49.3°±0.2°, 50.3°±0.2°, 51.3°±0.2°, and 43.5°±0.2°, having an X-ray powder diffraction pattern comprising at least nine peaks selected from the group consisting of 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 the following angular degrees in degrees 2θ: 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°, 23.9°±0.2°, 24.3°±0.2°, 25.3°±0.2°, 26.3°±0.2°, 27.3°±0.2°, 28.3°±0.2°, 29.3°±0.2°, 30.3°±0.2°, 31.3°±0.2°, 32.3°±0.2°, 33.3°±0.2°, 34.3°±0.2°, 35.3°±0.2°, 36.3°±0.2°, 37.3°±0.2°, 38.3°±0.2°, 39.3°±0.2°, 40.3°±0.2°, 41.3°±0.2°, 42.3°±0.2°, 43.3°±0.2°, 44.3°±0.2°, 45.3°±0.2°, 46.3°±0.2°, 47.3°±0.2°, 48.3°±0.2°, 49.3°±0.2°, 50.3°±0.2°, 51.3°±0.2°, and 43.5°±0.2°, having an X-ray powder diffraction pattern comprising at least 10 peaks selected from the group consisting of 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°.

[0112] 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 including a peak at 14.3°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern including a peak at 19.7°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern including a peak at 25.7°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks at 14.3°±0.2° and 25.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks at 14.3°±0.2° and 19.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks at 19.7°±0.2° and 25.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks at 14.3°±0.2°, 19.7°±0.2°, and 25.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks at 14.3°±0.2°, 19.7°±0.2°, 20.2°±0.2°, and 25.7°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks 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 degrees 2θ.In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks 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 degrees 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks 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 degrees 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks 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 degrees 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks 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 degrees 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising peaks 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 degrees 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern substantially as shown in Figure 1, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0113] It is understood that peak intensities may vary between diffractograms for the same crystalline form based on any number of factors known to those of skill in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, instrumentation used, etc. In some cases, peak intensities may be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary, and identical diffraction peak intensities are not necessarily required. An example is the XRPD for Form I shown in Figure 7, which shows substantially the same peak positions but dramatic peak intensity differences. One skilled in the art would understand that Figures 1 and 7 are XRPDs of Form I despite the differences in peak intensities. Similarly, one skilled in the art would be able to easily compare the diffractograms provided herein with diffractograms generated for unknown crystalline forms and easily determine whether the diffractogram characterizes the same crystalline form as provided herein or a different form.

[0114] One aspect of the present invention relates to 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), 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 FIG. 2, where "substantially" means that the reported DSC profile may vary by about ±5° C. and that the reported DSC profile may vary by about ±20 joules per gram.

[0115] One aspect of the present invention relates to 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), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 1.0% or less by about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile that exhibits a weight loss of about 0.9% or less by about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile that exhibits a weight loss of about 0.7% or less by about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile that exhibits a weight loss of about 0.6% or less by about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric profile that exhibits a weight loss of about 0.5% or less up to about 125°C.

[0116] 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 that exhibits a weight loss of about 0.05% to about 1.0% by about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile that exhibits a weight loss of about 0.1% to about 0.9% by about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile that exhibits a weight loss of about 0.1% to about 0.7% by about 125°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric profile that exhibits a weight loss of about 0.1% to about 0.6% by about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric profile that exhibits a weight loss of about 0.1% to about 0.4% by about 125° C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric profile substantially as shown in FIG. 2, where "substantially" means that the reported TGA features may vary by about ±5° C. and that the reported TGA features may vary by about ±2% weight change (i.e., ±about 2% weight change).

[0117] One aspect of the present invention relates to 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), wherein the anhydrous crystalline form has a gravimetric vapor sorption profile that exhibits a weight change of about 0.015% or less after adsorption / desorption cycling 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 that exhibits a weight change of about 0.01% or less after adsorption / desorption cycling 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 that exhibits a weight change of about 0.008% or less after adsorption / desorption cycling 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 that exhibits a weight change of about 0.005% or less after adsorption / desorption cycling 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 that exhibits a weight change of about 0.003% or less after adsorption / desorption cycling 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 that exhibits substantially no weight change after adsorption / desorption cycling from 10% RH to 90% RH and back to 10% RH.

[0118] 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 exhibits a weight change of about 0.1% or less from about 10% relative humidity (RH) to about 90% RH, and a gravimetric vapor sorption profile that exhibits a weight change of about 0.015% or less after adsorption / desorption cycling 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 that exhibits a weight change of about 0.08% or less from about 10% relative humidity (RH) to about 90% RH, and a weight change of about 0.01% or less after adsorption / desorption cycling 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 that exhibits a weight change of about 0.05% or less from about 10% relative humidity (RH) to about 90% RH, and a weight change of about 0.008% or less after adsorption / desorption cycling 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 that exhibits a weight change of about 0.04% or less from about 10% RH to about 90% RH and a weight change of about 0.005% or less after adsorption / desorption cycling 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 that exhibits a weight change of about 0.03% or less from about 10% RH to about 90% RH and a weight change of about 0.003% or less after adsorption / desorption cycling 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 that exhibits about 0.2% or less weight change from about 10% RH to about 90% RH and substantially no weight change after adsorption / desorption cycling 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, where "substantially" means that the reported GVS profile may vary by plus or minus about 5% relative humidity (i.e., ± about 5% relative humidity) and may vary by plus or minus about 2% weight change (i.e., ± about 2% weight change).

[0119] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising at least three peaks 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 degrees 2θ; a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of about 81°C to about 89.5°C; a thermogravimetric analysis profile showing a weight loss of about 0.05% to about 1.0% by about 125°C; and / or Gravimetric vapor sorption profile showing a weight change of approximately 0.015% or less after adsorption / desorption cycling from 10% RH to 90% RH and back to 10% RH 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), having the formula:

[0120] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern containing peaks at 14.3°±0.2°, 19.7°±0.2°, and 25.7°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of about 82.5°C to about 88.5°C; a thermogravimetric analysis profile showing a weight loss of about 0.7% or less by about 125°C; and / or Gravimetric vapor sorption profile showing a weight change of approximately 0.005% or less after adsorption / desorption cycling from 10% RH to 90% RH and back to 10% RH having This relates to 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).

[0121] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks 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 degrees 2θ; a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of about 83°C to about 88°C; a thermogravimetric analysis profile showing a weight loss of about 0.5% or less by about 125°C; and / or Gravimetric vapor sorption profile showing a weight change of approximately 0.003% or less after adsorption / desorption cycling from 10% RH to 90% RH and back to 10% RH 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), having the formula:

[0122] One aspect of the invention is that the anhydrous crystalline form is An X-ray powder diffraction pattern substantially as shown in FIG. A differential scanning calorimetry thermogram substantially as shown in FIG. a thermogravimetric analysis profile substantially as shown in FIG. 2; and / or For 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), having a gravimetric vapor sorption profile substantially as shown in FIG.

[0123] 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 a crystalline form described herein in 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.

[0124] A manufacturing batch 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) was prepared having the particle size distribution characteristics shown in Table 4 below. [Table 4]

[0125] 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) 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.

[0126] 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) has a particle size D50 of about 80 μM to about 150 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D50 of about 90 μM to about 145 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D50 of about 100 μM to about 140 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D50 of about 100 μM to about 135 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D50 of about 105 μM to about 130 μM.

[0127] 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) has a particle size D90 of about 280 μM to about 490 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D90 of about 290 μM to about 485 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D90 of about 300 μM to about 480 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D90 of about 305 μM to about 475 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D90 of about 310 μM to about 470 μM.

[0128] B. (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A, anhydrous crystalline form)

[0129] One aspect of the present invention relates to a novel anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) and methods related thereto.

[0130] A summary of representative physical properties for the anhydrous crystalline forms is provided below in Tables 5 and 6. [Table 5]

[0131] Certain other XRPD peaks for the crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) are shown in Table 6 below. [Table 6]

[0132] One aspect of the present invention relates to a crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A). In some embodiments, the crystalline form is an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A). An anhydrous crystalline form refers to a crystalline form containing 2% or less 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.

[0133] In one aspect of the invention, the anhydrous crystalline form has the following angles in degrees 2θ: 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 27.2°±0.2°, 28.2°±0.2°, 29.2°±0.2°, 30.2°±0.2°, 31.2°±0.2°, 32.2°±0.2°, 33.2°±0.2°, 34.2°±0.2°, 35.2°±0.2°, 36.2°±0.2°, 37.2°±0.2°, 38.2°±0.2°, 39.2°±0.2°, 40.2°±0.2°, 41.2°±0.2°, 42.2°±0.2°, 43.2°±0.2°, 44.2°±0.2°, 45.2°±0.2°, 46.2°±0.2°, 47.2°±0.2°, 48.2°±0.2°, 49.2°±0.2°, 50.2°±0.2°, 51.2°±0.2°, 52.2°±0.2°, 53.2°±0 An anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) having an X-ray powder diffraction pattern containing at least three peaks selected from the group consisting of 6.9°±0.2°, 27.1°±0.2°, and 28.0°±0.2°. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.1°±0.2°, and 28.0°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.1°±0.2°, and 28.0°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least six peaks selected from the group consisting of 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.1°±0.2°, and 28.0°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least seven peaks selected from the group consisting of 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.1°±0.2°, and 28.0°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least eight peaks selected from the group consisting of 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.1°±0.2°, and 28.0°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least nine peaks selected from the group consisting of 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.1°±0.2°, and 28.0°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 10 peaks selected from the group consisting of 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.1°±0.2°, and 28.0°±0.2° in degrees 2θ.

[0134] One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 25.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 18.4°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 19.0°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.4°±0.2° and 19.0°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.4°±0.2° and 25.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 19.0°±0.2° and 25.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.4°±0.2°, 19.0°±0.2°, and 25.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.4°±0.2°, 19.0°±0.2°, 23.1°±0.2°, and 25.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 15.2°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 23.1°±0.2°, and 25.7°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 15.2°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 23.1°±0.2°, and 25.7°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 15.2°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.1°±0.2°, and 25.7°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 8.3°±0.2°, 15.2°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.1°±0.2°, and 25.7°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 8.3°±0.2°, 15.2°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, and 25.7°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, and 25.7°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 9, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0135] It is understood that peak intensities may vary from diffractogram to diffractogram for the same crystalline form based on any number of factors known to those of skill in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, instrumentation used, etc. In some cases, peak intensities may be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary, and identical diffraction peak intensities are not necessarily required. One of skill in the art should be able to easily compare the diffractograms provided herein with diffractograms generated for unknown crystalline forms and determine whether the diffractogram characterizes the same crystalline form as provided herein, or a different form.

[0136] One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 129°C to about 136°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 130.5°C to about 135.5°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 131°C to about 134°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 131.5°C to about 133.5°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 132° C. to about 133° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure 10, where "substantially" means that the reported DSC profile may vary by about ±5° C. and that the reported DSC profile may vary by about ±20 joules per gram.

[0137] One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 1.0% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.7% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.4% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.2% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.15% or less by about 125° C.

[0138] One aspect of the present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.05% to about 1.0% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.05% to about 0.7% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.05% to about 0.4% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.05% to about 0.2% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric profile that exhibits a weight loss of about 0.05% to about 0.15% up to about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric profile substantially as shown in Figure 10, where "substantially" means that the reported TGA features may vary by about ±5° C. and that the reported TGA features may vary by about ±2% weight change (i.e., ±about 2% weight change).

[0139] One aspect of the invention is that the anhydrous crystalline form is

[0140] an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 8.3°±0.2°, 11.5°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.1°±0.2°, and 28.0°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 129°C to about 136°C; and / or The anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) has a thermogravimetric profile exhibiting a weight loss of about 0.05% to about 1.0% up to about 125°C.

[0141] One aspect of the invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.4°±0.2°, 19.0°±0.2°, and 25.7°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 131°C to about 134°C; and / or Thermogravimetric profile showing weight loss of about 0.7% or less up to about 125°C The present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), having the formula:

[0142] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks at 8.3°±0.2°, 15.2°±0.2°, 16.7°±0.2°, 18.4°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 21.5°±0.2°, 23.1°±0.2°, and 25.7°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 132°C to about 133°C; and / or Thermogravimetric profile showing weight loss of about 0.4% or less up to about 125°C The present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), having the formula:

[0143] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern substantially as shown in FIG. a differential scanning calorimetry thermogram substantially as shown in FIG. 10; and / or Thermogravimetric analysis profile substantially as shown in FIG. The present invention relates to an anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A), having the formula:

[0144] In some embodiments, the anhydrous crystalline form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) can be isolated as a crystalline form described herein in 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.

[0145] C. 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (compound 8A, crystalline form)

[0146] One aspect of the present invention relates to a novel anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) and methods relating thereto.

[0147] A summary of representative physical properties for the crystalline forms is provided in Tables 7 and 8. [Table 7]

[0148] Certain other XRPD peaks for the anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) are shown in Table 8 below. [Table 8-1] [Table 8-2]

[0149] One aspect of the present invention relates to a crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A). In some embodiments, the crystalline form is an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A). An anhydrous crystalline form refers to a crystalline form containing 2% or less 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.

[0150] One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, 39.2°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, 39.2°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, 39.2°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least six peaks selected from the group consisting of 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, 39.2°±0.2°, and 42.3°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least seven peaks selected from the group consisting of 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, 39.2°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least eight peaks selected from the group consisting of 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, 39.2°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least nine peaks selected from the group consisting of 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, 39.2°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 10 peaks selected from the group consisting of 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, 39.2°±0.2°, and 42.3°±0.2° in degrees 2θ.

[0151] One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 24.9°±0.2°, in units of 2θ, at 24.9°±0.2° and 26.7°±0.2°, in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 24.9°±0.2° and 27.8°±0.2°, in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 24.9°±0.2° and 34.8°±0.2°, in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 24.9°±0.2° and 42.3°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.9°±0.2°, 24.9°±0.2°, and 26.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.9°±0.2°, 24.9°±0.2°, and 27.8°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.9°±0.2°, 24.9°±0.2°, and 34.8°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.9°±0.2°, 24.9°±0.2°, and 42.3°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 24.9°±0.2°, 26.7°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.9°±0.2°, 24.9°±0.2°, 26.7°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.9°±0.2°, 24.9°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 18.9°±0.2°, 21.3°±0.2°, 24.9°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 12.6°±0.2°, 18.9°±0.2°, 21.3°±0.2°, 24.9°±0.2°, 26.7°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 12.6°±0.2°, 18.9°±0.2°, 21.3°±0.2°, 24.9°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 12.6°±0.2°, 18.9°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 12.6°±0.2°, 18.9°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 11, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0152] It is understood that peak intensities may vary from diffractogram to diffractogram for the same crystalline form based on any number of factors known to those of skill in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, instrumentation used, etc. In some cases, peak intensities may be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary, and identical diffraction peak intensities are not necessarily required. One of skill in the art should be able to easily compare the diffractograms provided herein with diffractograms generated for unknown crystalline forms and determine whether the diffractogram characterizes the same crystalline form as provided herein, or a different form.

[0153] One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 70.5°C to about 75.5°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 71°C to about 75°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 71.5°C to about 74.5°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 72°C to about 74°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 72.5°C to about 73.5°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure 12, where "substantially" means that the reported DSC features may vary by about ±5°C and that the reported DSC features may vary by about ±20 joules per gram.

[0154] One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 1.0% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.8% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.5% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.4% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.35% or less by about 125° C.

[0155] One aspect of the present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.1% to about 1.0% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.15% to about 0.8% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.2% to about 0.5% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.25% to about 0.4% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.3% to about 0.35% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in Figure 12, where "substantially" means that the reported TGA features may vary by about ±5°C and that the reported TGA features may vary by about ±2% weight change (i.e., ±about 2% weight change).

[0156] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 12.6°±0.2°, 13.8°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 24.9°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 27.5°±0.2°, 27.8°±0.2°, 34.8°±0.2°, 39.2°±0.2°, and 42.3°±0.2° in degrees 2θ; a differential scanning calorimetry (DSC) thermogram containing an endotherm with an extrapolated onset temperature of about 70.5°C to about 75.5°C; and / or Thermogravimetric analysis (TGA) profile showing a weight loss of approximately 0.1% to approximately 1.0% up to approximately 125°C The present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), having the formula:

[0157] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks at 18.9°±0.2°, 24.9°±0.2°, 26.7°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 71.5°C to about 74.5°C; and / or Thermogravimetric profile showing a weight loss of about 1.0% or less up to about 125°C The present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), having the formula:

[0158] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks at 12.6°±0.2°, 18.9°±0.2°, 21.3°±0.2°, 24.9°±0.2°, 26.7°±0.2°, 27.8°±0.2°, 34.8°±0.2°, and 42.3°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 72.5°C to about 73.5°C; and / or Thermogravimetric profile showing weight loss of about 0.5% or less up to about 125°C The present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), having the formula:

[0159] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern substantially as shown in FIG. a differential scanning calorimetry thermogram substantially as shown in FIG. 12; and / or Thermogravimetric analysis profile substantially as shown in FIG. The present invention relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A), having the formula:

[0160] In some embodiments, the anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) can be isolated as a crystalline form described herein in 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.

[0161] D. (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, hydrochloride salt, crystalline form)

[0162] One aspect of the present invention relates to a novel anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) and methods relating thereto.

[0163] A summary of representative physical properties for the crystalline forms is provided in Tables 9 and 10. [Table 9]

[0164] Certain other XRPD peaks for the crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) are shown in Table 10 below. [Table 10]

[0165] One aspect of the present invention relates to a crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt). In some embodiments, the crystalline form is an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt). An anhydrous crystalline form refers to a crystalline form containing 2% or less 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.

[0166] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 13.7°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 13.7°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 13.7°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least six peaks selected from the group consisting of 13.7°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least seven peaks selected from the group consisting of 13.7°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least eight peaks selected from the group consisting of 13.7°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least nine peaks selected from the group consisting of 13.7°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 10 peaks selected from the group consisting of 13.7°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ.

[0167] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 20.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 21.1°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 24.3°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2° and 21.1°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2° and 24.3°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 21.1°±0.2° and 24.3°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, and 24.3°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 24.3°±0.2°, and 29.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 23.2°±0.2°, and 24.3°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 23.2°±0.2°, 24.3°±0.2°, and 29.5°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, and 29.5°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 24.3°±0.2°, and 29.5°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, and 29.5°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 24.3°±0.2°, 29.5°±0.2°, 23.2°±0.2°, 15.3°±0.2°, and 14.8°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, and 29.5°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 14.8°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, and 29.5°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 13, where "substantially" means that the reported peaks may vary by about ±0.2 degrees 2θ.

[0168] It is understood that peak intensities may vary from diffractogram to diffractogram for the same crystalline form based on any number of factors known to those of skill in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, instrumentation used, etc. In some cases, peak intensities may be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary, and identical diffraction peak intensities are not necessarily required. One of skill in the art should be able to easily compare the diffractograms provided herein with diffractograms generated for unknown crystalline forms and determine whether the diffractogram characterizes the same crystalline form as provided herein, or a different form.

[0169] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 154°C to about 164°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155°C to about 163°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 157°C to about 162°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 158.5°C to about 160.5°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 159°C to about 160°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure 14, where "substantially" means that the reported DSC features may vary by about ±5°C and that the reported DSC features may vary by about ±20 joules per gram.

[0170] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 1.0% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.8% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.6% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.4% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.35% or less by about 125° C.

[0171] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.05% to about 1.0% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.1% to about 0.8% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.15% to about 0.6% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.2% to about 0.4% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.25% to about 0.35% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in FIG. 14, where "substantially" means that the reported TGA features may vary by about ±5°C and that the reported TGA features may vary by about ±2% weight change (i.e., ±about 2% weight change).

[0172] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 13.7°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 23.2°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 29.5°±0.2°, and 29.8°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 154°C to about 164°C; and / or The anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) has a thermogravimetric profile exhibiting a weight loss of about 0.05% to about 1.0% up to about 125°C.

[0173] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 24.3°±0.2°, and 29.5°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 157°C to about 162°C; and / or Thermogravimetric profile showing a weight loss of about 1.0% or less up to about 125°C The anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) has the formula:

[0174] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks at 20.5°±0.2°, 21.1°±0.2°, 24.3°±0.2°, 29.5°±0.2°, 23.2°±0.2°, 15.3°±0.2°, and 14.8°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of about 159°C to about 160°C; and / or Thermogravimetric profile showing weight loss of about 0.4% or less up to about 125°C The anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) has the formula:

[0175] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern substantially as shown in FIG. a differential scanning calorimetry thermogram substantially as shown in FIG. 14, and / or Thermogravimetric analysis profile substantially as shown in FIG. The anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) has the formula:

[0176] In some embodiments, the anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt) can be isolated as a crystalline form described herein in 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.

[0177] E. 2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A, crystalline form)

[0178] One aspect of the present invention relates to a novel anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) and methods relating thereto.

[0179] A summary of representative physical properties for the crystalline forms is provided in Tables 11 and 12. [Table 11]

[0180] Certain other XRPD peaks for the crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) are shown in Table 12 below. [Table 12]

[0181] One aspect of the present invention relates to a crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A). In some embodiments, the crystalline form is an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A). An anhydrous crystalline form refers to a crystalline form containing 2% or less 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.

[0182] One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.4°±0.2°, 7.5°±0.2°, 14.7°±0.2°, 14.8°±0.2°, 22.0°±0.2°, 29.5°, and 37.1°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 7.4°±0.2°, 7.5°±0.2°, 14.7°±0.2°, 14.8°±0.2°, 22.0°±0.2°, 29.5°, and 37.1°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 7.4°±0.2°, 7.5°±0.2°, 14.7°±0.2°, 14.8°±0.2°, 22.0°±0.2°, 29.5°, and 37.1°±0.2° in degrees 2θ.

[0183] One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 7.4°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 7.5°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 14.7°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 14.8°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2° and 14.7°±0.2° in 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2° and 14.8°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2° and 14.7°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2° and 14.8°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 14.7°±0.2°, and 22.0°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 14.8°±0.2°, and 22.0°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2°, 14.7°±0.2°, and 22.0°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2°, 14.8°±0.2°, and 22.0°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 14.7°±0.2°, and 29.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 14.8°±0.2°, and 29.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2°, 14.7°±0.2°, and 29.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2°, 14.8°±0.2°, and 29.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 14.7°±0.2°, 22.0°±0.2°, and 29.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 14.8°±0.2°, 22.0°±0.2°, and 29.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2°, 14.7°±0.2°, 22.0°±0.2°, and 29.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2°, 14.8°±0.2°, 22.0°±0.2°, and 29.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 14.7°±0.2°, 22.0°±0.2°, 29.5°±0.2°, and 37.1°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 14.8°±0.2°, 22.0°±0.2°, 29.5°±0.2°, and 37.1°±0.2° in units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2°, 14.7°±0.2°, 22.0°±0.2°, 29.5°±0.2°, and 37.1°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.5°±0.2°, 14.8°±0.2°, 22.0°±0.2°, 29.5°±0.2°, and 37.1°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 7.5°±0.2°, 14.7°±0.2°, 14.8°±0.2°, 22.0°±0.2°, 29.5°±0.2°, and 37.1°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 15, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0184] It is understood that peak intensities may vary from diffractogram to diffractogram for the same crystalline form based on any number of factors known to those of skill in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, instrumentation used, etc. In some cases, peak intensities may be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary, and identical diffraction peak intensities are not necessarily required. One of skill in the art should be able to easily compare the diffractograms provided herein with diffractograms generated for unknown crystalline forms and determine whether the diffractogram characterizes the same crystalline form as provided herein, or a different form.

[0185] One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 25° C. to about 31° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 26.5° C. to about 30° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 26.5° C. to about 29.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 27° C. to about 29° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 27.5° C. to about 28.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure 16, where "substantially" means that the reported DSC features may vary by about ±5°C and that the reported DSC features may vary by about ±20 joules per gram.

[0186] One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 1.0% or less by about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.7% or less by about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.6% or less by about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.4% or less by about 70° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.2% or less by about 70° C.

[0187] One aspect of the present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.02% to about 1.0% by about 70°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.03% to about 0.7% by about 70°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.04% to about 0.6% by about 70°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.05% to about 0.4% by about 70°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.1% to about 0.2% by about 70°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in Figure 16, where "substantially" means that the reported TGA features may vary by about ±5°C and that the reported TGA features may vary by about ±2% weight change (i.e., ±about 2% weight change).

[0188] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 7.4°±0.2°, 7.5°±0.2°, 14.7°±0.2°, 14.8°±0.2°, 22.0°±0.2°, 29.5°, and 37.1°±0.2° in degrees 2θ; a differential scanning calorimetry (DSC) thermogram containing an endotherm with an extrapolated onset temperature of about 25°C to about 31°C; and / or The anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) has a thermogravimetric profile that exhibits a weight loss of about 1.0% or less up to about 70°C.

[0189] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 7.4°±0.2°, 7.5°±0.2°, 14.7°±0.2°, 14.8°±0.2°, 22.0°±0.2°, 29.5°, and 37.1°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 26.5°C to about 29.5°C; and / or Thermogravimetric analysis profile showing a weight loss of approximately 0.02% to approximately 1.0% up to approximately 70°C The present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) having the formula:

[0190] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks at 7.4°±0.2°, 7.5°±0.2°, 14.7°±0.2°, 14.8°±0.2°, 22.0°±0.2°, 29.5°±0.2°, and 37.1°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 27.5°C to about 28.5°C; and / or Thermogravimetric analysis profile showing a weight loss of approximately 0.05% to approximately 0.4% up to approximately 70°C The present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) having the formula:

[0191] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern substantially as shown in FIG. a differential scanning calorimetry thermogram substantially as shown in FIG. 16; and / or Thermogravimetric analysis profile substantially as shown in FIG. The present invention relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) having the formula:

[0192] In some embodiments, the anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) can be isolated as a crystalline form described herein in 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.

[0193] F. Crystalline (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt)

[0194] One aspect of the present invention relates to a novel anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) and methods related thereto.

[0195] A summary of representative physical properties for crystalline Compound 5A (HCl salt) is provided in Tables 13 and 14. [Table 13]

[0196] Certain other XRPD peaks for the anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) are shown in Table 14 below. [Table 14]

[0197] One aspect of the present invention relates to a crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt). In some embodiments, the crystalline form is an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt). An anhydrous crystalline form refers to a crystalline form containing 2% or less 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.

[0198] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N—((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 6.5°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25.9°±0.2°, and 32.1°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 6.5°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25.9°±0.2°, and 32.1°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 6.5°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25.9°±0.2°, and 32.1°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least six peaks selected from the group consisting of 6.5°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25.9°±0.2°, and 32.1°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least seven peaks selected from the group consisting of 6.5°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25.9°±0.2°, and 32.1°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least eight peaks selected from the group consisting of 6.5°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25.9°±0.2°, and 32.1°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least nine peaks selected from the group consisting of 6.5°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25.9°±0.2°, and 32.1°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 10 peaks selected from the group consisting of 6.5°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25.9°±0.2°, and 32.1°±0.2° in degrees 2θ.

[0199] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 13.0°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising a peak at 19.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 25.9°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 13.0°±0.2° and 19.5°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 13.0°±0.2° and 25.9°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 19.5°±0.2° and 25.9°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 13.0°±0.2°, 19.5°±0.2°, and 25.9°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 13.0°±0.2°, 19.5°±0.2°, 20.4°±0.2°, and 25.9°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 12.1°±0.2°, 13.0°±0.2°, 19.5°±0.2°, 20.4°±0.2°, and 25.9°±0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.4°±0.2°, and 25.9°±0.2° in degrees 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, and 25.9°±0.2° in degrees 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 17, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0200] It is understood that peak intensities may vary from diffractogram to diffractogram for the same crystalline form based on any number of factors known to those of skill in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, instrumentation used, etc. In some cases, peak intensities may be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary, and identical diffraction peak intensities are not necessarily required. One of skill in the art should be able to easily compare the diffractograms provided herein with diffractograms generated for unknown crystalline forms and determine whether the diffractogram characterizes the same crystalline form as provided herein, or a different form.

[0201] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 212°C to about 218.5°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 213°C to about 218°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 214°C to about 217.5°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 214.5°C to about 217°C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 215° C. to about 216.5° C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially as shown in Figure 18, where "substantially" means that the reported DSC profile may vary by about ±5° C. and that the reported DSC profile may vary by about ±20 joules per gram.

[0202] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 1.0% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.8% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.6% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.4% or less by about 125° C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.2% or less by about 125° C.

[0203] One aspect of the present invention relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.01% to about 1.0% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.02% to about 0.8% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.03% to about 0.6% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.04% to about 0.4% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile that exhibits a weight loss of about 0.05% to about 0.2% by about 125°C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially as shown in Figure 18, where "substantially" means that the reported TGA features may vary by about ±5°C and that the reported TGA features may vary by about ±2% weight change (i.e., ±about 2% weight change).

[0204] One aspect of the invention is that the anhydrous crystalline form is

[0205] an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 6.5°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.5°±0.2°, 24.8°±0.2°, 25.9°±0.2°, and 32.1°±0.2° in degrees 2θ; a differential scanning calorimetry (DSC) thermogram containing an endotherm with an extrapolated onset temperature of about 212°C to about 218.5°C; and / or Thermogravimetric profile showing a weight loss of about 1.0% or less up to about 125°C The anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) has the formula:

[0206] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern containing peaks selected from the group consisting of 13.0°±0.2°, 19.5°±0.2°, and 25.9°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 214°C to about 217.5°C; and / or The anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) has a thermogravimetric profile exhibiting a weight loss of about 0.02% to about 0.8% up to about 125°C.

[0207] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks at 12.1°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 19.5°±0.2°, 20.4°±0.2°, and 25.9°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 214.5°C to about 217°C; and / or The anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) has a thermogravimetric profile exhibiting a weight loss of about 0.04% to about 0.4% up to about 125°C.

[0208] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern substantially as shown in FIG. a differential scanning calorimetry thermogram substantially as shown in FIG. 18, and / or Thermogravimetric analysis profile substantially as shown in FIG. The anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) has the formula:

[0209] In some embodiments, the anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt) can be isolated as a crystalline form described herein in 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.

[0210] G. Crystalline 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, Form I)

[0211] One aspect of the present invention relates to a novel 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) and methods relating thereto.

[0212] A summary of representative physical properties for crystalline Compound 1 (tosylate salt) is provided in Tables 15 and 16. [Table 15]

[0213] Certain other XRPD peaks for crystalline 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) are shown in Table 16 below. [Table 16]

[0214] One aspect of the present invention relates to a 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, Form I).

[0215] In one aspect of the invention, the crystalline form is 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° in units of 2θ. The present invention relates to a 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, Form I), having an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least four peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least five peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least six peaks 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° in degrees 2θ.In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least seven peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least eight peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least nine peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising at least 10 peaks 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° in degrees 2θ.

[0216] One aspect of the present invention relates to a 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), wherein the crystalline form has an X-ray powder diffraction pattern comprising a peak at 9.1°±0.2° in 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising a peak at 21.1°±0.2° in 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising a peak at 23.3°±0.2° in 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks at 9.1°±0.2° and 21.1°±0.2° in 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising peaks at 9.1°±0.2° and 23.3°±0.2° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising peaks at 21.1°±0.2° and 23.3°±0.2° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising peaks at 9.1°±0.2°, 21.1°±0.2°, and 23.3°±0.2° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising peaks at 9.1°±0.2°, 11.3°±0.2°, 21.1°±0.2°, and 23.3°±0.2° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks at 9.1°±0.2°, 11.3°±0.2°, 21.1°±0.2°, 22.8°±0.2°, and 23.3°±0.2° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks at 9.1°±0.2°, 11.3°±0.2°, 13.2°±0.2°, 16.3°±0.2°, and 21.1°±0.2° in degrees 2θ.In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks at 9.1°±0.2°, 11.3°±0.2°, 21.1°±0.2°, 23.3°±0.2°, and 23.8°±0.2° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ.In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks at 9.1°±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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ.In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern comprising peaks 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° in degrees 2θ. In some embodiments, the crystalline form (Compound 1, tosylate salt) has an X-ray powder diffraction pattern substantially as shown in Figure 24, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0217] It is understood that peak intensities may vary from diffractogram to diffractogram for the same crystalline form based on any number of factors known to those of skill in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, instrumentation used, etc. In some cases, peak intensities may be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary, and identical diffraction peak intensities are not necessarily required. One of skill in the art should be able to easily compare the diffractograms provided herein with diffractograms generated for unknown crystalline forms and determine whether the diffractogram characterizes the same crystalline form as provided herein, or a different form.

[0218] One aspect of the present invention relates to a 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), wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 154°C to about 159°C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 154.5°C to about 158.5°C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155°C to about 158°C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155.5° C. to about 157.5° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 156° C. to about 157° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a differential scanning calorimetry thermogram substantially as shown in FIG. 25, where "substantially" means that the reported DSC profile may vary by about ±5° C. and that the reported DSC profile may vary by about ±20 joules per gram.

[0219] One aspect of the present invention relates to a 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), wherein the crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 1.0% or less by about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.9% or less by about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.7% or less by about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.6% or less by about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.5% or less up to about 125°C.

[0220] One aspect of the present invention relates to a 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), wherein the crystalline form has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.05% to about 1.0% by about 125°C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.1% to about 0.9% by about 125°C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.2% to about 0.7% by about 125°C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.3% to about 0.6% by about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis (TGA) profile that exhibits a weight loss of about 0.4% to about 0.5% by about 125° C. In some embodiments, the crystalline form (Compound 1, tosylate salt) has a thermogravimetric analysis profile substantially as shown in FIG. 25, where "substantially" means that the reported TGA profile may vary by about ±5° C. and that the reported TGA profile may vary by about ±2% weight change (i.e., ±about 2% weight change).

[0221] In one aspect of the present invention, the crystalline form is an X-ray powder diffraction pattern comprising at least three peaks 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° in degrees 2θ; a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of about 154°C to about 159°C; and / or The present invention relates to a 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), having a thermogravimetric analysis profile exhibiting a weight loss of about 0.05% to about 1.0% up to about 125°C.

[0222] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks at 9.1°±0.2°, 11.3°±0.2°, 21.1°±0.2°, 22.8°±0.2°, and 23.3°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of about 155°C to about 158°C; and / or Thermogravimetric profile showing weight loss of about 0.9% or less up to about 125°C The present invention relates to a 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), having the formula:

[0223] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern comprising peaks at 9.1°±0.2°, 11.3°±0.2°, 13.2°±0.2°, 16.3°±0.2°, and 21.1°±0.2° in degrees 2θ; a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 155.5°C to about 157.5°C; and / or Thermogravimetric profile showing weight loss of about 0.6% or less up to about 125°C 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, tosylate salt), having the formula:

[0224] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern substantially as shown in Figure 24; a differential scanning calorimetry thermogram substantially as shown in FIG. 25; and / or Thermogravimetric analysis profile substantially as shown in FIG. The present invention relates to a 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), having the formula:

[0225] 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, tosylate salt) can be isolated as a crystalline form described herein in 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. Isotopically labeled compounds of the present invention

[0226] In the compounds disclosed and described herein, the atoms at each position of the compounds can independently have an isotopic distribution of chemical elements in proportion to the amount normally found in nature, or in proportion to the amount normally found in nature, unless otherwise indicated by the context. Thus, one aspect of the present invention is a compound of formula (Ia) [ka] [In the formula, R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of hydrogen and deuterium; X is carbon-12( 12 C) and carbon-13( 13 C) with the proviso that at least one R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is deuterium].

[0227] In some embodiments, each R 1 is independently deuterium. In some embodiments, each R 2 is independently deuterium. In some embodiments, each R 3 are independently deuterium. In some embodiments, R 4 is deuterium. In some embodiments, each R 5 is independently deuterium. In some embodiments, each R 6 is independently deuterium. In some embodiments, each R 7 is independently deuterium. In some embodiments, each R 8 is independently deuterium. In some embodiments, each R 9 are independently deuterium. In some embodiments, R 10 is deuterium. In some embodiments, R 11 is deuterium.

[0228] In some embodiments, X is carbon-12( 12 In some embodiments, X is carbon-13 ( 13 C).

[0229] In some embodiments, each R 1 are independently deuterium, and X is carbon-13( 13 C).

[0230] Compounds of formula (Ia) can be prepared using the methods described herein by introducing one or more isotopes into any of the intermediates using methods known in the art, for example, the representative method shown in Example 6.

[0231] Chemical elements have atomic numbers defined by the number of protons in the atomic nucleus. Each atomic number identifies a particular element, but not an isotope, and atoms of a given element may have a range in the number of neutrons they contain. The number of both protons and neutrons in the nucleus is the atom's mass number, and each isotope of a given element has a different mass number. Compounds in which one or more atoms have an isotopic distribution for a chemical element in a proportional amount different from the amount normally found in nature are generally referred to as isotopically labeled compounds. Each chemical element represented in a compound structure can include any isotopic distribution of said element. For example, within a compound structure, a hydrogen atom can be explicitly disclosed or understood to be present in the compound. At any position in a compound where a hydrogen atom can be present, that hydrogen atom can be present in an amount proportional to and different from the amount normally found in nature, including, but not limited to, protium ( 1 H) and deuterium ( 2 The compounds may be present in an isotopic distribution of hydrogen, including H). Thus, reference to a compound herein encompasses all possible isotopic distributions for each atom, unless the context clearly indicates otherwise. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As will be recognized by those skilled in the art, any of the compounds disclosed and described herein may contain radioactive isotopes. Thus, one or more atoms may be present in a proportion greater than that found in nature. 2 H or 3H, or a proportion greater than that found in nature 11 C. 13 C or 14 The use of compounds disclosed and described herein with isotope distributions different from that normally found in nature, such as those having C, is also contemplated. By way of general example and without limitation, isotopes of hydrogen include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Carbon isotopes include carbon-11 ( 11 C), carbon-12( 12 C), carbon-13( 13 C), and carbon-14 ( 14 C). Isotopes of nitrogen include nitrogen-13( 13 N), nitrogen-14( 14 N) and nitrogen-15( 15 N). Isotopes of oxygen include oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), and oxygen-18( 18 O). Fluorine isotopes include fluorine-17( 17 F), fluorine-18( 18 F) and fluorine-19( 19 Phosphate isotopes include phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), phosphorus-34( 34 P), phosphorus-35( 35 P) and phosphorus-36( 36 P). Isotopes of sulfur include sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S) and sulfur-38( 38 S). Chlorine isotopes include chlorine-35( 35 Cl), chlorine-36( 36 Cl) and chlorine-37(37 The isotopes of bromine include bromine-75( 75 Br), Bromine-76( 76 Br), Bromine-77( 77 Br), Bromine-79( 79 Br), Bromine-81( 81 Br) and bromine-82( 82 Br). Iodine isotopes include iodine-123 ( 123 I), iodine-124( 124 I), iodine-125( 125 I), iodine-131( 131 I) and iodine-135( 135I). In some embodiments, atoms at each position of the compound have an isotopic distribution for each chemical element in a proportionate amount relative to the amount normally found in nature. In some embodiments, atoms at at least one position of the compound have an isotopic distribution for a chemical element in a proportionate amount different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a chemical element in a proportionate amount relative to the amount normally found in nature). In some embodiments, atoms at at least two positions of the compound independently have an isotopic distribution for a chemical element in a proportionate amount different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a chemical element in a proportionate amount relative to the amount normally found in nature). In some embodiments, atoms at at least three positions of the compound independently have an isotopic distribution for a chemical element in a proportionate amount different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a chemical element in a proportionate amount relative to the amount normally found in nature). In some embodiments, atoms at at least four positions of the compound independently have an isotopic distribution for a chemical element in a proportionate amount different from the amount normally found in nature (the remaining atoms have an isotopic distribution for a chemical element in a proportionate amount relative to the amount normally found in nature). In some embodiments, atoms at at least five positions of the compound independently have an isotopic distribution for the chemical element in a proportional amount that differs from the amount normally found in nature (the remaining atoms have an isotopic distribution for the chemical element in a proportional amount relative to the amount normally found in nature). In some embodiments, atoms at at least six positions of the compound independently have an isotopic distribution for the chemical element in a proportional amount that differs from the amount normally found in nature (the remaining atoms have an isotopic distribution for the chemical element in a proportional amount relative to the amount normally found in nature).

[0232] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d," it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor at each designated deuterium position of, in certain embodiments, at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Certain Methods of the Invention

[0233] The present invention is directed, inter alia, to methods useful 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) and crystalline forms thereof.

[0234] Any of the methods, either collectively as one or more steps described herein below and above, or as individual steps, can be carried out under an inert atmosphere. Thus, in some embodiments, the method steps described herein are carried out under a substantially inert atmosphere.

[0235] In some embodiments, the method steps described herein are performed under a substantially inert atmosphere comprising argon or nitrogen. In some embodiments, the method steps described herein are performed under a substantially inert atmosphere comprising nitrogen.

[0236] The reactions of the methods described herein can be carried out in a suitable solvent, which can be easily selected by one skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the reaction step, an appropriate solvent can be selected for a specific reaction step. In some embodiments, the reaction can be carried out in the absence of a solvent, such as when at least one of the intermediates or reagents is liquid.

[0237] Suitable solvents can include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 1,2-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane, chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride, dichlorofluoromethane, chlorodifluoromethane, trifluoromethane, 1,2-dichlorotetrafluorethane, hexafluoroethane, and mixtures thereof.

[0238] Suitable solvents can include ether solvents such as 1,2-dimethoxyethane (DME), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, 5-methyl-2-hexanone (MIAK), 4-methyl-2-pentanone (MIBK), tert-amyl methyl ether (TAME, also known as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), mixtures thereof, and the like.

[0239] Suitable solvents can include alcohols or protic solvents such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, glycerol, and mixtures thereof.

[0240] Suitable solvents include benzene, chlorobenzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, n-heptane, ethylbenzene, o-xylene, m-xylene, p-xylene, mixtures of xylenes, octane, indane, nonane, naphthalene, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, isopropyl acetate, sulfolane, 1,3-dimethyl The solvent may include aprotic solvents such as methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidinone, tetramethylurea, nitromethane, and nitrobenzene, and amides (including but not limited to N,N-dimethylformamide, N,N-dimethylacetamide, formamide, N-methylacetamide, N-methylformamide, N,N-dimethylpropionamide, hexamethylphosphoramide), and mixtures thereof.

[0241] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, naphthalene, and mixtures thereof.

[0242] The methods described herein can be monitored by any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, gas chromatography (GC), or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0243] In preparing compounds by the methods described herein, conventional isolation and purification procedures such as concentration, filtration, extraction, solid phase extraction, recrystallization, enantiomeric enrichment by recrystallization, chromatography, and the like can be used to isolate the desired product.

[0244] Example processes and certain intermediates of the present invention are shown below in Schemes I through VII.

[0245] A representative coupling step of 2-cyclopropylacetic acid (compound 1A) with N,O-dimethylhydroxylamine or a salt thereof in the presence of a coupling step reagent (e.g., 1,1'-carbonyldiimidazole), a coupling step base (e.g., triethylamine) and a coupling step solvent (e.g., dichloromethane) to prepare 2-cyclopropyl-N-methoxy-N-methylacetamide (compound 2A) is presented in Scheme I below. [ka]

[0246] A representative reaction step between 2-cyclopropyl-N-methoxy-N-methylacetamide (compound 2A) and an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a solvent for the reaction step (e.g., tetrahydrofuran (THF)) to prepare 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A) is presented in Scheme II below. [ka]

[0247] A representative condensation step of 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 condensation step acid (e.g., p-toluenesulfonic acid) and a condensation step solvent (e.g., toluene) to prepare a compound of Formula (Ie) is presented in Scheme III below. [ka] [In the formula, R 1c , R 2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen.

[0248] A representative reduction step of a compound of formula (Ie) in the presence of a reduction catalyst (e.g., sponge nickel and Pd / Cu—C), hydrogen, and a solvent for the reduction step (e.g., ethanol) to prepare a compound of formula (Ig) is presented below in Scheme IV. [ka] [In the formula, R 1c , R 2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen.

[0249] A representative deprotection step of a compound of formula (Ig) or a salt thereof in the presence of a deprotection catalyst (e.g., Pd), hydrogen, and a solvent for the deprotection step (e.g., ethanol) to prepare (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (compound 6A) or a salt thereof is presented in Scheme V below. [ka] [In the formula, R 1c , R 2cand R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen.

[0250] A representative cyclization step between (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (compound 6A) or a salt thereof and 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (compound 8A) or a tautomeric form thereof in the presence of a solvent for the cyclization step (e.g., n-heptane) to prepare (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 is presented in Scheme VI below.

[0251] [ka]

[0252] 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-yn in the presence of an alkylation step solvent (e.g., methyl tert-butyl ether (MTBE), toluene, and mixtures thereof), a phase transfer catalyst (e.g., tetra-n-butylammonium bromide (TBAB)), an alkylation step base (e.g., potassium hydroxide), and water. A representative alkylation step between (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 suitable leaving group (e.g., Br)) to prepare methyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof is presented below in Scheme VII. [ka]

[0253] One aspect of the present invention includes any combination of one or more process steps, and intermediates related thereto, used in 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 / or pharmaceutically acceptable salts, and crystalline forms thereof, such as the processes exemplified by Schemes I, II, III, IV, V, VI, VII, and VII (above), and compounds contained therein.

[0254] One aspect of the present invention relates to one or more intermediates useful in 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 / or pharmaceutically acceptable salts, and crystalline forms thereof, such as Compounds (2A), (3A), (4A), (5A), (6A), (7A), (8A), and (9A), as well as compounds of Formula (Ia), (Ic), (Ie), (Ig), and (Ii), and compounds prepared by the methods exemplified in Schemes I, II, III, IV, V, VI, VII, and VII (above).

[0255] Certain synthetic 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) are described in PCT Application PCT / FR00 / 01995 (International Publication No. WO2001 / 05776), filed July 11, 2000. Several improvements have been discovered and are described herein.

[0256] One such improvement is the use of PTC conditions, shown in Scheme VII, which do not require a moisture-sensitive base, such as sodium hydride, as described in WO2001 / 05776, and dimethylformamide (see Example 25).

[0257] Another improvement involves the steps shown in Scheme III-IV, which converted the ketone (compound 3A) to a chiral amine (compound 6A) in high yield and high enantiomeric excess.

[0258] Compounds of the invention also include all isotopes of atoms occurring in the intermediates and / or final compounds. Isotopes include atoms having the same atomic number but different mass numbers, for example, isotopes of hydrogen include deuterium and tritium.

[0259] I. A process useful 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) or a pharmaceutical salt thereof (alkylation step).

[0260] One aspect of the present invention is 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: [ka] 9A) or a salt thereof, comprising the steps of: (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; [ka] with a compound of formula (Ii): [ka] wherein LG is a leaving group, in the presence of an alkylation step solvent, a phase transfer catalyst, an alkylation 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.

[0261] In some embodiments, LG is selected from the group: C1-C4 alkylsulfonyloxy, C6-C 10 arylsulfonyloxy, halogen and hydroxy, and C1-C4 alkylsulfonyloxy and C6-C 10 Each arylsulfonyloxy is optionally substituted with one or more groups selected from the group: C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, and nitro.

[0262] In some embodiments, the compound of formula (Ii) is a compound of the following formula: [ka] 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. In some embodiments, the phrase "one or more groups" is one, two, or three groups. In some embodiments, the alkyl group is optionally substituted with one or more halogen groups. In some embodiments, the alkyl group is optionally substituted with one or more fluoro groups.

[0263] In some embodiments, the compound of formula (Ii) is a compound of the following formula: [ka] [In the formula, R 1a , R 2a and R 3a are each independently selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, and nitro. In some embodiments, R 1a , R 2a and R 3a are each independently selected from the group consisting of H, methyl, methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, trifluoromethoxy, and nitro. 1a , R 2a and R 3a are each independently selected from the group consisting of H, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, and nitro. 1a , R 2a and R 3a are each independently selected from the group consisting of H, methyl, fluoro, trifluoromethyl, trifluoromethoxy, and nitro. 1a , R 2a and R 3a are each independently selected from the group consisting of H and methyl.

[0264] In some embodiments, LG is a halogen.

[0265] In some embodiments, LG is Cl, Br, or I.

[0266] In some embodiments, LG is Br.

[0267] In some embodiments, 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 p-toluenesulfonate. In some embodiments, the compound of formula (Ii) is selected from the group consisting of propargyl bromide, propargyl methanesulfonate, propargyl trifluoromethanesulfonate, propargyl benzenesulfonate, and propargyl p-toluenesulfonate.

[0268] In some embodiments, the compound of Formula (Ii) is propargyl bromide.

[0269] In some embodiments, the compound of Formula (Ii) and compound 9A are present in substantially equimolar amounts. In some embodiments, the compound of Formula (Ii) is present in molar excess relative to compound 9A. In some embodiments, the compound of Formula (Ii) is present in about 30% molar excess relative to compound 9A. In some embodiments, the compound of Formula (Ii) is present in about 25% molar excess relative to compound 9A. In some embodiments, the compound of Formula (Ii) is present in about 20% molar excess relative to compound 9A.

[0270] In some embodiments, compound 9A and the phase transfer catalyst are present in substantially equimolar amounts. In some embodiments, the molar ratio of compound 9A to the phase transfer catalyst is about 1:0.05 to about 1:0.9. In some embodiments, the molar ratio of compound 9A to the phase transfer catalyst is about 1:0.05 to about 1:0.8. In some embodiments, the molar ratio of compound 9A to the phase transfer catalyst is about 1:0.05 to about 1:0.7. In some embodiments, the molar ratio of compound 9A to the phase transfer catalyst is about 1:0.05 to about 1:0.6. In some embodiments, the molar ratio of compound 9A to the phase transfer catalyst is about 1:0.05 to about 1:0.5.

[0271] In some embodiments, the molar ratio of compound 9A to the phase transfer catalyst is about 1:0.05 to about 1:0.4. In some embodiments, the molar ratio of compound 9A to the phase transfer catalyst is about 1:0.1 to about 1.3:0.2. In some embodiments, the molar ratio of compound 9A to the phase transfer catalyst is about 1:0.15.

[0272] In some embodiments, the molar ratio of compound 9A to phase transfer catalyst to base in the alkylation step is about 1:0.05:5 to about 1:0.4:25. In some embodiments, the molar ratio of compound 9A to phase transfer catalyst to base in the alkylation step is about 1:0.1:10 to about 1:0.2:20. In some embodiments, the molar ratio of compound 9A to phase transfer catalyst to base in the alkylation step is about 1:0.15:16.

[0273] In some embodiments, the solvent for the alkylation step is any suitable solvent, such as those described herein or mixtures thereof.

[0274] In some embodiments, the solvent for the alkylation step is selected from halogenated solvents, ether solvents, aprotic solvents, and mixtures thereof. In some embodiments, the solvent for the alkylation step is selected from dichloromethane, tetrachloroethylene, 1,1-dichloroethane, 1,2-dichloroethane, 1,2-dichlorobenzene, chlorobenzene, 1,2-dimethoxyethane (DME), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, ethylene glycol diethyl ether, tert-amyl methyl ether (TAME, also known as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), benzene, cyclohexane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, n-heptane, ethylbenzene, o-xylene, m-xylene, p-xylene, mixtures of xylenes, octane, and mixtures thereof. In some embodiments, the solvent for the alkylation step is selected from 1,2-dimethoxyethane (DME), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, ethylene glycol diethyl ether, tert-amyl methyl ether (TAME, also known as 2-methoxy-2-methylbutane), methyl tert-butyl ether (MTBE), benzene, toluene, and mixtures thereof. In some embodiments, the solvent for the alkylation step is selected from methyl tert-butyl ether (MTBE), toluene, and mixtures thereof.

[0275] In some embodiments, the phase transfer catalyst is a quaternary ammonium salt. In some embodiments, the phase transfer catalyst is a quaternary ammonium salt selected from tricaprylylmethylammonium chloride (Aliquat 336), tetra-n-butylammonium bromide (TBAB), benzyltriethylammonium chloride (BTEAC), cetyltrimethylammonium bromide (CTAB), tetra-n-butylammonium chloride (TBAC), tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride (TEAC), benzyltributylammonium chloride (BTBAC), cetyltrimethylammonium chloride (CTAC), tetramethylammonium chloride, cetyltrimethylammonium chloride (CTAC), octyltrimethylammonium chloride and combinations thereof. In some embodiments, the phase transfer catalyst is tetra-n-butylammonium bromide (TBAB).

[0276] In some embodiments, the base for the alkylation step is any suitable base, such as a base described herein or a mixture thereof.

[0277] In some embodiments, the base for the alkylation step is an "inorganic base" as described herein.

[0278] In some embodiments, the base of the alkylation step is an alkali metal hydroxide. In some embodiments, the base of the alkylation step is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide. In some embodiments, the base of the alkylation step is an alkali metal hydroxide selected from sodium hydroxide and potassium hydroxide. In some embodiments, the base of the alkylation step is potassium hydroxide.

[0279] In some embodiments, the alkylation step comprises: forming a first alkylation mixture comprising an alkylation step solvent, an alkylation catalyst, and compound 9A at a first alkylation temperature; and adding an alkylation step base and a compound of formula (Ii) to the first alkylation mixture at a first alkylation temperature to form an alkylated biphasic mixture at a second alkylation temperature. Further includes:

[0280] In some embodiments, the alkylation step further comprises heating a first alkylation mixture comprising an alkylation solvent, an alkylation catalyst, and compound 9A to a temperature of about 40° C. to about 75° C., followed by cooling to the first alkylation temperature. In some embodiments, the alkylation step further comprises heating a first alkylation mixture comprising an alkylation solvent, an alkylation catalyst, and compound 9A to a temperature of about 55° C. to about 65° C., followed by cooling to the first alkylation temperature. In some embodiments, the alkylation step further comprises heating a first alkylation mixture comprising an alkylation solvent, an alkylation catalyst, and compound 9A to a temperature of about 60° C., followed by cooling to the first alkylation temperature.

[0281] In some embodiments, the addition of the alkylation-step base to the first alkylation mixture is carried out as an aqueous solution of the alkylation-step base.

[0282] In some embodiments, the alkylation step base is added to the first alkylation mixture as an aqueous solution of the alkylation step base, wherein the concentration, in weight / weight percent (% w / w) of the alkylation step base and water, is about 40 to about 60. In some embodiments, the alkylation step base is added to the first alkylation mixture as an aqueous solution of the alkylation step base, wherein the concentration, in weight / weight percent (% w / w) of the alkylation step base and water, is about 45 to about 55. In some embodiments, the alkylation step base is added to the first alkylation mixture as an aqueous solution of the alkylation step base, wherein the concentration, in weight / weight percent (% w / w) of the alkylation step base and water, is about 52 to about 53. In some embodiments, the addition of the alkylation-step base to the first alkylation mixture is carried out as an aqueous solution of the alkylation-step base, wherein the concentration in weight / weight percent (% w / w) of the alkylation-step base and water is about 52.4.

[0283] In some embodiments, the addition of the compound of Formula (Ii) to the first alkylation mixture is carried out as a solution of the compound of Formula (Ii) in a solvent for the alkylation step. In some embodiments, the addition of the compound of Formula (Ii) to the first alkylation mixture is carried out as a solution of the compound of Formula (Ii) in a solvent for the alkylation step, wherein the concentration of the compound of Formula (Ii) in the solvent for the alkylation step, in terms of weight / weight percent (% w / w), is about 65 to about 90. In some embodiments, the addition of the compound of Formula (Ii) to the first alkylation mixture is carried out as a solution of the compound of Formula (Ii) in a solvent for the alkylation step, wherein the concentration of the compound of Formula (Ii) in the solvent for the alkylation step, in terms of weight / weight percent (% w / w), is about 75 to about 85. In some embodiments, the addition of the compound of Formula (Ii) to the first alkylation mixture is carried out as a solution of the compound of Formula (Ii) in the alkylation step solvent, wherein the concentration, in weight / weight percent (% w / w), of the compound of Formula (Ii) in the alkylation step solvent is about 80.

[0284] In some embodiments, the addition of the alkylation step base and the compound of Formula (Ii) to the first alkylation mixture is carried out simultaneously at a rate that maintains the first alkylation temperature.

[0285] In some embodiments, the addition of the alkylation step base and the compound of Formula (Ii) to the first alkylation mixture is carried out continuously at a rate that maintains the first alkylation temperature. In some embodiments, the continuous addition is carried out by adding the alkylation step base and then the compound of Formula (Ii) to the first alkylation mixture at a rate that maintains the first alkylation temperature during each addition.

[0286] In some embodiments, the first alkylation temperature is from about -15°C to about 15°C. In some embodiments, the first alkylation temperature is from about -10°C to about 10°C. In some embodiments, the first alkylation temperature is from about -5°C to about 7°C. In some embodiments, the first alkylation temperature is from about 0°C to about 5°C.

[0287] In some embodiments, the second alkylation temperature is from about -10°C to about 20°C. In some embodiments, the second alkylation temperature is from about -5°C to about 15°C. In some embodiments, the second alkylation temperature is from about 0°C to about 10°C. In some embodiments, the second alkylation temperature is from about 4°C to about 6°C.

[0288] In some embodiments, the alkylation is carried out under stirring. In some embodiments, the alkylation is carried out under vigorous stirring. In some embodiments, the alkylation is carried out under vigorous stirring at a rate that increases the aqueous-organic interface.

[0289] In some embodiments, the alkylation step comprises: (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (compound 6A) or a salt thereof: [ka] with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (compound 8A) or its tautomeric form: [ka] and cyclizing the resulting compound (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 by reacting the resulting compound (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 the reactant in the presence of a solvent for the cyclization step 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.

[0290] In some embodiments, the alkylation step comprises reacting a compound of formula (Ig) or a salt thereof [ka] [In the formula, R 1c , R 2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen, in the presence of a deprotection catalyst, hydrogen, and a solvent for the deprotection step to form (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof.

[0291] In some embodiments, the alkylation step comprises reacting a compound of formula (Ig) or a salt thereof: [ka] [In the formula, R 1c , R2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. preparing a compound of formula (Ie): [ka] [In the formula, R 1c , R 2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. in the presence of a reduction catalyst, hydrogen and a solvent for the reduction step to form a compound of formula (Ig) or a salt thereof.

[0292] In some embodiments, the alkylation step comprises reacting a compound of formula (Ie): [ka] [In the formula, R 1c , R 2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. preparing 2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A): [ka] a compound of formula (Ic) or a salt thereof [ka] in the presence of a condensation step acid and a condensation step solvent to form a compound of formula (Ie) The method further comprises preparing the composition comprising:

[0293] In some embodiments, the alkylation step comprises the reaction of 2-cyclopropyl-N-methoxy-N-methylacetamide (compound 2A): [ka] with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a solvent for the reaction step to form 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A). The method further comprises preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A) by

[0294] In some embodiments, the alkylating step further comprises isolating 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. In some embodiments, 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 is the free base. In some embodiments, 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 is crystalline. In some embodiments, 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 is crystalline Form I.

[0295] In some embodiments, the alkylating step further comprises formulating 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 to form a pharmaceutical composition. In some embodiments, the formulating step comprises combining 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 with pharmaceutical excipients.

[0296] In some embodiments, the alkylating step further comprises isolating 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.

[0297] In some embodiments, the alkylating step comprises formulating 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 or a pharmaceutically acceptable salt thereof to form a pharmaceutical composition. In some embodiments, the formulating step comprises combining 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 or a pharmaceutically acceptable salt thereof with pharmaceutical excipients. In some embodiments, the formulating step comprises preparing a spray-dried dispersion as described in the Examples.

[0298] In some embodiments, 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 is a free base. In some embodiments, 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 is crystalline. In some embodiments, 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 is crystalline Form I.

[0299] II. Methods useful for the preparation of (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 (cyclization step).

[0300] One aspect of the present invention is (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: [ka] 1. A method for preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (compound 6A) or a salt thereof: [ka] with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (compound 8A) or its tautomeric form: [ka] and cyclizing in the presence of a solvent for the cyclization step 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. The present invention relates to a method, including:

[0301] In some embodiments, the tautomeric form of compound 8A has the following chemical structure: [ka] It has.

[0302] In some embodiments, the solvent for the cyclization step is any suitable solvent, such as those described herein or mixtures thereof.

[0303] In some embodiments, the solvent for the cyclization step is an aprotic solvent. In some embodiments, the solvent for the cyclization step is an aprotic solvent selected from benzene, cyclohexane, pentane, hexane, acetonitrile, toluene, o-xylene, m-xylene, p-xylene, a mixture of xylenes, heptane, n-heptane, octane, n-octane, ethylbenzene, and mixtures thereof. In some embodiments, the solvent for the cyclization step is an aprotic solvent selected from benzene, cyclohexane, hexane, toluene, cycloheptane, o-xylene, m-xylene, p-xylene, a mixture of xylenes, heptane, n-heptane, octane, n-octane, ethylbenzene, and mixtures thereof. In some embodiments, the solvent for the cyclization step comprises a mixture of heptanes. In some embodiments, the solvent for the cyclization step is n-heptane.

[0304] In some embodiments, compound 6A and compound 8A are present in substantially equimolar amounts. In some embodiments, compound 6A is present in molar excess relative to compound 8A. In some embodiments, compound 6A is present in about 5% molar excess relative to compound 8A. In some embodiments, compound 6A is present in about 2% molar excess relative to compound 8A. In some embodiments, compound 6A is present in about 1% molar excess relative to compound 8A.

[0305] In some embodiments, the cyclization step further comprises adding compound 6A to a first cyclization mixture comprising compound 8A and a solvent for the cyclization step at a first cyclization temperature.

[0306] In some embodiments, the first cyclization temperature is about 50°C to about 110°C. In some embodiments, the first cyclization temperature is about 60°C to about 95°C. In some embodiments, the first cyclization temperature is about 70°C to about 90°C. In some embodiments, the first cyclization temperature is about 80°C to about 87°C. In some embodiments, the first cyclization temperature is about 85°C.

[0307] In some embodiments, the cyclization is carried out under stirring.

[0308] III. Methods useful for preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (compound 6A) or a salt thereof (deprotection step). One aspect of the present invention is (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (compound 6A) or a salt thereof: [ka] 1. A method for preparing A compound of formula (Ig) or a salt thereof [ka] [In the formula, R 1c , R 2cand R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. in the presence of a deprotection catalyst, hydrogen, and a solvent for the deprotection step to form (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof.

[0309] In some embodiments, the deprotection catalyst comprises palladium. In some embodiments, the deprotection catalyst comprises palladium supported on carbon. In some embodiments, the deprotection catalyst comprises from about 2% palladium supported on carbon to about 20% palladium supported on carbon. In some embodiments, the deprotection catalyst comprises from about 5% palladium supported on carbon to about 15% palladium supported on carbon. In some embodiments, the deprotection catalyst comprises about 10% palladium supported on carbon.

[0310] In some embodiments, the weight ratio of the compound of Formula (Ig) to the deprotection catalyst is about 1:0.01 to about 1:0.15. In some embodiments, the weight ratio of the compound of Formula (Ig) to the deprotection catalyst is about 1:0.02 to about 1:0.1. In some embodiments, the weight ratio of the compound of Formula (Ig) to the deprotection catalyst is about 1:0.03 to about 1:0.07. In some embodiments, the weight ratio of the compound of Formula (Ig) to the deprotection catalyst is about 1:0.05.

[0311] In some embodiments, the solvent for the deprotection step is any suitable solvent, such as those described herein or mixtures thereof.

[0312] In some embodiments, the solvent for the deprotection step comprises an alcohol solvent. In some embodiments, the solvent for the deprotection step 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. In some embodiments, the solvent for the deprotection step comprises an alcohol solvent selected from methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof. In some embodiments, the solvent for the deprotection step comprises an alcohol solvent selected from methanol, ethanol, and mixtures thereof. In some embodiments, the solvent for the deprotection step is methanol.

[0313] In some embodiments, the deprotection step comprises: forming a first deprotection mixture comprising a compound of formula (Ig), a deprotection catalyst and a solvent for the deprotection step; pressurizing the first deprotecting mixture with hydrogen to form a second deprotecting mixture; and heating the second deprotection mixture to the first deprotection temperature; Further includes:

[0314] In some embodiments, pressurizing the first deprotection mixture with hydrogen is carried out at about 5 to about 12 bar. In some embodiments, pressurizing the first deprotection mixture with hydrogen is carried out at about 9 to about 11 bar. In some embodiments, pressurizing the first deprotection mixture with hydrogen is carried out at about 9.8 to about 10.2 bar.

[0315] In some embodiments, the first deprotection temperature is about 40°C to about 80°C. In some embodiments, the first deprotection temperature is about 50°C to about 70°C. In some embodiments, the first deprotection temperature is about 58°C to about 62°C.

[0316] Some embodiments include R 1c , R 2c and R 3c are each independently selected from H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo. 1c , R 2c and R 3c and N are each H (i.e., (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N—((S)-1-phenylethyl)ethan-1-amine (Compound 5A)).

[0317] In some embodiments, the deprotection is carried out under stirring.

[0318] IV. Useful Methods for Preparing Compounds of Formula (Ig) or Salts Thereof (Reduction Step). One aspect of the present invention is a compound of formula (Ig) or a salt thereof: [ka] [In the formula, R 1c , R 2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. 1. A method for preparing Compounds of formula (Ie): [ka] in the presence of a reduction catalyst, hydrogen and a solvent for the reduction step to form a compound of formula (Ig) or a salt thereof. The present invention relates to a method, including:

[0319] In some embodiments, the reduction catalyst is sponge nickel or Pd / Cu—C.

[0320] In some embodiments, the reduction catalyst is sponge nickel. In some embodiments, the weight ratio of the compound of Formula (Ie) to the reduction catalyst is about 1:0.5 to about 1:0.9. In some embodiments, the weight ratio of the compound of Formula (Ie) to the reduction catalyst is about 1:0.6 to about 1:0.8. In some embodiments, the weight ratio of the compound of Formula (Ie) to the reduction catalyst is about 1:0.65 to about 1:0.75. In some embodiments, the weight ratio of the compound of Formula (Ie) to the reduction catalyst is about 1:0.7.

[0321] In some embodiments, the reduction catalyst is Pd / Cu—C. In some embodiments, the Pd / Cu—C catalyst contains about 1% to about 10% Pd and about 0.2% to about 4% Cu. In some embodiments, the Pd / Cu—C catalyst contains about 2% to about 6% Pd and about 0.5% to about 2% Cu. In some embodiments, the Pd / Cu—C catalyst contains about 4% Pd and 1% Cu. In some embodiments, the weight ratio of the compound of Formula (Ie) to the reduction catalyst is about 1:0.01 to about 1:0.3. In some embodiments, the weight ratio of the compound of Formula (Ie) to the reduction catalyst is about 1:0.015 to about 1:0.1. In some embodiments, the weight ratio of the compound of Formula (Ie) to the reduction catalyst is about 1:0.02 to about 1:0.05. In some embodiments, the weight ratio of the compound of Formula (Ie) to the reduction catalyst is about 1:0.03.

[0322] In some embodiments, the solvent for the reduction step is any suitable solvent, such as those described herein or mixtures thereof.

[0323] In some embodiments, the solvent for the reduction step comprises an alcohol solvent. In some embodiments, the solvent for the reduction step 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. In some embodiments, the solvent for the reduction step comprises an alcohol solvent selected from methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof. In some embodiments, the solvent for the deprotection step comprises an alcohol solvent selected from methanol, ethanol, and mixtures thereof. In some embodiments, the solvent for the reduction step comprises ethanol.

[0324] In some embodiments, the reduction step comprises: forming a first reduction mixture comprising a reduction catalyst and a reduction step solvent; adding a compound of formula (Ie) to the first reduction mixture to form a second reduction mixture; pressurizing the second reducing mixture with hydrogen to form a third reducing mixture; and heating the third reducing mixture to the first reduction temperature; Further includes:

[0325] In some embodiments, the compound of Formula (Ie) is added to the first reduction mixture as a solution of the compound of Formula (Ie) in toluene. In some embodiments, the compound of Formula (Ie) is added to the first reduction mixture as an about 40% to about 80% toluene solution of the compound of Formula (Ie). In some embodiments, the compound of Formula (Ie) is added to the first reduction mixture as an about 50% to about 70% toluene solution of the compound of Formula (Ie). In some embodiments, the compound of Formula (Ie) is added to the first reduction mixture as an about 60% to about 65% toluene solution of the compound of Formula (Ie).

[0326] In some embodiments, pressurizing the second reducing mixture with hydrogen is carried out at about 5 to about 12 bar. In some embodiments, pressurizing the second reducing mixture with hydrogen is carried out at about 9 to about 11 bar. In some embodiments, pressurizing the second reducing mixture with hydrogen is carried out at about 9.8 to about 10.2 bar.

[0327] In some embodiments, the first reduction temperature is from about 25°C to about 55°C. In some embodiments, the first reduction temperature is from about 30°C to about 45°C. In some embodiments, the first reduction temperature is from about 33°C to about 37°C.

[0328] Some embodiments include R 1c , R 2c and R 3c are each independently selected from H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo. 1c , R 2c and R 3c and R are each H (i.e., (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine (compound 4A)).

[0329] In some embodiments, the reduction is carried out under stirring.

[0330] V. Useful methods for preparing compounds of formula (Ie) (condensation step). One aspect of the present invention is a compound of formula (Ie): [ka] [In the formula, R 1c , R 2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. 1. A method for preparing 2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A): [ka] with a compound of formula (Ic) or a salt thereof: [ka] in the presence of a condensation step acid and a condensation step solvent to form a compound of formula (Ie) The present invention relates to a method, including:

[0331] In some embodiments, the compound of Formula (Ic) and compound 3A are present in substantially equimolar amounts. In some embodiments, the compound of Formula (Ic) is present in molar excess relative to compound 3A. In some embodiments, the molar ratio of compound 3A to compound of Formula (Ic) is about 1:1 to about 1:1.5. In some embodiments, the molar ratio of compound 3A to compound of Formula (Ic) is about 1:1.1 to about 1:1.3. In some embodiments, the molar ratio of compound 3A to compound of Formula (Ic) is about 1:1.2.

[0332] In some embodiments, the molar ratio of compound 3A to the compound of Formula (Ic) to the acid in the condensation step is about 1:1:0.01 to about 1:1.5:0.2. In some embodiments, the molar ratio of compound 3A to the compound of Formula (Ic) to the acid in the condensation step is about 1:1.1:0.03 to about 1:1.3:0.1. In some embodiments, the molar ratio of compound 3A to the compound of Formula (Ic) to the acid in the condensation step is about 1:1.2:0.05.

[0333] In some embodiments, the acid of the condensation step comprises a Bronsted acid. In some embodiments, the acid of the condensation step comprises a Bronsted acid selected from acetic acid, trifluoroacetic acid (TFA), p-toluenesulfonic acid (pTSA), HPO, HSO, methanesulfonic acid (MSA), formic acid, and HCl. In some embodiments, the acid of the condensation step is p-toluenesulfonic acid (pTSA).

[0334] In some embodiments, the solvent for the condensation step is any suitable solvent, such as those described herein or mixtures thereof.

[0335] In some embodiments, the solvent for the condensation step is an aprotic solvent. In some embodiments, the solvent for the condensation step is an aprotic solvent selected from benzene, cyclohexane, pentane, hexane, acetonitrile, toluene, cycloheptane, o-xylene, m-xylene, p-xylene, a mixture of xylenes, heptane, n-heptane, octane, n-octane, ethylbenzene, and mixtures thereof. In some embodiments, the solvent for the condensation step is acetonitrile or toluene. In some embodiments, the solvent for the condensation step is acetonitrile. In some embodiments, the solvent for the condensation step is toluene.

[0336] In some embodiments, the condensation is carried out at the boiling point of the solvent for the condensation step.

[0337] In some embodiments, the condensation further comprises removing water. In some embodiments, the condensation further comprises removing water using a Dean-Stark process, a drying agent, or a combination thereof. In some embodiments, the condensation further comprises removing water using a drying agent. In some embodiments, the condensation further comprises removing water using a Dean-Stark process.

[0338] In some embodiments, the condensing further comprises isolating the compound of Formula (Ie) from a condensation step mixture comprising a compound of Formula (Ie) and a compound of Formula (Ic). In some embodiments, the isolation comprises substantially removing the compound of Formula (Ic) from the condensation step mixture using an isolation step acid. In some embodiments, the isolation step acid is a water-soluble acid. In some embodiments, the isolation step acid is an ammonium halide. In some embodiments, the isolation step acid is ammonium chloride (i.e., NH4Cl).

[0339] Some embodiments include R 1c , R 2c and R 3c are each independently selected from H, methoxy, methyl, trifluoromethyl, fluoro, chloro, and bromo. 1c , R 2c and R 3c and R are each H (i.e., (S)-(−)-1-phenylethylamine). In some embodiments, the compound of Formula (Ic) is (S)-(−)-1-phenylethylamine.

[0340] In some embodiments, the condensation is carried out under stirring.

[0341] VI. Useful methods (reaction steps) for preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A). One aspect of the present invention is 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A): [ka] 2-Cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A): [ka] with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a solvent for the reaction step to form 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A). The present invention relates to a method, including:

[0342] In some embodiments, the organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene is forming a first reaction mixture comprising magnesium and a reaction step solvent; adding a magnesium activator to the first reaction mixture at a first reaction temperature to form a second reaction mixture; and adding 4-bromo-2-fluoro-1-methylbenzene to the second reaction mixture at the second reaction temperature to form a 4-bromo-2-fluoro-1-methylbenzene organomagnesium reagent; It is prepared by a method comprising:

[0343] In some embodiments, the first reaction temperature is from about 15°C to about 45°C. In some embodiments, the first reaction temperature is from about 25°C to about 40°C. In some embodiments, the first reaction temperature is from about 25°C to about 35°C.

[0344] In some embodiments, the second reaction temperature is from about 20°C to about 65°C. In some embodiments, the second reaction temperature is from about 25°C to about 60°C. In some embodiments, the second reaction temperature is from about 30°C to about 50°C.

[0345] In some embodiments, the solvent for the reaction step is any suitable solvent, such as those described herein or mixtures thereof.

[0346] In some embodiments, the solvent for the reaction step is an ether solvent. In some embodiments, the solvent for the reaction step is selected from diethyl ether, 1,2-dimethoxyethane (DME), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF). In some embodiments, the solvent for the reaction step is selected from tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF). In some embodiments, the solvent for the reaction step is tetrahydrofuran (THF).

[0347] In some embodiments, the magnesium activator is I2, 1,2-dibromoethane, diisobutylaluminum hydride (DIBAL-H), LiAlH4, NaBH4, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), and borane dimethyl sulfide complex (BH3-SMe2). In some embodiments, the magnesium activator is diisobutylaluminum hydride (DIBAL-H).

[0348] In some embodiments, the organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene is [ka] is.

[0349] In some embodiments, the reaction is carried out under stirring.

[0350] VII. Methods (coupling steps) useful for preparing 2-cyclopropyl-N-methoxy-N-methylacetamide (compound 2A). One aspect of the present invention is 2-cyclopropyl-N-methoxy-N-methylacetamide (compound 2A). [ka] 1. A method for preparing the compound of formula (I), comprising coupling 2-cyclopropylacetic acid (compound 1A) with N,O-dimethylhydroxylamine or a salt thereof in the presence of a coupling step reagent, a coupling step base, and a coupling step reagent to form 2-cyclopropyl-N-methoxy-N-methylacetamide (compound 2A). The present invention relates to a method, including:

[0351] In some embodiments, the coupling step further comprises mixing 2-cyclopropylacetic acid (compound 1A), a coupling-step reagent, and a coupling-step solvent together to form a first coupling mixture.

[0352] In some embodiments, the first coupling mixture is at a suitable first temperature to form 2-cyclopropyl-N-methoxy-N-methylacetamide (compound 2A).

[0353] In some embodiments, the first coupling mixture has a first coupling temperature of about -15°C to about 35°C. In some embodiments, the first coupling mixture has a first coupling temperature of about -10°C to about 30°C. In some embodiments, the first coupling mixture has a first coupling temperature of about -10°C to about 25°C. In some embodiments, the first coupling mixture has a first coupling temperature of ≦25°C.

[0354] In some embodiments, the coupling further comprises adding N,O-dimethylhydroxylamine or a salt thereof to the first coupling mixture to form a second coupling mixture at a second coupling temperature.

[0355] In some embodiments, the second coupling temperature is ≦30° C. In some embodiments, the second coupling temperature is about −15° C. to about 30° C. In some embodiments, the second coupling temperature is about −10° C. to about 25° C. In some embodiments, the second coupling temperature is about 20° C. to about 25° C.

[0356] In some embodiments, N,O-dimethylhydroxylamine or a salt thereof is added to the first coupling mixture at a rate that maintains the temperature at the second coupling temperature.

[0357] In some embodiments, the coupling step further comprises adding a coupling-step base to the second coupling mixture.

[0358] In some embodiments, the coupling step further comprises adding a coupling-step base to the second coupling mixture and maintaining the third coupling temperature at about −10° C. to about 25° C. In some embodiments, the coupling step further comprises adding a coupling-step base to the second coupling mixture and maintaining the third coupling temperature at about 20° C. to about 25° C.

[0359] In some embodiments, the reagent for the coupling step is a tetramethyluronium-based coupling reagent. In some embodiments, the reagent for the coupling step is 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylammonium hexafluorophosphate (2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium In some embodiments, the coupling reagent is 1,1'-carbonyldiimidazole (CDI).

[0360] In some embodiments, the solvent for the coupling step is any suitable solvent, such as those described herein or mixtures thereof.

[0361] In some embodiments, the solvent for the coupling step is an aprotic solvent. In some embodiments, the solvent for the coupling step is selected from halogenated solvents, ethereal solvents, and mixtures thereof. In some embodiments, the solvent for the coupling step comprises dichloromethane (DCM).

[0362] In some embodiments, the base of the coupling step is a tertiary amine. In some embodiments, the base of the coupling step is selected from N,N-diisopropylethylamine (DIEA), triethylamine (TEA), N-methylmorpholine (NMM), 4-dimethylaminopyridine (DMAP), 2,4,6-trimethylpyridine (collidine), 2,3,5,6-tetramethylpyridine (TEMP), and 2,6-di-tert-butyl-4-(dimethylamino)pyridine (DBDMAP). In some embodiments, the base of the coupling step is triethylamine.

[0363] In some embodiments, the coupling is carried out under stirring. intermediate compound

[0364] One aspect of the present invention includes all combinations of one or more compounds described herein, and salts, solvates, and hydrates thereof.

[0365] One aspect of the present invention is a compound of formula (Ic): [ka] [In the formula, R 1c , R 2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. Regarding.

[0366] Some embodiments include R 1c , R 2c and R 3c are each independently selected from H, methoxy, methyl, trifluoromethyl, fluoro, chloro and bromo.

[0367] Some embodiments include R 1c , R 2c and R 3cand (S)-(-)-1-phenylethylamine, [ka] Regarding.

[0368] One aspect of the present invention is a compound of formula (Ie): [ka] [In the formula, R 1c , R 2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. Regarding.

[0369] Some embodiments include R 1c , R 2c and R 3c are each independently selected from H, methoxy, methyl, trifluoromethyl, fluoro, chloro and bromo.

[0370] Some embodiments include R 1c , R 2c and R 3c and (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine (compound 4A) [ka] Regarding.

[0371] One aspect of the present invention is a compound of certain formula (Ig): [ka] or its salts: [In the formula, R 1c , R2c and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. Regarding.

[0372] Some embodiments include R 1c , R 2c and R 3c are each independently selected from H, methoxy, methyl, trifluoromethyl, fluoro, chloro and bromo.

[0373] Some embodiments include R 1c , R 2c and R 3c and n is H, respectively (i.e., (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A)): [ka] Regarding.

[0374] Some embodiments include R 1c , R 2c and R 3c are H, respectively.

[0375] Some embodiments include R 1c , R 2c and R 3c and each are H, the HCl salt. In some embodiments, the HCl salt is crystalline. In some embodiments, the crystalline form of the HCl salt is crystalline (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (Compound 5A, HCl salt), as described herein. Disorders, Uses and Methods of Treatment

[0376] 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) is a corticotropin-releasing factor type 1 (CRF1) antagonist. Thus, Compound 1 as the free base, pharmaceutically acceptable salts such as the tosylate salt, and their crystalline forms are useful in methods of antagonizing corticotropin-releasing factor type 1 by contacting the receptor. In some embodiments, the contacting is performed in vivo. In some embodiments, the contacting is performed ex vivo. In some embodiments, Compound 1 as the free base, pharmaceutically acceptable salts, and their crystalline forms can be used in methods of antagonizing corticotropin-releasing factor type 1 in a patient in need thereof by administering an effective amount of Compound 1, a pharmaceutically acceptable salt, or a crystalline form thereof, as the free base.

[0377] Provided herein are methods for treating or preventing (ie, reducing the likelihood of occurrence of) corticotropin-releasing factor type 1 disorder.

[0378] In some embodiments, Compound 1, pharmaceutical salts, and crystalline forms thereof are useful for treating or preventing disorders. In some embodiments, Compound 1, pharmaceutical salts, and crystalline forms thereof are useful for treating or preventing subtypes of disorders. In some embodiments, Compound 1, pharmaceutical salts, and crystalline forms thereof are useful for treating or preventing symptoms of disorders. In some embodiments, Compound 1 is a free base. In some embodiments, Compound 1 (free base) is anhydrous crystalline Form I described herein. In some embodiments, Compound 1 is as a pharmaceutical salt, where the salt is a tosylate salt. In some embodiments, the tosylate salt of Compound 1 is crystalline Form I described herein.

[0379] One aspect of the present invention relates to a method of treating a disorder in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of an anhydrous crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein, wherein the subject has an abnormal level of CRF1.

[0380] One aspect of the present invention relates to a method of treating a corticotropin-releasing factor type 1 (CRF1) disorder in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of an anhydrous crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein.

[0381] One aspect of the present invention relates to a method of treating congenital adrenal hyperplasia (CAH) in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of an anhydrous crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base), a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein.

[0382] One aspect of the present invention relates to the use of an anhydrous crystalline form described herein (Compound 1, free base) or a crystalline form described herein (Compound 1, tosylate base) for the manufacture of a medicament for the treatment of a subject having an abnormal level of CRF1.

[0383] One aspect of the present invention relates to the use of an anhydrous crystalline form described herein (Compound 1, free base) or a crystalline form described herein (Compound 1, tosylate base) for the manufacture of a medicament for the treatment of a corticotropin-releasing factor type 1 (CRF1) disorder.

[0384] One aspect of the present invention relates to the use of an anhydrous crystalline form described herein (Compound 1, free base) or a crystalline form described herein (Compound 1, tosylate base) for the manufacture of a medicament for the treatment of congenital adrenal hyperplasia (CAH).

[0385] One aspect of the present invention relates to an anhydrous crystalline form described herein (Compound 1, free base); a crystalline form described herein (Compound 1, tosylate base); a pharmaceutical composition described herein, a pharmaceutical product described herein, or a composition described herein for use in a method of treatment of the human or animal body by therapy.

[0386] One aspect of the present invention relates to an anhydrous crystalline form described herein (Compound 1, free base); a crystalline form described herein (Compound 1, tosylate base); a pharmaceutical composition described herein; a pharmaceutical product described herein; or a composition described herein, for use in a method for treating a disorder in a subject having an abnormal level of CRF1.

[0387] One aspect of the present invention relates to an anhydrous crystalline form described herein (Compound 1, free base); a crystalline form described herein (Compound 1, tosylate base); a pharmaceutical composition described herein; a pharmaceutical product described herein; or a composition described herein, for use in a method of treating a corticotropin-releasing factor type 1 (CRF1) disorder.

[0388] One aspect of the present invention relates to an anhydrous crystalline form described herein (Compound 1, free base); a crystalline form described herein (Compound 1, tosylate base); a pharmaceutical composition described herein; a pharmaceutical product described herein; or a composition described herein, for use in a method of treating congenital adrenal hyperplasia (CAH). Pharmaceutical compositions, compositions, formulations and dosage forms

[0389] The present disclosure further provides a composition comprising a crystalline form of Compound 1, such as the free base and tosylate salt of Compound 1 described herein, and an excipient, such as a pharmaceutically acceptable excipient, for use in a method for treating a corticotropin-releasing factor type 1 (CRF1) disease or disorder, such as congenital adrenal hyperplasia. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable, non-toxic, inert substance or ingredient that does not interfere with the activity of a drug substance. An excipient may also be referred to as a carrier. The formulation methods and excipients described herein are exemplary and in no way limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. Additionally, antioxidants and suspending agents may also be used.

[0390] For compositions formulated as liquid solutions, acceptable carriers and / or diluents include physiological saline and sterilized water, and may contain antioxidants, buffers, bacteriostatic agents, and other common additives as needed.The compositions can also be formulated as pills, capsules, granules, or tablets containing diluents, dispersants and surfactants, binders, and lubricants.Those skilled in the art can further formulate active pharmaceutical ingredients (e.g., the free base and tosylate salt of Compound 1 described herein) in an appropriate manner and in accordance with accepted practices, such as those disclosed in Remington, supra.

[0391] The method of administration preferably includes systemic administration of the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 described herein) in the form of a pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral administration methods. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules, as well as liquids, syrups, suspensions, and emulsions. These compositions may also contain flavoring agents, preservatives, suspending agents, thickening agents, and emulsifying agents, as well as other pharmaceutically acceptable additives. For parenteral administration, the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 described herein) can be prepared into an aqueous injection solution, which can contain buffers, antioxidants, bacteriostats, and other additives commonly used in such solutions.

[0392] Pharmaceutical preparations for oral administration can be obtained by any suitable method, usually by uniformly mixing the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 described herein) with a liquid or finely divided solid carrier, or both, in the required proportions, then processing the mixture after adding suitable adjuvants, if necessary, and, if desired, shaping the resulting mixture into the desired shape to obtain tablets or dragee cores.

[0393] Ordinary excipients such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants and disintegrants may be used in tablets and capsules for oral administration.Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.Alternatively, oral preparations may be in the form of dry powders, which can be reconstituted with water or other suitable liquid vehicles before use.Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring and coloring agents may be added to liquid preparations.Non-oral dosage forms can be prepared by dissolving the compound of the present invention in a suitable liquid vehicle, sterilizing the solution by filtration, and then lyophilizing, or simply filling suitable vials or ampoules and sealing them.

[0394] As used herein, "excipient" refers to a substance added to a composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. "Diluent" refers to a type of excipient, an ingredient in a pharmaceutical composition that has no pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small to manufacture and / or administer. A diluent may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable, non-toxic, inert substance or ingredient that does not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. Additionally, antioxidants and suspending agents may also be used. For compositions formulated as liquid solutions, acceptable carriers and / or diluents include saline and sterile water, and may contain antioxidants, buffers, bacteriostats, and other common additives as needed. In some embodiments, the diluent may be, but is not limited to, an aqueous buffer solution such as phosphate-buffered saline. The compositions can also be formulated as capsules, granules, or tablets containing, in addition to the compounds disclosed and described herein, diluents, dispersants and surfactants, binders, and lubricants. Those skilled in the art can formulate the compositions disclosed and described herein in an appropriate manner and in accordance with accepted practices, such as those disclosed in Remington, supra. The compound can be further formulated.

[0395] One aspect of the present invention relates to a method for preparing a pharmaceutical composition, the method comprising combining a crystalline form described herein (Compound 1, free base), a crystalline form described herein (Compound 1, tosylate base); or a composition described herein and a pharmaceutically acceptable carrier.

[0396] When preparing pharmaceutical compositions, the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 described herein) is usually mixed (i.e., blended) with an excipient, diluted by an excipient, or enclosed within a carrier, such as in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, the excipient can be a solid, semi-solid, or liquid substance that serves as a vehicle, carrier, or medium for the drug substance. Thus, the composition can take the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, soft and hard gelatin capsules, suppositories, sterile solutions for injection, and sterile packaged powders.

[0397] When preparing pharmaceutical compositions in solid form, such as powders, tablets, capsules, cachets, suppositories and dispersible granules, excipients can be one or more substances that can also serve as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.Similarly, solid form preparations intended to be converted into liquid form preparations for oral administration immediately before use are also included.Such liquid forms include solutions, suspensions and emulsions.These preparations may contain, in addition to the active ingredient, colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0398] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously within the wax by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0399] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solutions. Injectable preparations, such as injectable sterile aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be injectable sterile solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0400] The pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the pharmaceutical compositions may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

[0401] The pharmaceutical compositions may be formulated as aqueous solutions, hydroalcoholic solutions, solid suspensions, emulsions, liposomal suspensions, or lyophilized powders for reconstitution. Such pharmaceutical compositions may be administered directly or as a mixture for further dilution / reconstitution. Routes of administration include intravenous bolus, intravenous infusion, irrigation, and infusion. Suitable solvents include water, alcohol, PEG, propylene glycol, and lipids. pH adjustment using an acid, e.g., HCl or citric acid, can be used to improve solubility, and the resulting composition is subjected to appropriate sterilization procedures known in the art, such as sterile filtration. In some embodiments, the pH of the aqueous solution is about 2.0 to about 4.0. In some embodiments, the pH of the aqueous solution is about 2.5 to about 3.5.

[0402] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active ingredient in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.

[0403] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided drug substance in water containing a thickening substance such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agent.

[0404] For topical administration to the epidermis, the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 described herein) can be formulated as a gel, ointment, cream, or lotion, or as a transdermal patch.Similarly, formulations suitable for topical administration in the oral cavity include lozenges containing the active pharmaceutical ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles containing the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 described herein) in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes containing the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 described herein) in a suitable liquid carrier.Ointments and creams can be formulated, for example, using an aqueous or oily base with the addition of suitable thickeners and / or gelling agents. Lotion may be formulated using an aqueous or oily base, and generally also contains one or more of emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants.In some embodiments, topical preparations can contain one or more conventional carriers.In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc.The carrier composition of creams can be based on water combined with glycerin and one or more other components, for example, glycerin monostearate, PEG-glycerin monostearate and cetylstearyl alcohol.Gels can be suitably formulated using isopropyl alcohol and water, combined with other components such as, for example, glycerol, hydroxyethyl cellulose, etc.

[0405] Solution or suspension can be directly applied to nasal cavity by conventional means, for example, by using dropper, pipette or spray.Preparation can be provided in single dose form or multi-dose form.In the latter case of dropper or pipette, this can be achieved by patient administering a suitable volume of solution or suspension.In the case of spray, this can be achieved by, for example, metering atomizing spray pump.

[0406] Administration to the respiratory tract can also be achieved by aerosol formulations provided in pressurized packs containing a suitable propellant. When administered as an aerosol, for example as a nasal aerosol, or by inhalation, this can be done, for example, using a spray, nebulizer, pump nebulizer, inhalation device, metered dose inhaler, or dry powder inhaler. Pharmaceutical forms for administration of active pharmaceutical ingredients (e.g., the free base and tosylate salt of Compound 1 described herein) as aerosols can be prepared by methods well known to those skilled in the art. When preparing them, solutions or dispersions of, for example, the active pharmaceutical ingredients (e.g., the free base and tosylate salt of Compound 1 described herein) in water, water / alcohol mixtures, or suitable saline solutions can be used, using conventional additives such as benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, solubilizers, dispersants, etc., and where appropriate, conventional propellants include, for example, carbon dioxide, CFCs such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane. The aerosol may also conveniently contain a surfactant such as lecithin. The dosage of drug may be controlled by providing a metered valve.

[0407] Alternatively, the pharmaceutical composition may be provided in the form of a dry powder of the compound, for example, a powder mix, in a suitable powder base, such as lactose, starch, starch derivatives (such as hydroxypropylmethylcellulose), and polyvinylpyrrolidone (PVP).Advantageously, the powder carrier forms a gel in the nasal cavity.The powder composition may be provided in unit dose form, for example, in capsules or cartridges of, for example, gelatin, or in blister packs, from which the powder can be administered by an inhaler.

[0408] The active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 described herein) may also be administered in a rapidly dissolving or slow-release composition, in which case the composition comprises a biodegradable rapidly dissolving or slow-release carrier (e.g., a polymeric carrier). Rapidly dissolving or slow-release carriers are well known in the art, and are used to form complexes that entangle the compound of the present invention or a pharmaceutically acceptable salt thereof in the carrier, which decomposes / dissolves either rapidly or slowly in an appropriate environment (e.g., aqueous, acidic, basic, etc.).

[0409] The pharmaceutical preparation is preferably present in unit dosage form.In this form, the preparation is subdivided into unit doses containing appropriate amounts.Unit dosage form can be a packaged preparation, and this package contains discrete amounts of preparation such as tablets, capsules and powders packaged in vials or ampoules.Similarly, unit dosage form can be capsules, tablets, cachets or lozenges themselves, or any of the appropriate number of these in packaged form.

[0410] Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

[0411] The compositions may be formulated in unit dosage form, each dosage containing the drug substance or an equivalent mass of the drug substance. The term "unit dosage form" refers to a physically discrete unit of formulation suitable as a unit dosage for human subjects and other mammals, each unit containing a predetermined quantity of drug substance calculated to produce the desired therapeutic effect, in association with suitable excipients as described herein.

[0412] The compositions described herein can be formulated to provide immediate and / or time-modified release (also referred to as sustained, extended, controlled, or slow release) of the active pharmaceutical ingredient (e.g., the free base and tosylate salts of Compound 1 described herein) after administration to a subject using procedures known in the art. For example, tablets can be coated or otherwise compounded to provide a dosage form that offers the advantage of extended action. The tablet can include an inner and outer component, the latter component wrapped around the former component. The two components can be separated by an enteric layer that resists disintegration in the stomach, allowing the inner component to pass intact into the duodenum or be capable of delayed release. A variety of materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0413] Liquid forms for oral administration or which may be incorporated by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, and similar vehicles.

[0414] The pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions can be packaged for immediate use or lyophilized, and the lyophilized preparation can be combined with a sterile aqueous carrier before administration. The pH of the compound preparation is usually between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be understood that the use of certain of the above-mentioned excipients can result in the formation of pharmaceutically acceptable salts.

[0415] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can contain suitable excipients as described herein. In some embodiments, the compositions are administered orally or via the nasal airway for local or systemic effect. The compositions can be nebulized by the use of inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a tent-like face mask or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0416] The composition may be provided in a pack or dispenser device, which may contain one or more unit dosage forms containing the active pharmaceutical ingredient, if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice attached to the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the drug form for human or veterinary administration. Such notice may, for example, be the label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions that can include the compounds described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition.

[0417] As used herein, "dose" or "administration" refers to a measured amount of a drug substance taken by a patient at one time. In certain embodiments where the drug substance is neither a free base nor a free acid, the amount is the molar equivalent to the corresponding amount of the free base or free acid.

[0418] When preparing solid compositions such as tablets, the active pharmaceutical ingredient (e.g., the free base and tosylate salt of Compound 1 described herein) can be mixed with excipients to form a solid preformulated composition containing a homogeneous mixture of the components. These preformulated compositions are referred to as homogeneous, meaning that the active pharmaceutical ingredient is typically dispersed evenly throughout the composition, and thus the compositions can be readily subdivided into equally effective unit dosage forms such as tablets and capsules.

[0419] Usually, the kit provided contains one or more unit doses of the compound described herein in oral or injectable doses.Such kit can include the container that contains unit dose, the package insert that describes the use of drug in treating the pathological condition of interest and the accompanying benefits, and optionally, the instrument or device that delivers the composition.

[0420] The compounds, crystalline forms and compositions of the present invention may be effective over a wide dosage range and are generally administered in a therapeutically effective amount. However, it will be understood that the amount of compound actually administered will typically be determined by a physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0421] The amount of compound or composition administered to a subject will also vary depending on what is being administered, the purpose of administration, such as prophylaxis or treatment, the condition of the subject, the mode of administration, etc. In therapeutic applications, compositions can be administered to a subject already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptomology and / or pathology of the disease and its complications. The therapeutically effective dose will depend on the disease state being treated, as well as factors such as the severity of the disease, the age, weight, and general condition of the subject, and will be dependent on the judgment of the attending clinician.

[0422] Desired dose can be conveniently provided in a single dose, or can be provided as a divided dose, which is administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.Sub-doses themselves can be further divided, for example, into several discrete loosely spaced administrations.In particular, when a relatively large amount is administered, a daily dose can be divided into several, for example, two, three or four administrations, if considered appropriate.If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the indicated daily dose.

[0423] Pharmaceutical compositions and pharmaceutical products comprising crystalline Compound 1, free base.

[0424] One aspect of the present invention relates to a pharmaceutical composition comprising a 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), as described herein, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule.

[0425] One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each comprising a 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), as described herein.

[0426] One aspect of the present invention relates to a method for preparing a pharmaceutical composition, comprising combining a 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), as described herein, and a pharmaceutically acceptable carrier.

[0427] Pharmaceutical compositions and pharmaceutical products containing crystalline compound 1, tosylate salt

[0428] One aspect of the present invention relates to a pharmaceutical composition comprising a 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), as described herein, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule.

[0429] One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each comprising a 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), as described herein.

[0430] One aspect of the present invention relates to a method for preparing a pharmaceutical composition, comprising combining a 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), as described herein, and a pharmaceutically acceptable carrier.

[0431] Pharmaceutical compositions and pharmaceutical products containing compositions of Compound 1

[0432] One aspect of the present invention relates to a pharmaceutical composition comprising a composition 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 herein, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule.

[0433] One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit, each comprising a composition 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 herein.

[0434] One aspect of the present invention relates to a method for preparing a pharmaceutical composition, comprising combining a composition 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 herein, and a pharmaceutically acceptable carrier.

[0435] One aspect of the present invention relates to a method for preparing a pharmaceutical composition, comprising combining 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) and a pharmaceutically acceptable carrier, wherein the anhydrous crystalline form is prepared by any of the methods described herein.

[0436] Composition of Compound 1. One aspect of the present invention is a method for producing a semiconductor device 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, and b. Below: (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) at least one compound selected from ethanol; and The present invention relates to a composition comprising propargyl bromide.

[0437] In some embodiments, the composition comprising Compound 1 or a pharmaceutically acceptable salt thereof is selected from the group consisting of: (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-( and propargyl bromide. In some embodiments, the composition comprising Compound 1 or a pharmaceutically acceptable salt thereof comprises at least two compounds selected from Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprising Compound 1 or a pharmaceutically acceptable salt thereof comprises at least three compounds. In some embodiments, the composition comprising Compound 1 or a pharmaceutically acceptable salt thereof comprises at least four compounds. In some embodiments, the composition comprising Compound 1 or a pharmaceutically acceptable salt thereof comprises at least five compounds.

[0438] In some embodiments, 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) is a free base.

[0439] In some embodiments, the composition contains at least 97% 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 determined by HPLC. In some embodiments, the composition contains at least 98% 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 determined by HPLC. In some embodiments, the composition contains at least 99% 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 determined by HPLC.

[0440] In some embodiments, the composition contains 0.3% or less of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC. In some embodiments, the composition contains 0.2% or less of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC. In some embodiments, the composition contains 0.1% or less of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) as determined by HPLC.

[0441] In some embodiments, the composition contains 0.8% or less of (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) as determined by HPLC. In some embodiments, the composition contains 0.7% or less of (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) as determined by HPLC. In some embodiments, the composition contains 0.6% or less of (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), as determined by HPLC.

[0442] In some embodiments, the composition contains 0.15% or less of (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), as determined by HPLC. In some embodiments, the composition contains 0.1% or less of (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), as determined by HPLC. In some embodiments, the composition contains 0.05% or less of (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), as determined by HPLC.

[0443] In some embodiments, the composition contains 0.3% or less of 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) as determined by chiral HPLC. In some embodiments, the composition contains 0.2% or less of 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) as determined by chiral HPLC. In some embodiments, the composition contains 0.1% or less of 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), as determined by chiral HPLC.

[0444] In some embodiments, the composition contains 5000 ppm or less of ethanol as determined by gas chromatography. In some embodiments, the composition contains 3000 ppm or less of ethanol as determined by gas chromatography. In some embodiments, the composition contains 1000 ppm or less of ethanol as determined by gas chromatography.

[0445] In some embodiments, the composition contains 200 ppm or less of propargyl bromide as determined by gas chromatography. In some embodiments, the composition contains 100 ppm or less of propargyl bromide as determined by gas chromatography. In some embodiments, the composition contains 30 ppm or less of propargyl bromide as determined by gas chromatography.

[0446] In some embodiments, 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) is anhydrous crystalline Form I described herein. [Example]

[0447] The synthesis of the detailed compounds is described in the examples provided herein.The compounds described above and below in this specification are named according to MarvinSketch 18.24.0 or ChemDraw Professional 18.2.0.48.In certain instances, when common names are used, it is understood that these common names are recognized by those skilled in the art.

[0448] The following examples are included to demonstrate embodiments of the present disclosure, however, those of skill in the art should in light of the present disclosure appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0449] Analytical HPLC analysis was performed on an LC-MS system equipped with a UV detector (Dionex™ UVD 170u UV / Visible Detector), a Corona array detector (Thermo™ Veo™ RS), and a mass spectrometer (Dionex MSQ Plus™). Reverse-phase preparative HPLC purification was performed on a Phenomenex C18 Kinetix 5μ 100A 150x21.2mm column on an LCMS system using an ACN / water gradient containing 0.05% TFA. All final compounds were analyzed by HPLC analysis, and peaks were monitored for purity at 210, 254, and 280nM. 1 H was recorded in an appropriate NMR solvent such as DMSO-d6 on a Bruker 400 MHz spectrometer equipped with a broadband NMR probe. 1H chemical signals are given in parts per million (ppm) using the residual solvent signal as reference. Chemical shifts are expressed in ppm (δ) and coupling constants (J) are reported in hertz (Hz). Reactions were carried out under an atmosphere of dry nitrogen unless otherwise stated.

[0450] Compound 8A was previously described by Sanofi-Aventis in International Publication No. WO2010 / 125414.

[0451] Example 1 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). See Figure 5 for the general synthetic scheme.

[0452] Step 1A: Preparation of 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A). [ka]

[0453] A suspension of 1,1'-carbonyldiimidazole (CDI, 152.6 kg, 1.01 equiv.) in DCM (682 kg, 513 L, 7.3 w / w relative to 2-cyclopropylacetic acid) was treated with a solution of 2-cyclopropylacetic acid (compound 1A, 93.6 kg, 1 equiv.) in DCM (248 kg, 186 L, 2.65 w / w) over at least 1 h while maintaining a temperature of ≤25 °C to offset significant effervescence. The resulting mixture was stirred at 22 °C for 15 min, and then N,O-dimethylhydroxylamine·HCl (93.6 kg, 1.03 equiv.) was added in small portions while maintaining a temperature of ≤30 °C. To this stirred mixture was then added triethylamine (46.4 kg, 0.49 equiv.) at 20–25 °C. The resulting mixture was stirred at 22 °C for at least 1 h. The mixture was washed once with KHSO4 solution (0.24 M, 357.1 kg, 0.09 equiv.), once with KHSO4 solution (0.40 M, 365.4 kg, 0.15 equiv.), once with KHSO4 solution (0.80 M, 384.5 kg, 0.30 equiv.), and once with NaHCO3 solution (0.60 M, 393.1 kg, 0.24 equiv.). Residual DCM was removed by two cycles of THF (166.6 kg, 1.78 w / w) and vacuum distillation (50–60 °C, down to a minimum volume / until distillation stopped) to give compound 2A. THF (333.2 kg, 3.56 w / w) was added, and the yield was determined by correcting for the sample's LOD and GC-FID purity (131.5 kg, 98.2%, corrected). 1 H-NMR (400 MHz, DMSO-d6) δ (ppm) -0.01 - 0.03 (m, 2H), 0.32 - 0.36 (m, 2H), 0.81 - 0.90 (br m, 1H), 2.18 (d, J=6.80 Hz, 2H), 2.97 (s, 3 H), 3.53 (s, 3H).ESI-MS:144.0[M+H] + .

[0454] Step 1B: Preparation of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).

change

[0455] Mg (turnings, 28.6 kg, 1.37 equiv.) was suspended in THF (244.7 kg, 2.0 w / w), and DIBAL-H (1 M in n-heptane, 18.9 kg, 0.03 equiv.) was added dropwise at 30°C. The resulting mixture was stirred at 30°C for at least 10 minutes, and then 4-bromo-2-fluoro-1-methylbenzene (neat, 21.1 kg, 0.13 equiv.) was added over at least 30 minutes at 30-50°C. This mixture was then treated with a solution of 4-bromo-2-fluoro-1-methylbenzene (191.6 kg, 1.18 equiv.) in THF (414.5 kg, 3.37 w / w) at 30-50°C over 3 hours or less. The mixture was stirred at 30°C for at least 1 hour. The mixture was cooled to 12-18°C and subsequently treated with 2-cyclopropyl-N-methoxy-N-methylacetamide (compound 2A, 123.0 kg, 1 equivalent, 25.9% w / w solution in THF) at 15-25°C over at least 1 hour. The resulting mixture was stirred at 20-25°C for at least 1 hour. The stirred mixture was then treated with aqueous HCl (3 M, 10.3% w / w, 668.9 kg, 2.24 equivalents) at 10-25°C, and the resulting mixture was stirred for at least 2 hours until no magnesium turnings were observed (confirming a pH of 3.0-3.5). The layers were separated, and the aqueous layer was discarded. The organic layer was distilled at 55-65°C and 400 mbar until distillation stopped. Heptane (290.3 kg, 2.36 w / w) was added. The layers were separated, and the organic layer was washed once with NaHCO3 solution (0.63 M, 211.6 kg, 0.15 equiv.) and once with NaCl solution (2.57 M, 213.0 kg, 0.55 equiv.). Residual solvent was removed by vacuum distillation at 58-62 °C until distillation stopped, followed by one charge and discharge of toluene (275.5 kg, 2.24 w / w) at 107-117 °C until distillation stopped. Toluene (275.5 kg, 2.24 w / w) was added, and the yield was determined by correcting for the LOD and GC-FID purity of the sample (150.7 kg, 91.3%, corrected). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 0.07 - 0.21 (m, 2 H), 0.40 - 0.54 (m, 2 H), 1.02 (ttt, J=8.16, 8.16, 6.68, 6.68, 4.86, 4.86 Hz, 1 H), 2.30 (d, J=1.77 Hz, 3 H), 2.91 (d, J=6.57 Hz, 2 H), 7.44 (t, J=7.83 Hz, 1 H), 7.57 - 7.78 (m, 2 H).ESI-MS:193.1[M+H] + .

[0456] Step 1C: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine (Compound 4A). [ka]

[0457] A mixture of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (compound 3A, 150.7 kg, 1 equivalent, as a 27.6% w / w toluene solution), (S)-(-)-1-phenylethylamine (112.9 kg, 1.19 equivalents), and p-toluenesulfonic acid (7.4 kg, 0.05 equivalents) was heated to reflux at 110-120 °C for 23-25 ​​h in a reactor assembled in a Dean-Stark configuration. The solvent was then removed at 125-135 °C under atmospheric pressure until distillation ceased, and a portion of toluene (275 kg, 2.24 w / w) was added to obtain a suspension. This suspension was then heated to reflux at 110-120 °C for 23-25 ​​h. The mixture was cooled to 22 °C and washed twice with aqueous NH₄Cl (10%, 301.2 kg, 0.72 equiv.) and once with aqueous NaHCO₃ (5%, 301.2 kg, 0.23 equiv., pH confirmed to be 8-9). The solvent was removed at 125-135 °C and atmospheric pressure to a target volume of 256 L, the mixture was filtered through CELITE®, and the cake was washed with toluene (25 kg). The resulting mixture containing compound 4A was used directly in the next step without further isolation. The yield was determined by correcting for the LOD and GC-FID purity of this sample (208.4 kg, 90.0%, corrected). EI-MS: 294.1 [M H ] + , 190.1[M-C6H5CH(CH3)] + , 105.1[C6H5CH(CH3)] + .

[0458] Step 1D: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine (compound 5A) as the hydrochloride salt. [ka]

[0459] Sponge nickel catalyst (144 kg, 0.70 w / w, shipped as a 50% w / w suspension in water) was added to a hydrogenation reactor equipped with a dip tube, which allowed material to be removed from the top of the internal mass and minimize the amount of water introduced. The supernatant was discarded, and ethanol (329.3 kg, 1.58 w / w, anhydrous) was added, the suspension was stirred, and then allowed to settle. This process was repeated four more times, ensuring a supernatant of ≦1% HO w / w (Karl Fischer (KF)). Compound 4A (208.4 kg, 1 equivalent, as a 62.6% toluene solution) was added to this mixture in the hydrogenation reactor. Ethanol (389.4 kg, 1.86 w / w) was used to rinse the addition flask to the hydrogenation reactor. The hydrogenation reactor was pressurized / depressurized twice with nitrogen (2 bar) and twice with hydrogen (5 bar), and then pressurized with hydrogen (9.8-10.2 bar). The resulting mixture was heated to 33-37 °C and stirred for 17-19 hours. The system was depressurized / pressurized three times with nitrogen (1 bar). The suspension was filtered and washed three times with ethanol (total amount: 493.8 kg, 2.37 w / w). The filtrate was combined with concentrated HCl (83.4 kg, 1.07 equiv.), and the resulting mixture was stirred at 20-24 °C for 25-35 minutes. The mixture was concentrated by distillation at 78-80 °C and atmospheric pressure to remove water and achieve a target distillation volume of 1167 L (5.6 L / kg relative to imine compound 4A). The solution's KF was confirmed (≤1.5% HO w / w). The mixture was stirred at 48-52°C for 55-65 minutes, then at 68-72°C for 55-65 minutes, then cooled to 20-24°C at 12°C / hr and stirred for 25-35 minutes, then cooled to 0-4°C at 10°C / hr and stirred for 55-65 minutes. The suspension was filtered, the cake washed twice with pre-chilled ethanol (total, 329.2 kg, 1.58 w / w, 0°C), and the collected solid was dried at 40°C to give compound 5A as the HCl salt (156.5 kg, 66.4% uncorrected). 1 H NMR (400 MHz, DMSO-d6) δ (ppm) -0.33 - -0.06 (m, 2 H), 0.11 - 0.31 (m, 3 H), 1.57 (d, J=6.57 Hz, 3 H), 1.95 (br t, J=7.07 Hz, 2 H), 2.26 (d, J=1.26 Hz, 3 H), 3.68 (br d, J=7.83 Hz, 1 H), 3.92 (br t, J=6.44 Hz, 1 H), 6.98 (dd, J=7.71, 1.14 Hz, 1 H), 7.28 - 7.36 (m, 2 H), 7.37 - 7.50 (m, 5 H).E SI-MS: 298.2 m / z [M+H] + .

[0460] Step 1E: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) as the hydrochloride salt. [ka]

[0461] Compound 5A (HCl salt, 156.5 kg, 1.00 equiv.) and Pd / C (7.8 kg, 10% Pd basis) were added to an inert hydrogenation reactor. The reactor was then pressurized / depressurized twice with nitrogen (2 bar), followed by the addition of methanol (494.5 kg, 3.16 w / w). The reactor was depressurized / pressurized three times with nitrogen (2 bar), then three times with hydrogen (5 bar), pressurized with hydrogen (9.8-10.2 bar), heated to 58-62°C, and stirred for 7-9 hours. The reaction mixture was cooled to 20-24°C. The reactor was depressurized / pressurized three times with nitrogen (1 bar), and the suspension was filtered and washed three times with methanol (total amount: 492.9 kg, 3.15 w / w). The solution was concentrated at 63-67 °C and atmospheric pressure to a distillation target volume of 1408 L (9.0 L / kg, compound 6A). n-Heptane (1173.8 kg, 7.5 w / w) was added, and the resulting mixture was heated to reflux in a Dean-Stark configuration at 65-80 °C and atmospheric pressure to remove methanol. The suspension was cooled to 31-35 °C, filtered, and the cake was washed with n-heptane (147.1 kg, 0.94 w / w). The solid was dried at 40 °C to give compound 6A as the HCl salt (101.0 kg, 93.8%, uncorrected, 99.6% ee). 1 H NMR (400 MHz, DMSO-d6) δ (ppm) -0.12 - 0.14 (m, 2 H), 0.26 - 0.42 (m, 2 H), 0.44 - 0.55 (m, 1 H), 1.70 - 1.83 (m, 2 H), 2.23 (d, J=1.52 Hz, 3 H), 4.24 (t, J=7.33 Hz, 1 H), 7.22 - 7.29 (m, 1 H), 7.29 - 7.36 (m, 1 H), 7.40 (dd, J=10.99, 1.39 Hz, 1 H).ESI-MS:194.2[M+H] + , 177.0[M-NH2] + .

[0462] Step 1F: Preparation of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A). [ka]

[0463] A mixture of n-heptane (146 kg), water (142 kg), compound 6A (HCl salt, 57.4 kg), and aqueous sodium hydroxide (30% w / w, 41.0 kg) was stirred together. The layers were partitioned, and the aqueous layer was removed. The organic layer was washed with water (170 kg), and the layers were partitioned. The organic layer was set aside. n-heptane (145 kg) and 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (compound 8A, 66.1 kg; the preparation of compound 8A has been previously described in International Publication No. WO 2010 / 125414) were added to a reactor and heated to 85°C. The previously set aside organic layer containing the free base of compound 6A was added to the reactor at 84-85°C and rinsed with n-heptane (20 kg). The resulting mixture was stirred at 83°C for 2 hours. The solvent was then exchanged to methanol at 55°C by charging and uncharging (addition / vacuum distillation) methanol (180 kg) four times to a target volume of 287 L remaining in the reactor. The suspension was cooled to 5°C, and water (570 kg) was added over 4 hours at 5-10°C, with the first 60 kg being added very slowly. The...

Claims

[Claim 1] Compound 1, pharmaceutically acceptable salts, and methods for preparing crystalline forms thereof as described in the present specification, compositions containing the same, etc.

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