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-thiazole-2-amine

Abstract

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

Description

Technical Field

[0001] Field of the Invention The present disclosure relates to the fields of chemistry and medicine, and more specifically, to 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-thiazole-2-amine (Compound 1), pharmaceutically acceptable salts, and methods for making its crystalline forms for the treatment of congenital adrenal hyperplasia (CAH).

Background Art

[0002] Background of the Invention Classical congenital adrenal hyperplasia (CAH) is a disorder that includes a group of autosomal recessive disorders that result in an enzyme deficiency that alters adrenal steroidogenesis due to 21-hydroxylase deficiency, a state in which cortisol biosynthesis is almost or completely absent. One clinical manifestation of the absence of cortisol is the lack of feedback inhibition of pituitary adrenocorticotropic hormone (ACTH) secretion. The increase in ACTH levels causes adrenal hyperplasia, and the enzyme mutation causes diversion of steroids, which are cortisol precursors, to alternative pathways. Most notably, the androgen pathway causes virilization and other developmental complications in females, and the excessive accumulation of ACTH in males is associated with the formation of testicular adrenal rest tumors. In addition, since the same enzyme (21-hydroxylase) is used in the pathway for mineralocorticoid biosynthesis, many of these patients are at risk of developing aldosterone deficiency, which can lead to dehydration and death due to salt loss. The prevalence of classical 21-hydroxylase deficiency CAH in the US population based on newborn screening was recorded as 1:10,000 to 1:20,800 (Trakakis et al., "An update to 21-hydroxylase deficient congenital adrenal hyperplasia," Gynecol. Endocrinol. (2010) 26(1):63-71, Hertzberg et al., "Birth prevalence rates of newborn screening disorders in relation to screening practices in the United States," J. Pediatr. (2011) 159(4):555-560).

[0003] Pediatric patients and females from birth to adolescence are particularly the most vulnerable groups of CAH patients and are thought to be a subgroup of patients in whom the medical need is least met (Cheng and Speiser, "Treatment outcomes in congenital adrenal hyperplasia," Adv. Pediatr. (2012) 59(1):269-281; Merke and Poppas, "Management of adolescents with congenital adrenal hyperplasia," Lancet Diabetes Endocrinol. (2013) 1(4):341-352). Excessive androgen production in these young patients causes premature puberty and adrenarche symptoms, changes in the pattern of skeletal maturation, short stature due to premature fusion of growth plates, as well as significant hirsutism and acne problems. Although life is appropriately protected by steroid replacement strategies based on physiological dosing of glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone), these dosages are often inadequate to suppress the accumulation of ACTH and the overproduction of progesterone and androgens (e.g., 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone). Uncontrolled symptoms of androgen excess have a substantial impact on the daily function and development of these patients.

[0004] Currently, exogenous corticosteroids have become the standard care for treating patients with classical CAH. This treatment is used to correct cortisol deficiency and reduce elevated ACTH levels and androgen excess. However, the dosage and duration of steroid use required to suppress ACTH typically far exceed the normal physiological levels used for cortisol replacement only (as in patients with Addison's disease). This increased exposure to glucocorticoids can result in iatrogenic Cushing's syndrome, increased cardiovascular risk factors, impaired glucose tolerance, decreased growth rate, and decreased bone mineral density in CAH patients (Elnecave et al., "Bone mineral density in girls with classical congenital adrenal hyperplasia due to CYP21 deficiency," J. Pediatr. Endocrinol. Metab. (2008) 21(12):1155-1162; King et al., "Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia," J. Clin. Endocrinol. Metab. (2006) 91(3):865-869 and Migeon and Wisniewski, "Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Growth, development, and therapeutic considerations," Endocrinol. Metab. Clin. North Am. (2001) 30(1):193-206).

[0005] An orally active compound that blocks CRF1, for example, 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-thiazole-2-amine (Compound 1), in patients with CAH, at an amount that is thought to enable the use of lower and more physiological doses of glucocorticoids (e.g., hydrocortisone), has been demonstrated in clinical trials to reduce 17-hydroxyprogesterone (17-OHP) and androstenedione levels from baseline. The structure of Compound 1 is shown below. [Chemical formula]

[0006] Therefore, there is a fairly high 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-thiazole-2-amine (Compound 1) to support further clinical trials and commercial efforts. [Prior Art Documents] [Non-Patent Documents]

[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):865-869 [Non-Patent Document 7] 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 Problems

[0008] Summary of the Invention The present invention provides, inter alia, a 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-thiazole-2-amine (Compound 1) and intermediates therefor.

[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-thiazole-2-amine (Compound 1), pharmaceutically acceptable salts, crystalline forms, and pharmaceutical compositions, which are 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-thiazole-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof Chemical Formula A method for preparing the same, comprising (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

Chemical formula

Chemical formula

[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

Chemical formula

Chemical formula

Chemical formula

[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

Chemical formula

Chemical formula

[0013] One aspect of the present invention is a compound of formula (Ig) or a salt thereof

Chemical formula

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

[0015] One aspect of the present invention is a method for preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) [Chemical formula] comprising 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A) [Chemical formula] Reacting 4-bromo-2-fluoro-1-methylbenzene with an organomagnesium reagent 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-thiazole-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-thiazole-2-amine (Compound 1, tosylate).

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

[0019] 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 the crystalline form (Compound 1, free base) described herein.

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

[0021] 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 the crystalline form (Compound 1, tosylate) 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-yn-1-yl-1,3-thiazole-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-methylthiazole-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)thiazole-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)thiazole-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-thiazoleamine (Compound IIc) at least one compound selected from ethanol, and propargyl bromide relates to a composition containing the same.

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

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

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

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

[0027] One aspect of the present invention relates to the use of the anhydrous crystalline form described herein (Compound 1, free base) or the 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 the anhydrous crystalline form described herein (Compound 1, free base) or the 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 relates to the anhydrous crystalline form (Compound 1, free base), the crystalline form (Compound 1, tosylate base), the pharmaceutical composition, the pharmaceutical product, or the composition described herein for use in a method of treating the body of a human or animal by treatment.

[0030] One aspect of the present invention relates to the anhydrous crystalline form (Compound 1, free base), the crystalline form (Compound 1, tosylate base), the pharmaceutical composition, the pharmaceutical product, or the 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 relates to the anhydrous crystalline form (Compound 1, free base), the crystalline form (Compound 1, tosylate base), the pharmaceutical composition, the pharmaceutical product, or the 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 relates to the anhydrous crystalline form (Compound 1, free base), the crystalline form (Compound 1, tosylate base), the pharmaceutical composition, the pharmaceutical product, or the 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) [Chemical formula] [wherein, R 1c , R 2c , and R 3c are each independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen] relates to.

[0034] One aspect of the present invention is a compound of formula (Ig) or a salt thereof

Chemical formula

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

[0036] These and other aspects of the present invention disclosed herein will be described in more detail as the disclosure progresses. In an embodiment of the present invention, for example, the following items are provided. (Item 1) 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

Chemical formula

Chemical formula

Chemical formula

change

change

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Brief Description of the Drawings

[0037]

Figure 1

[0038]

Figure 2

[0039]

Figure 3

[0040]

Figure 4

[0041]

Figure 5

[0042]

Figure 6

[0043]

Figure 7

[0044]

Figure 8

[0045]

Figure 9

[0046]

Figure 10

[0047]

Figure 11

[0048]

Figure 12

[0049]

Figure 13

[0050]

Figure 14

[0051]

Figure 15

[0052]

Figure 16

[0053]

Figure 17

[0054]

Figure 18

[0055]

Figure 19

[0056]

Figure 20

[0057]

Figure 21

[0058]

Figure 22

[0059]

Figure 23

[0060]

Figure 24

[0061]

Figure 25

[0062] DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are disclosed herein for use in the present disclosure, and other suitable methods and materials known in the art can also be used. The materials, methods, and examples are merely illustrative and not intended to be limiting. All publications, patent applications, patents, sequences, database registrations, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, this specification, including definitions, will control.

[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 recited value includes the recited value and also includes values within ±20% of the recited value, more specifically, values within ±10%, ±5%, ±2%, and ±1% of the recited value.

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

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

[0066] As used herein, "administer" or "administering" refers to a method of giving a dosage of a compound or pharmaceutical formulation to a vertebrate or invertebrate, including mammals, birds, fish, or amphibians. Preferred methods 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 10 The term "C6-C aryl" refers to a saturated ring system containing 6-10 carbon atoms that is aromatic and contains a single ring or two fused rings, such as phenyl and naphthalenyl. When one or more substituents are present on the "aryl" ring, the substituents can 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 1-6 carbons (i.e., "C1-C6 alkyl") or 1-4 carbons (i.e., "C1-C4 alkyl"). Some embodiments are 1-5 carbons (i.e., C1-C5 alkyl), some embodiments are 1-3 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 bonded to the sulfur of the SO3 group. The "C1-C4 alkylsulfonyloxy" group has the formula C1-C4 alkyl S(=O)2O- or the following [Chem.] can be represented by.

[0070] The term "C1-C4 alkyl" has the same definition as found herein. By way of example, methanesulfonate [CH3S(=O)2O-, or (methylsulfonyl)oxy], ethanesulfonate, propanesulfonate, isopropylsulfonate, butanesulfonate, and the like can be mentioned.

[0071] The term "C1-C6 alkoxy" refers to a radical consisting of a C1-C6 alkyl group directly bonded 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. By way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, sec-butoxy, and the like can be mentioned.

[0072] The term "amorphous" means a solid in an amorphous state. An amorphous solid has an irregular molecular arrangement and thus does not have a distinguishable crystal lattice or unit cell and, as a result, does not have a definable long-range order. The solid state form of the 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] The term "C6-C 10 arylsulfonyloxy" refers to a radical consisting of an aryl group directly bonded to the sulfur atom of the SO3 group, of the formula aryl-S(=O)2O- or the following [Chem.] It can be represented by

[0074] The term "aryl" has the same definition as found herein. By way of example, benzenesulfonate [PhS(=O)2O−, or (phenylsulfonyl)oxy, besylate], (naphthalen-1-ylsulfonyl)oxy, and (naphthalen-2-ylsulfonyl)oxy are included.

[0075] The term "composition" refers to a compound or its crystalline form including salts, solvates, and hydrates of the compounds of the present invention, although not limited to, in combination with at least one additional constituent, such as compositions obtained / prepared during synthesis, preformulation, in-process testing / control (e.g., TLC, HPLC, NMR samples).

[0076] The term "crystallinity %" or "crystalline purity" refers to the percentage of the crystalline form in a preparation or sample. It is understood that the 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, the crystalline form can be isolated as the desired form (i.e., the crystalline form described herein) having a crystalline purity of at least about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt%. In some embodiments, the crystalline form can be isolated with a purity of about 90 wt% or higher. In some embodiments, the crystalline form can be isolated with a purity of about 95 wt% or higher. In some embodiments, the crystalline form can be isolated with a purity of about 99 wt% or higher.

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

[0078] The terms "in need of treatment" and "in need thereof", when referring to treatment, are used interchangeably to mean a determination made by a caregiver (e.g., a physician, nurse, nurse practitioner, etc. in the case of a human, or a veterinarian in the case of an animal including non-human mammals) that an individual or animal is in need of treatment or would benefit from treatment. This determination is made based on a variety of factors within the caregiver's area of expertise, which factors include 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. Accordingly, the compounds of the invention can be used prophylactically or protectively, or the compounds of the invention can be used to alleviate, inhibit or remit a disease, condition or disorder.

[0079] The term "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo. In some embodiments, the halogen is chloro, bromo, or iodo. In some embodiments, the halogen is fluoro, chloro, or bromo. In some embodiments, the halogen is fluoro. In some embodiments, the halogen is chloro. In some embodiments, the halogen is bromo. In some embodiments, the 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. C1-C6 haloalkyl, when fully substituted, can be represented by the formula C n L 2n+1 (where 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 can be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the haloalkyl contains 1-5 carbons (i.e., C1-C5 haloalkyl). In some embodiments, the haloalkyl contains 1-4 carbons (i.e., C1-C4 haloalkyl). In some embodiments, the haloalkyl contains 1-3 carbons (i.e., C1-C3 haloalkyl). In some embodiments, the 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 -OH group.

[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, the "individual" refers to a human. In the context of a clinical trial or screening or activity experiment, the subject can be a healthy volunteer or healthy participant who does not have an underlying CFR-mediated disorder or condition, or a volunteer or participant who has received a diagnosis for a disorder or condition that requires medical treatment as determined by a medical professional. In a context other than a clinical trial, a subject who has received a diagnosis for a disorder or condition and is under the care of a medical professional is typically described as a patient.

[0083] The term "inorganic base" refers to a base that does not contain at least one C-H bond and 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 is replaced 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, M. B. and March, J., John Wiley & Sons, New York: 2001 and T. W. Greene, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, 1999. Such leaving groups include, but are not limited to, halogen, optionally substituted 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 -NO2 group.

[0086] The term "pediatric subject" refers to a subject who is less than 21 years of age at the time of diagnosis or treatment. The term "pediatric" can further be divided into various subpopulations including neonates (from birth to 1 month of age), infants (from 1 month to 2 years of age), children (from 2 years to 12 years of age), and adolescents (from 12 years to 21 years (up to but not including the 22nd birthday)). See, for example, Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996, Rudolph et al., Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002, and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

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

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

[0089] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc., which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. The use of any conventional media or agent is contemplated in therapeutic formulations, except when it is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the formulations. 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., in Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010), Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0090] The term "pharmaceutical composition" refers to a particular composition containing 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 rendered easy to investigate for a specified effective outcome in mammals (e.g., but not limited to, humans). Those skilled in the art will understand and recognize the techniques suitable for determining whether the active ingredient has the desired effective outcome, as required by those skilled in the art.

[0091] The term "phase transfer catalyst" refers to any ionic catalyst, such as a quaternary ammonium salt, that can transfer reactants from one phase to another when a reaction occurs. Suitable leaving groups are well known in the art. By way of example, 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 bromide, diallyldimethylammonium chloride, didodecyldimethylammonium bromide, didodecyldimethylammonium bromide, dihexadecyldimethylammonium bromide, dimethyldioctadecylammonium bromide, dimethylditetradecylammonium bromide, dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, dodecylethyldimethylammonium bromide, dodecyltrimethylammonium chloride, domiphen bromide, tetraethylammonium heptadecafluorooctanesulfonate, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, hexyltrimethylammonium bromide, malondialdehyde tetrabutylammonium salt, methyltrioctylammonium bromide, methyltrioctylammonium chloride, methyltrioctylammonium hydrogen sulfate, methyltrioctylammonium thiosalicylate, myristyltrimethylammonium bromide,Tetrabutylammonium acetate, tetrabutylammonium benzoate, tetrabutylammonium bisulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium cyanide, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetrabutylammonium methanesulfonate, tetrabutylammonium methoxide, tetrabutylammonium nonafluorobutanesulfonate, tetrabutylammonium perchlorate, tetrabutylammonium monobasic phosphate, tetrabutylammonium succinimide, tetrabutylammonium sulfate, tetrabutylammonium tetrabutylborate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium tetraphenylborate, tetrabutylammonium thiocyanate, tetrabutylammonium p-toluenesulfonate, tetrabutylammonium trifluoromethanesulfonate, tetradodecylammonium bromide, tetradodecylammonium chloride, tetraethylammonium acetate tetrahydrate, tetraethylammonium benzoate, tetraethylammonium bicarbonate, tetraethylammonium bromide, tetraethylammonium chloride, tetraethylammonium cyanide, tetraethylammonium hexafluorophosphate, tetraethylammonium iodide, tetraethylammonium tetrafluoroborate, tetraethylammonium p-toluenesulfonate, tetraethylammonium trifluoromethanesulfonate, tetraheptylammonium bromide, tetrahexadecylammonium bromide, tetrahexylammonium bromide, tetrahexylammonium chloride, tetrahexylammonium hexafluorophosphate, tetrahexylammonium hydrogen sulfate, tetrahexylammonium iodide, tetrahexylammonium tetrafluoroborate, tetrakis(decyl)ammonium bromide, tetramethylammonium acetate, tetramethylammonium bis(trifluoromethanesulfonyl)imide, tetramethylammonium bisulfate, tetramethylammonium bromide, tetramethylammonium chlorideTetramethylammonium chloride, tetramethylammonium hexafluorophosphate, tetramethylammonium hydrogen sulfate, tetramethylammonium hydrogen sulfate, tetramethylammonium iodide, tetramethylammonium silicate, tetramethylammonium sulfate, tetramethylammonium tetrafluoroborate, tetraoctadecylammonium bromide, tetraoctylammonium bromide, tetraoctylammonium chloride, tetraamylammonium bromide, tetraamylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium iodide, tetrapropylammonium tetrafluoroborate, tributylammonium pyrophosphate, tributylmethylammonium bromide, tributylmethylammonium chloride, tridodecylmethylammonium chloride, tridodecylmethylammonium iodide, triethylhexylammonium bromide, triethylmethylammonium chloride, trihexyltetradecylammonium bromide, trimethyloctadecylammonium bromide, trimethyloctylammonium bromide, trimethyloctylammonium chloride, trimethylphenylammonium bromide, trimethylphenylammonium chloride, trimethyl-tetradecylammonium chloride, etc.

[0092] The term "prescription" refers to the act of instructing, authorizing, or recommending the use of a drug, or other treatment, therapy, or procedure. In some embodiments, a healthcare provider may verbally advise, recommend, or authorize an individual to use a compound, dosing regimen, or other treatment. 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 can advise the individual where to obtain the compound without providing the compound. In some embodiments, the healthcare provider can provide the individual with a written prescription for the compound, dosing regimen, or treatment. The prescription can be written on paper or recorded on an electronic medium. Additionally, the prescription can be called in (verbally) to a pharmacy or clinic or sent by fax (in writing). In some embodiments, a sample of the compound or treatment is given to the individual. As used herein, giving a sample of the compound constitutes an implied 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 by the present disclosure herein. Healthcare providers can include, for example, physicians, nurses, nurse practitioners, or other medical professionals who can prescribe or administer a compound (drug) for a disorder disclosed herein. Additionally, healthcare providers can include those who can recommend, prescribe, administer, or cause an individual not to receive a compound or drug, 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 treatment on a prophylactic or preventative basis to an individual who may ultimately exhibit, but has not yet exhibited, at least one symptom of a disorder. Such individuals can be identified based on the presence of risk factors, such as biomarkers, that are known to correlate with subsequent development of the disease. Alternatively, prophylactic treatment can be administered as a preventative measure without prior identification of a risk factor. 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 "react", "contact", or "treat", when describing a particular chemical reaction or process, are used as known in the art and generally refer to bringing chemical reagents and / or intermediates together in such a manner that molecular-level interactions can achieve a chemical or physical transformation. In some embodiments, the reaction comprises two reagents, where, with respect to the first reagent, one equivalent or more of the second reagent is used. The reaction steps of the methods described herein can be carried out under such conditions for a time suitable to prepare the specified product. Also herein, additional terms are used solely to provide descriptive clarity between various method steps, each of which has the same definition as those described above. 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 invention or a pharmaceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0096] As used herein, the term "subject" 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, and any other vertebrate or invertebrate animal. In some embodiments, the subject is a human.

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

[0098] As used herein, the term "substituted" refers to the replacement of at least one of the hydrogen atoms of a chemical group by a non-hydrogen substituent or group, and the non-hydrogen substituent may be monovalent or divalent. When a chemical group or substituent is divalent, it is understood that this group is further substituted by another substituent or group. When a chemical group herein is "substituted", it may have up to the total substitution valence. For example, a methyl group may be substituted by 1, 2, or 3 substituents, a methylene group may be substituted by 1 or 2 substituents, a phenyl group may be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group may be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and so on. Similarly, "substituted with one or more substituents" refers to the substitution of a group that is substituted from one substituent to the total number of substituents physically possible by that group. "Optionally substituted" is understood to refer to a group that is "unsubstituted" or "substituted" with a certain group as used herein. Thus, when a group is "optionally substituted with one or more substituents", the group is either "unsubstituted" or "substituted", and when substituted, the group is understood to be substituted from one substituent to the total number of substituents physically possible by that group as described above. In some embodiments, the group may be "optionally substituted with 1, 2, 3, or 4 substituents". In some embodiments, the group may be "optionally substituted with 1, 2, or 3 substituents". In some embodiments, the group may be "optionally substituted with 1 or 2 substituents". In some embodiments, the group may be "optionally substituted with 1 substituent". Further, 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, nitro.

[0099] As used herein, "treating" or "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of all or part of the symptoms associated with a disease, disorder or condition, whether detectable or not, diminution of the extent of the disease, stabilization of the disease state (i.e., not getting worse), delay or slowing of the progression of the disease, alleviation or palliation of the medical condition (e.g., one or more symptoms of the disease), and remission (partial or complete). "Treatment" can also mean an extension of survival as compared to the expected survival if not receiving treatment.

[0100] The term "therapeutically effective amount" refers to an amount of a compound of the invention or a pharmaceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof, that elicits a biological or pharmaceutical response in a tissue, system, animal, or human that can include one or more of the following, as desired by an individual, researcher, veterinarian, physician, or other clinician or caregiver. (1) Prevention of a disorder, e.g., prevention of a disease, condition, or disorder in an individual who may be susceptible to, but has not yet experienced or shown, the associated pathology or symptoms (2) Inhibition of a disorder, e.g., inhibition of a disease, condition, or disorder (i.e., suppression of further development of the pathology and / or symptoms) in an individual who is experiencing or showing the associated pathology or symptoms, and (3) Improvement of a disorder, e.g., improvement of a disease, condition, or disorder (i.e., reversal of the pathology and / or symptoms) in an individual who is experiencing or showing the associated pathology or symptoms. Crystal form

[0101] The 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-thiazole-2-amine (Compound 1) and intermediates thereof can be identified 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 forms can be measured by any of the following methods, for example, thermogravimetric analysis (TGA), DSC, etc.

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

[0103] For XRPD, the relative intensities of the peaks can vary depending on the sample preparation technique, the sample mounting procedure, and the equipment used. Further, instrument variations and other factors can often affect the 2θ values. Accordingly, the assignment of the peaks in the diffraction pattern may vary by plus or minus about 0.2° (i.e., ± about 0.2°). For TGA, the temperature features reported herein may vary by plus or minus about 5 °C (i.e., ± about 5 °C). The TGA % weight change reported herein over a specific temperature range may vary by plus or minus about 2% weight change (i.e., ± about 2% weight change), for example, due to variations in the mass of the sample and the size of the sample. 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 characteristics of the GVS reported herein may vary by plus or minus about 5% relative humidity (i.e., ± about 5% relative humidity). The characteristics of the GVS 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-thiazole-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-thiazole-2-amine (Compound 1, free base) and methods related thereto.

[0107] An overview of representative physical properties for the anhydrous crystalline form 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-thiazole-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 are provided in Table 3, where there was no substantial weight change after the cycle 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-thiazole-2-amine (Compound 1, free base). The anhydrous crystalline form I (Compound 1, free base) 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-thiazole-2-amine 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] 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-thiazole-2-amine (Compound 1, free base) having an X-ray powder diffraction pattern comprising at least 3 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 units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least 4 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 units of 2θ.In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least 5 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 units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least 6 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 units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least 7 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 units of 2θ.In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least 8 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 units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least 9 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 units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern comprising at least 10 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 units of 2θ.

[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-thiazole-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction pattern comprising peaks at 14.3° ± 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° 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 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 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 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°, 25.7° ± 0.2°, 26.8° ± 0.2°, and 29.6° ± 0.2° in units of 2θ.In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has an X-ray powder diffraction pattern that is substantially as shown in Figure 1, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0113] Peak intensity may vary depending on any number of factors known to those skilled in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, the equipment used, etc., even for the same crystal form. In some cases, the peak intensity can be quite dramatic. Therefore, the diffraction peak intensities shown herein are exemplary and the same diffraction peak intensity is not necessarily required. One example is the XRPD for Form I shown in Figure 7, which shows substantially the same peak positions but with dramatic peak intensity differences. Those skilled in the art should understand that Figures 1 and 7 are XRPDs of Form I despite the difference in peak intensity. Similarly, those skilled in the art should be able to easily compare the diffraction diagrams provided herein with those created for an unknown crystal form and readily determine whether the diffraction diagram characterizes the same crystal form as provided herein or a different form.

[0114] 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-thiazole-2-amine (Compound 1, free base) having a differential scanning calorimetry (DSC) thermogram comprising an endotherm having 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 having 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 having 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 having 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 having an extrapolated onset temperature of about 83.5°C to about 87.5°C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a differential scanning calorimetry thermogram substantially as shown in Figure 2, where "substantially" means that the reported DSC features may vary by about ±5°C and the reported DSC features may vary by about ±20 joules per gram.

[0115] 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-thiazole-2-amine (Compound 1, free base) having a thermogravimetric analysis (TGA) profile showing 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 showing 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 showing 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 showing 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 analysis profile showing a weight loss of about 0.5% or less by 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-thiazole-2-amine (Compound 1, free base) having a thermogravimetric analysis (TGA) profile in which the anhydrous crystalline form exhibits a weight loss of about 0.05% to about 1.0% up to about 125 °C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing a weight loss of about 0.1% to about 0.9% up to about 125 °C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing a weight loss of about 0.1% to about 0.7% up to about 125 °C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing a weight loss of about 0.1% to about 0.6% up to about 125 °C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile showing a weight loss of about 0.1% to about 0.4% up to about 125 °C. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a thermogravimetric analysis profile substantially shown in Figure 2, where "substantially" means that the reported TGA features may vary by about ±5 °C and 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 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-thiazole-2-amine (Compound 1, free base) having a gravimetric vapor sorption profile in which the anhydrous crystalline form exhibits a weight change of about 0.015% or less after an adsorption / desorption cycle from 10% relative humidity (RH) to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile in which the anhydrous crystalline form exhibits a weight change of about 0.01% or less after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile in which the anhydrous crystalline form exhibits a weight change of about 0.008% or less after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile in which the anhydrous crystalline form exhibits a weight change of about 0.005% or less after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile in which the anhydrous crystalline form exhibits substantially no weight change after an adsorption / desorption cycle 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-thiazole-2-amine (Compound 1, free base) that exhibits a weight change of about 0.1% or less from about 10% relative humidity (RH) to about 90% RH and a weight change of about 0.015% or less after adsorption / desorption cycles from 10% RH to 90% RH and back to 10% RH, having a gravimetric vapor sorption profile. In some embodiments, the anhydrous crystalline form (Compound 1, free base) 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 cycles from 10% RH to 90% RH and back to 10% RH, having a gravimetric vapor sorption profile. In some embodiments, the anhydrous crystalline form (Compound 1, free base) 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 cycles from 10% RH to 90% RH and back to 10% RH, having a gravimetric vapor sorption profile. In some embodiments, the anhydrous crystalline form (Compound 1, free base) 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 cycles from 10% RH to 90% RH and back to 10% RH, having a gravimetric vapor sorption profile. In some embodiments, the anhydrous crystalline form (Compound 1, free base) 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 cycles from 10% RH to 90% RH and back to 10% RH, having a gravimetric vapor sorption profile.In some embodiments, the anhydrous crystalline form (Compound 1, free base) exhibits a weight change of about 0.2% or less from about 10% RH to about 90% RH and shows substantially no weight change after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH, having a gravimetric vapor sorption profile. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a gravimetric vapor sorption profile substantially shown in Figure 3, where "substantially" means that the reported GVS characteristics may vary by plus or minus about 5% relative humidity (i.e., ± about 5% relative humidity), and may also vary by plus or minus about 2% weight change (i.e., ± about 2% weight change).

[0119] One aspect of the present 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 units of 2θ, a differential scanning calorimetry thermogram comprising an endotherm having 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 a gravimetric vapor sorption profile showing a weight change of about 0.015% or less after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH relating to the anhydrous crystalline form (Compound 1, free base) 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-thiazole-2-amine.

[0120] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including peaks at 14.3° ± 0.2°, 19.7° ± 0.2°, and 25.7° ± 0.2° in units of 2θ, a differential scanning calorimetry thermogram including an endotherm having 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 a gravimetric vapor sorption profile showing a weight change of about 0.005% or less after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH and 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-thiazole-2-amine (Compound 1, free base).

[0121] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including 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 units of 2θ, a differential scanning calorimetry thermogram including an endotherm having 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 a gravimetric vapor sorption profile showing a weight change of about 0.003% or less after an adsorption / desorption cycle from 10% RH to 90% RH and back to 10% RH 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-thiazole-2-amine (Compound 1, free base), which has

[0122] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern substantially shown in Figure 1, a differential scanning calorimetry thermogram substantially shown in Figure 2, a thermogravimetric analysis profile substantially shown in Figure 2, and / or a gravimetric vapor sorption profile substantially shown in Figure 3 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-thiazole-2-amine (Compound 1, free base), which has

[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-thiazole-2-amine (Compound 1, free base) can be isolated as the crystalline form described herein with a crystal purity of at least about 75 wt%. In some embodiments, about 80 wt%. In some embodiments, about 85 wt%. In some embodiments, about 90 wt%. In some embodiments, about 95 wt%. In some embodiments, about 96 wt%. In some embodiments, about 97 wt%. In some embodiments, about 98 wt%. In some embodiments, about 99 wt%.

[0124] A production 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-thiazole-2-amine (Compound 1, free base) having the characteristics of the particle size distribution shown in Table 4 below was prepared.

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-thiazole-2-amine (Compound 1, free base) has a particle size D10 of from about 8 μM to about 35 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of from about 10 μM to about 30 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of from about 10 μM to about 27 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of from about 12 μM to about 25 μM. In some embodiments, the anhydrous crystalline form (Compound 1, free base) has a particle size D10 of from about 12 μM to about 23 μM.

[0126] In some embodiments, the anhydrous crystalline form (Compound 1, free base) 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-thiazole-2-amine 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 (Compound 1, free base) 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-thiazole-2-amine 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-methylthiazole-2-amine (Compound 9A, anhydrous crystalline form)

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

[0130] An overview of representative physical properties for the anhydrous crystalline form is shown in Tables 5 and 6 below. [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-methylthiazole-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-methylthiazole-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-methylthiazole-2-amine (Compound 9A). 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] 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-methylthiazole-2-amine (Compound 9A) having an X-ray powder diffraction pattern comprising at least 3 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 4 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 5 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 units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 6 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 7 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 8 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 units of 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least ten 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 units of 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) having an X-ray powder diffraction pattern in which the anhydrous crystalline form includes peaks at 25.7° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 that includes a peak at 19.0° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes peaks at 15.2° ± 0.2°, 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 that includes 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 units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially shown in FIG. 9, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0135] The peak intensity may vary depending on any number of factors known to those skilled in the art, such as preferred orientation effects, preparation techniques, sample mounting procedures, the equipment used, etc., even for the same crystal form. In some cases, the peak intensity can be quite dramatic. Therefore, the diffraction peak intensities shown herein are illustrative and the same diffraction peak intensity is not necessarily required. A person skilled in the art should be able to easily compare the diffraction diagrams provided herein with those created for an unknown crystal form and readily determine whether the diffraction diagram characterizes the same crystal form as provided herein or a different form.

[0136] One aspect of the present invention relates to an anhydrous crystal form of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazole-2-amine (Compound 9A) having a differential scanning calorimetry (DSC) thermogram comprising an endotherm having an extrapolated onset temperature of about 129 °C to about 136 °C. In some embodiments, the anhydrous crystal form has a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of about 130.5 °C to about 135.5 °C. In some embodiments, the anhydrous crystal form has a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of about 131 °C to about 134 °C. In some embodiments, the anhydrous crystal form has a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of about 131.5 °C to about 133.5 °C. In some embodiments, the anhydrous crystal form has a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of about 132 °C to about 133 °C. In some embodiments, the anhydrous crystal form has a differential scanning calorimetry thermogram substantially shown in Figure 10, where "substantially" means that the reported DSC features may vary by about ±5 °C and the reported DSC features 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-methylthiazole-2-amine (Compound 9A) having a thermogravimetric analysis (TGA) profile showing 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 showing 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 showing 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 showing 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 showing 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-methylthiazole-2-amine (Compound 9A), wherein the anhydrous crystalline form has a thermogravimetric analysis (TGA) profile showing 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 showing 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 showing 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 showing 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 showing a weight loss of about 0.05% to about 0.15% by about 125 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially shown in Figure 10, where "substantially" means that the reported TGA characteristics may vary by about ±5 °C and the reported TGA characteristics may vary by about ±2% weight change (i.e., ± about 2% weight change).

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

[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 units of 2θ, a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of about 129 °C to about 136 °C, and / or a thermogravimetric analysis profile showing a weight loss of about 0.05% to about 1.0% by about 125 °C Relates to an anhydrous crystalline form (Compound 9A) of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazole-2-amine having

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

[0142] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including 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° in units of 2θ, a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of about 132°C to about 133°C, and / or a thermogravimetric analysis profile showing a weight loss of about 0.4% or less by about 125°C Relates to an anhydrous crystalline form (Compound 9A) of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazole-2-amine having

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

[0144] In some embodiments, the anhydrous crystalline form (Compound 9A) of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazole-2-amine can be isolated as a crystalline form herein with a crystal 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 (Compound 8A) of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one and methods related thereto.

[0147] An overview of representative physical properties for the crystalline form 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 the anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A). The 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) having an X-ray powder diffraction pattern in which the anhydrous crystalline form comprises at least 3 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 4 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 5 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 6 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° in units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 7 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 8 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 9 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 units of 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 units of 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) having an X-ray powder diffraction pattern whose anhydrous crystalline form includes a peak at 24.9° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes peaks 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially shown in FIG. 11, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0152] It is understood that peak intensities can vary by 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, the equipment used, etc. In some cases, the peak intensities can be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary and the same diffraction peak intensities are not necessarily required. One of skill in the art should be able to readily compare the diffractograms provided herein with diffractograms created for an unknown crystalline form and easily confirm whether that 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) having a differential scanning calorimetry (DSC) thermogram including an endotherm having an extrapolated onset temperature of from about 70.5 °C to about 75.5 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of from about 71 °C to about 75 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of from about 71.5 °C to about 74.5 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of from about 72 °C to about 74 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of from about 72.5 °C to about 73.5 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram substantially shown in FIG. 12, where "substantially" means that the reported DSC features may vary by about ±5 °C and 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) having a thermogravimetric analysis (TGA) profile showing 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 showing 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 showing 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 showing 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 showing 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) having a thermogravimetric analysis (TGA) profile in which the anhydrous crystalline form 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 showing 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 showing 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 showing 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 showing 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 shown in FIG. 12, where "substantially" means that the reported TGA characteristics may vary by about ±5 °C and the reported TGA characteristics may vary by about ±2% weight change (i.e., ± about 2% weight change).

[0156] One aspect of the present invention is that the anhydrous crystalline form 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 units of 2θ, a differential scanning calorimetry (DSC) thermogram comprising an endotherm having an extrapolated onset temperature of about 70.5 °C to about 75.5 °C, and / or a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.1% to about 1.0% by about 125 °C relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) having.

[0157] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including 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° in units of 2θ, a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of about 71.5 °C to about 74.5 °C, and / or a thermogravimetric analysis profile showing a weight loss of about 1.0% or less by about 125 °C and relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A).

[0158] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including 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° in units of 2θ, a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of about 72.5 °C to about 73.5 °C, and / or a thermogravimetric analysis profile showing a weight loss of about 0.5% or less by about 125 °C and relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A).

[0159] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern substantially shown in Figure 11, a differential scanning calorimetry thermogram substantially shown in Figure 12, and / or a thermogravimetric analysis profile substantially shown in Figure 12 and relates to an anhydrous crystalline form of 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A).

[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 with a crystal 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, 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 related thereto.

[0163] An overview of representative physical properties for the crystalline form 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). The 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) having an X-ray powder diffraction pattern in which the anhydrous crystalline form comprises at least 3 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 4 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 5 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 6 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° in units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 7 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 8 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 9 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° in units of 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° in units of 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) having an X-ray powder diffraction pattern in which the anhydrous crystalline form includes peaks at 20.5° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 that includes a peak at 24.3° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes peaks at 20.5° ± 0.2°, 21.1° ± 0.2°, 23.2° ± 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 that includes 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 units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 units of 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° 2θ.

[0168] Peak intensities can vary by 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, the equipment used, etc. In some cases, peak intensities can be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary and the same diffraction peak intensities are not necessarily required. One of skill in the art should be able to readily compare the diffractograms provided herein with diffractograms created for an unknown crystalline form and easily confirm whether that 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) having a differential scanning calorimetry (DSC) thermogram including an endotherm having 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 including an endotherm having 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 including an endotherm having 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 including an endotherm having 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 including an endotherm having 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 shown in Figure 14, where "substantially" means that the reported DSC features may vary by about ±5°C and 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) having a thermogravimetric analysis (TGA) profile showing 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 showing 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 showing 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 showing 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 showing 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) having a thermogravimetric analysis (TGA) profile in which the anhydrous crystalline form 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 in which it 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 in which it 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 in which it 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 in which it 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 shown in FIG. 14, where "substantially" means that the reported TGA features may vary by about ±5 °C and the reported TGA features may vary by about ±2% weight change (i.e., ± about 2% weight change).

[0172] One aspect of the present invention is that the anhydrous crystalline form 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 units of 2θ, a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of about 154 °C to about 164 °C, and / or a thermogravimetric analysis profile showing a weight loss of about 0.05% to about 1.0% by about 125 °C of an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt).

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

[0174] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including 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° in units of 2θ, a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of about 159°C to about 160°C, and / or a thermogravimetric analysis profile showing a weight loss of about 0.4% or less by about 125°C and relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt).

[0175] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern substantially shown in FIG. 13, a differential scanning calorimetry thermogram substantially shown in FIG. 14, and / or a thermogravimetric analysis profile substantially shown in FIG. 14 and relates to an anhydrous crystalline form of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A, HCl salt).

[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 with a crystal 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 related thereto.

[0179] An overview of representative physical properties for the crystalline form 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 the anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A). The 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) having an X-ray powder diffraction pattern comprising at least 3 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 4 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 5 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 units of 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) having an X-ray powder diffraction pattern whose anhydrous crystalline form includes peaks at 7.4° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes a peak at 7.5° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes a peak at 14.7° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes a peak at 14.8° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes peaks at 7.4° ± 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes peaks at 7.5° ± 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 that includes peaks at 7.5° ± 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 that includes peaks at 7.4° ± 0.2°, 14.7° ± 0.2°, and 29.5° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes peaks at 7.4° ± 0.2°, 14.8° ± 0.2°, and 29.5° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes peaks at 7.5° ± 0.2°, 14.7° ± 0.2°, and 29.5° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes peaks at 7.5° ± 0.2°, 14.8° ± 0.2°, and 29.5° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes peaks at 7.4° ± 0.2°, 14.7° ± 0.2°, 22.0° ± 0.2°, and 29.5° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes peaks at 7.4° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, and 29.5° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes peaks at 7.5° ± 0.2°, 14.7° ± 0.2°, 22.0° ± 0.2°, and 29.5° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes peaks at 7.5° ± 0.2°, 14.8° ± 0.2°, 22.0° ± 0.2°, and 29.5° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 that includes 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 that includes peaks at 7.5° ± 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 that includes peaks at 7.5° ± 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 that includes 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially shown in FIG. 15, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0184] It is understood that peak intensities can vary by 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, the equipment used, etc. In some cases, peak intensities can be quite dramatic. Accordingly, the diffraction peak intensities shown herein are exemplary and the same diffraction peak intensities are not necessarily required. One of ordinary skill in the art should be able to readily compare the diffractograms provided herein with diffractograms created for an unknown crystalline form and easily confirm whether that 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) having a differential scanning calorimetry (DSC) thermogram including an endotherm with an extrapolated onset temperature of from about 25 °C to about 31 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of from about 26.5 °C to about 30 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of from about 26.5 °C to about 29.5 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of from about 27 °C to about 29 °C. In some embodiments, the anhydrous crystalline form has a differential scanning calorimetry thermogram including an endotherm with an extrapolated onset temperature of from 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 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) having a thermogravimetric analysis (TGA) profile showing 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 showing 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 showing 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 showing 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 showing 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) having a thermogravimetric analysis (TGA) profile with a weight loss of about 0.02% to about 1.0% up to about 70 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile with a weight loss of about 0.03% to about 0.7% up to about 70 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile with a weight loss of about 0.04% to about 0.6% up to about 70 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile with a weight loss of about 0.05% to about 0.4% up to about 70 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile with a weight loss of about 0.1% to about 0.2% up to about 70 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially shown in Figure 16, where "substantially" means that the reported TGA characteristics may vary by about ±5 °C and the reported TGA characteristics may vary by about ±2% weight change (i.e., ± about 2% weight change).

[0188] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including 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 units of 2θ, a differential scanning calorimetry (DSC) thermogram including an endotherm having an extrapolated onset temperature of about 25 °C to about 31 °C, and / or a thermogravimetric analysis profile showing a weight loss of about 1.0% or less up to about 70 °C and relates to an anhydrous crystalline form of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).

[0189] One aspect of the present invention is that the anhydrous crystalline form has An X-ray powder diffraction pattern comprising at least 4 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 units of 2θ, A differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of about 26.5°C to about 29.5°C, and / or A thermogravimetric analysis profile showing a weight loss of about 0.02% to about 1.0% by about 70°C Relates to an anhydrous crystalline form (Compound 3A) of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one having

[0190] One aspect of the present 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 units of 2θ, A differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of about 27.5°C to about 28.5°C, and / or A thermogravimetric analysis profile showing a weight loss of about 0.05% to about 0.4% by about 70°C Relates to an anhydrous crystalline form (Compound 3A) of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one having

[0191] One aspect of the present invention is that the anhydrous crystalline form is An X-ray powder diffraction pattern substantially shown in FIG. 15, A differential scanning calorimetry thermogram substantially shown in FIG. 16, and / or A thermogravimetric analysis profile substantially shown in FIG. 16 Relates to an anhydrous crystalline form (Compound 3A) of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one having

[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 with a crystal 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] An overview 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)ethane-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)ethane-1-amine (Compound 5A, HCl salt). The 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) having an X-ray powder diffraction pattern in which the anhydrous crystalline form includes at least 3 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern including at least 4 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern including at least 5 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern including at least 6 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 units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 7 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 8 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 units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern comprising at least 9 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 units of 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 units of 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) having an X-ray powder diffraction pattern in which the anhydrous crystalline form includes peaks at 13.0° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 that includes a peak at 25.9° ± 0.2° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 that includes 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 units of 2θ.In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the anhydrous crystalline form has an X-ray powder diffraction pattern substantially shown in FIG. 17, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0200] It is understood that peak intensities may vary by 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, the equipment used, etc. In some cases, the peak intensities can be quite dramatic. Accordingly, the diffraction peak intensities shown herein are exemplary and the same diffraction peak intensities are not necessarily required. One of skill in the art should be able to readily compare the diffractograms provided herein with diffractograms created for an unknown crystalline form and easily confirm whether that 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) having a differential scanning calorimetry (DSC) thermogram comprising an endotherm having 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 having 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 having 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 having 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 having 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 shown in Figure 18, where "substantially" means that the reported DSC features may vary by about ±5°C and the reported DSC features 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) having a thermogravimetric analysis (TGA) profile showing 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 showing 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 showing 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 showing 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 showing 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)ethane-1-amine (Compound 5A, HCl salt) having a thermogravimetric analysis (TGA) profile in which the anhydrous crystalline form exhibits a weight loss of about 0.01% to about 1.0% up to about 125 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile in which it exhibits a weight loss of about 0.02% to about 0.8% up to about 125 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile in which it exhibits a weight loss of about 0.03% to about 0.6% up to about 125 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile in which it exhibits a weight loss of about 0.04% to about 0.4% up to about 125 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile in which it exhibits a weight loss of about 0.05% to about 0.2% up to about 125 °C. In some embodiments, the anhydrous crystalline form has a thermogravimetric analysis profile substantially shown in Figure 18, where "substantially" means that the reported TGA characteristics may vary by about ±5 °C and the reported TGA characteristics may vary by about ±2% weight change (i.e., ± about 2% weight change).

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

[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 units of 2θ, a differential scanning calorimetry (DSC) thermogram comprising an endotherm having an extrapolated onset temperature of about 212 °C to about 218.5 °C, and / or a thermogravimetric analysis profile showing a weight loss of about 1.0% or less up to about 125 °C Regarding the anhydrous crystalline form (Compound 5A, HCl salt) of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine having

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

[0207] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including 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 units of 2θ, a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of about 214.5°C to about 217°C, and / or a thermogravimetric analysis profile showing a weight loss of about 0.04% to about 0.4% by about 125°C Regarding the anhydrous crystalline form (Compound 5A, HCl salt) of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine having

[0208] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern substantially shown in Figure 17, a differential scanning calorimetry thermogram substantially shown in Figure 18, and / or The thermogravimetric analysis profile substantially shown in FIG. 18 relates to an anhydrous crystalline form (Compound 5A, HCl salt) of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-((S)-1-phenylethyl)ethan-1-amine having

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

[0211] One aspect of the present invention relates to a novel crystalline form (Compound 1, tosylate) 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 and methods related thereto.

[0212] A summary of representative physical properties for crystalline Compound 1 (tosylate) 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) 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, Form I).

[0215] 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-thiazole-2-amine (Compound 1, tosylate, Form I) having an X-ray powder diffraction pattern in which the crystalline form comprises at least 3 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising at least 4 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising at least 5 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising at least 6 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 units of 2θ.In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising at least 7 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising at least 8 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern comprising at least 9 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) 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 units of 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-thiazole-2-amine (Compound 1, tosylate) having an X-ray powder diffraction pattern that includes a peak at 9.1° ± 0.2° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes a peak at 21.1° ± 0.2° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes a peak at 23.3° ± 0.2° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes peaks at 9.1° ± 0.2° and 21.1° ± 0.2° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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 that includes 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 that includes 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 that includes 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) has an X-ray powder diffraction pattern that includes peaks at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 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 that includes peaks at 9.1° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, and 21.1° ± 0.2° in units of 2θ.In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes peaks at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 23.3° ± 0.2°, and 23.8° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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° in units of 2θ.In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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° in units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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 units of 2θ.In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern that includes 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 units of 2θ. In some embodiments, the crystalline form (Compound 1, tosylate) has an X-ray powder diffraction pattern substantially 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 by 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, the equipment used, etc. In some cases, peak intensities can be quite dramatic. Thus, the diffraction peak intensities shown herein are exemplary and the same diffraction peak intensities are not necessarily required. One of ordinary skill in the art should be able to easily compare the diffractograms provided herein with diffractograms created for an unknown crystalline form and readily confirm whether that 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-thiazole-2-amine (Compound 1, tosylate) having a differential scanning calorimetry (DSC) thermogram comprising an endotherm having an extrapolated onset temperature of from about 154°C to about 159°C. In some embodiments, the crystalline form (Compound 1, tosylate) has a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of from about 154.5°C to about 158.5°C. In some embodiments, the crystalline form (Compound 1, tosylate) has a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of from about 155°C to about 158°C. In some embodiments, the crystalline form (Compound 1, tosylate) has a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of from about 155.5°C to about 157.5°C. In some embodiments, the crystalline form (Compound 1, tosylate) has a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of from about 156°C to about 157°C. In some embodiments, the crystalline form (Compound 1, tosylate) has a differential scanning calorimetry thermogram substantially as shown in Figure 25, where "substantially" means that the reported DSC features may vary by about ±5°C and the reported DSC features 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-thiazole-2-amine (Compound 1, tosylate) having a thermogravimetric analysis (TGA) profile showing a weight loss of about 1.0% or less by about 125 °C. In some embodiments, the crystalline form (Compound 1, tosylate) has a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.9% or less by about 125 °C. In some embodiments, the crystalline form (Compound 1, tosylate) has a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.7% or less by about 125 °C. In some embodiments, the crystalline form (Compound 1, tosylate) has a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.6% or less by about 125 °C. In some embodiments, the crystalline form (Compound 1, tosylate) has a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.5% or less by 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-thiazole-2-amine (Compound 1, tosylate) having a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.05% to about 1.0% by about 125 °C. In some embodiments, the crystalline form (Compound 1, tosylate) has a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.1% to about 0.9% by about 125 °C. In some embodiments, the crystalline form (Compound 1, tosylate) has a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.2% to about 0.7% by about 125 °C. In some embodiments, the crystalline form (Compound 1, tosylate) has a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.3% to about 0.6% by about 125 °C. In some embodiments, the crystalline form (Compound 1, tosylate) has a thermogravimetric analysis (TGA) profile showing a weight loss of about 0.4% to about 0.5% by about 125 °C. In some embodiments, the crystalline form (Compound 1, tosylate) has a thermogravimetric analysis profile substantially shown in Figure 25, where "substantially" means that the reported TGA features may vary by about ±5 °C and the reported TGA features may vary by about ±2% weight change (i.e., ± about 2% weight change).

[0221] One aspect of the present invention is that 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 units of 2θ, a differential scanning calorimetry thermogram comprising an endotherm having an extrapolated onset temperature of about 154 °C to about 159 °C, and / or A thermogravimetric analysis profile showing a weight loss of about 0.05% to about 1.0% by about 125 °C 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-thiazole-2-amine (Compound 1, tosylate) having

[0222] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including peaks at 9.1° ± 0.2°, 11.3° ± 0.2°, 21.1° ± 0.2°, 22.8° ± 0.2°, and 23.3° ± 0.2° in units of 2θ, a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of about 155 °C to about 158 °C, and / or a thermogravimetric analysis profile showing a weight loss of about 0.9% or less by about 125 °C 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-thiazole-2-amine (Compound 1, tosylate) having

[0223] One aspect of the present invention is that the anhydrous crystalline form has an X-ray powder diffraction pattern including peaks at 9.1° ± 0.2°, 11.3° ± 0.2°, 13.2° ± 0.2°, 16.3° ± 0.2°, and 21.1° ± 0.2° in units of 2θ, a differential scanning calorimetry thermogram including an endotherm having an extrapolated onset temperature of about 155.5 °C to about 157.5 °C, and / or a thermogravimetric analysis profile showing a weight loss of about 0.6% or less by about 125 °C Relates to an anhydrous crystalline form (Compound 1, tosylate) 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-thiazole-2-amine.

[0224] One aspect of the invention is that the anhydrous crystalline form is an X-ray powder diffraction pattern substantially shown in Figure 24, a differential scanning calorimetry thermogram substantially shown in Figure 25, and / or a thermogravimetric analysis profile substantially shown in Figure 25 Relates to a crystalline form (Compound 1, tosylate) 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-thiazole-2-amine having the above.

[0225] In some embodiments, the anhydrous crystalline form (Compound 1, tosylate) 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-thiazole-2-amine can be isolated as a crystalline form described herein with a crystal 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 invention

[0226] For the compounds disclosed and described in this specification, the atoms at each position of the compound can independently have an isotopic distribution of chemical elements in a proportional amount relative to the amount normally found in nature, or an isotopic distribution in a proportional amount different from the amount normally found in nature, unless otherwise explicitly indicated depending on the circumstances. Accordingly, one aspect of the present invention is a compound of formula (Ia)

Chemical formula

[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 is 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 7is, independently, deuterium. In some embodiments, each R 8 is, independently, deuterium. In some embodiments, each R 9 is, 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 C). In some embodiments, X is carbon-13 ( 13 C).

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

[0230] The compound 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, such as the representative methods shown in Example 6.

[0231] A chemical element has an atomic number defined by the number of protons in its nucleus. Each atomic number identifies a particular element but not an isotope, and atoms of a given element can have a wide range of numbers of neutrons. The number of both protons and neutrons in the nucleus is the mass number of the atom, and each isotope of a given element has a different mass number. A compound in which one or more atoms have an isotope distribution for a chemical element that is different from the amounts normally found in nature is generally said to be an isotope-labeled compound. Each chemical element represented within a compound structure can include any isotope distribution of said element. For example, within a compound structure, a hydrogen atom can be clearly disclosed as being present in the compound or can be understood as such. At any position in a compound where a hydrogen atom can be present, that hydrogen atom can be in a proportional amount relative to the amount normally found in nature and in proportional amounts different from the amount normally found in nature, including, but not limited to, protium ( 1(H) and deuterium ( 2 H) can exist in the isotope distribution of hydrogen including. Therefore, references to compounds herein include all potential isotope distributions for each atom, unless otherwise explicitly stated by the context. 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 can contain radioactive isotopes. Thus, one or more atoms have a higher proportion of 2 H or 3 H, or a higher proportion than is found in nature of 11 C, 13 C or 14 C, etc., having an isotope distribution different from that normally found in nature is also contemplated for the compounds disclosed and described herein. As a general example, but not limited to, isotopes of hydrogen include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Isotopes of carbon 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). Isotopes of fluorine include fluorine-17 ( 17 F), fluorine-18 ( 18 F) and fluorine-19 ( 19 F). Isotopes of phosphoric acid include phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33P), phosphorus-34( 34 P), phosphorus-35( 35 P) and phosphorus-36( 36 P) are included. 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). Isotopes of chlorine include chlorine-35( 35 Cl), chlorine-36( 36 Cl) and chlorine-37( 37 Cl). 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). Isotopes of iodine include iodine-123( 123 I), iodine-124( 124 I), iodine-125( 125 I), iodine-131( 131 I) and iodine-135( 135It includes (I). In some embodiments, the atoms at each position of the compound have an isotope distribution for each chemical element in a proportional amount relative to the amount normally found in nature. In some embodiments, the atoms at at least one position of the compound have an isotope distribution for a chemical element in a proportional amount different from the amount normally found in nature (the remaining atoms have an isotope distribution for a chemical element in a proportional amount relative to the amount normally found in nature). In some embodiments, the atoms at at least two positions of the compound independently have an isotope distribution for a chemical element in a proportional amount different from the amount normally found in nature (the remaining atoms have an isotope distribution for a chemical element in a proportional amount relative to the amount normally found in nature). In some embodiments, the atoms at at least three positions of the compound independently have an isotope distribution for a chemical element in a proportional amount different from the amount normally found in nature (the remaining atoms have an isotope distribution for a chemical element in a proportional amount relative to the amount normally found in nature). In some embodiments, the atoms at at least four positions of the compound independently have an isotope distribution for a chemical element in a proportional amount different from the amount normally found in nature (the remaining atoms have an isotope distribution for a chemical element in a proportional amount relative to the amount normally found in nature). In some embodiments, the atoms at at least five positions of the compound independently have an isotope distribution for a chemical element in a proportional amount different from the amount normally found in nature (the remaining atoms have an isotope distribution for a chemical element in a proportional amount relative to the amount normally found in nature). In some embodiments, the atoms at at least six positions of the compound independently have an isotope distribution for a chemical element in a proportional amount different from the amount normally found in nature (the remaining atoms have an isotope distribution for a chemical element in a proportional amount relative to the amount normally found in nature).

[0232] For the compounds provided herein, when the position of a particular atom is designated as having deuterium or "D" or "d", the abundance of deuterium at that position is understood to be 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 of 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) at each of the designated deuterium positions in certain embodiments. Certain methods of the present invention

[0233] The present invention is directed, inter alia, to methods 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-thiazole-2-amine (Compound 1) and its crystalline forms.

[0234] Any of the methods can be carried out under an inert atmosphere, either collectively as one or more of the following and above steps herein or individually as separate steps. 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 carried out under a substantially inert atmosphere comprising argon or nitrogen. In some embodiments, the method steps described herein are carried out under a substantially inert atmosphere comprising nitrogen.

[0236] The reactions of the methods described herein can be carried out in a suitable solvent that can be readily selected by one of ordinary skill in organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at a temperature at which the reaction is carried out, for example, a temperature in the range from the freezing temperature 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, a solvent appropriate for the specific reaction step can be selected. 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 a 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-dichlorotetrafluoroethane, 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), and mixtures thereof.

[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 can include aprotic solvents such as 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-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, the formation of the product can be monitored by spectroscopic means such as 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] When preparing a compound by the method described in this specification, the desired product can be isolated using ordinary isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, enrichment of enantiomers by recrystallization, chromatography, etc.

[0244] The example methods and certain intermediates of the present invention are shown in the following Schemes I - VII.

[0245] A representative coupling step of 2-cyclopropylacetic acid (Compound 1A) with N,O-dimethylhydroxylamine or its salt to prepare 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A) 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) is presented in the following Scheme I.

Chemical formula

[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 to prepare 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) in the presence of a reaction step solvent (e.g., tetrahydrofuran (THF)) is presented in the following Scheme II.

Chemical formula

[0247] In the presence of the acid in the condensation step (e.g., p-toluenesulfonic acid) and the solvent in the condensation step (e.g., toluene), a representative condensation step of the compound of formula (Ie) with 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) and the compound of formula (Ic) or a salt thereof to prepare the compound of formula (Ie) is presented in Scheme III below. [Chemical formula] [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 the compound of formula (Ie) to prepare the compound of formula (Ig) in the presence of a reduction catalyst (e.g., sponge nickel and Pd / Cu-C), hydrogen, and the solvent in the reduction step (e.g., ethanol) is presented in Scheme IV below. [Chemical formula] [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 the compound of formula (Ig) or a salt thereof to prepare (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof in the presence of a deprotection catalyst (e.g., Pd), hydrogen, and the solvent in the deprotection step (e.g., ethanol) is presented in Scheme V below. [Chemical formula] [In the formula, R 1c , R 2cand R 3c is independently selected from H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl and halogen.

[0250] A representative cyclization step of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazole-2-amine (Compound 9A) or a salt thereof, or (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethane-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-methylthiazole-2-amine (Compound 9A) or a salt thereof is presented in Scheme VI below.

[0251] [Chemical formula]

[0252] A representative alkylation step 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-thiazole-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof in the presence of a solvent for the alkylation step (e.g., methyl tert-butyl ether (MTBE), toluene and mixtures thereof), a phase transfer catalyst (e.g., tetra-n-butylammonium bromide (TBAB)), a base for the alkylation step (e.g., potassium hydroxide) and water, using (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazole-2-amine (Compound 9A) or a salt thereof and a compound of formula (Ii) [wherein LG is a suitable leaving group (e.g., Br)] is presented in Scheme VII below. [Chemical formula]

[0253] One aspect of the present invention includes any combination of one or more method steps, and intermediates related thereto, for the preparation of the methods exemplified by Schemes I, II, III, IV, V, VI, VII and VII (above), and compounds contained therein, 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-thiazole-2-amine (Compound 1) and / or a pharmaceutically acceptable salt, and crystalline forms thereof.

[0254] One aspect of the present invention relates to one or more intermediates such as Compounds (2A), (3A), (4A), (5A), (6A), (7A), (8A) and (9A), and compounds of Formulas (Ia), (Ic), (Ie), (Ig) and (Ii), which are 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-thiazole-2-amine (Compound 1) and / or a pharmaceutically acceptable salt, and crystalline forms thereof, and compounds prepared by the methods exemplified by 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-thiazole-2-amine (Compound 1) are described in PCT Application PCT / FR00 / 01995 (International Publication No. WO2001 / 05776), filed Jul. 11, 2000. Some improvements have been discovered and are described herein.

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

[0257] Other improvements include the steps shown in Schemes III - IV, which converted the ketone (Compound 3A) to the chiral amine (Compound 6A) in high yield and high enantiomeric excess.

[0258] The compounds of the present invention also include all isotopes of atoms present 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 method (alkylation step) 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-thiazole-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof.

[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-thiazole-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[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 arylsulfonyloxy are each 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: [Chemical formula] [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" means 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: [Chemical formula] [wherein, 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. 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, trifluoromethyl, trifluoromethoxy and nitro. In some embodiments, R 1a , R 2a and R 3a are each independently selected from the group consisting of H, methyl, fluoro, trifluoromethyl, trifluoromethoxy and nitro. In some embodiments, R 1a , R 2a and R 3a are each independently selected from the group consisting of H and methyl.

[0264] In some embodiments, LG is 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 a molar excess compared to Compound 9A. In some embodiments, the compound of formula (Ii) is present in about 30% molar excess compared to Compound 9A. In some embodiments, the compound of formula (Ii) is present in about 25% molar excess compared to Compound 9A. In some embodiments, the compound of formula (Ii) is present in about 20% molar excess compared 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 from about 1:0.05 to about 1:0.9. In some embodiments, the molar ratio of Compound 9A to the phase transfer catalyst is from about 1:0.05 to about 1:0.8. In some embodiments, the molar ratio of Compound 9A to the phase transfer catalyst is from about 1:0.05 to about 1:0.7. In some embodiments, the molar ratio of Compound 9A to the phase transfer catalyst is from about 1:0.05 to about 1:0.6. In some embodiments, the molar ratio of Compound 9A to the phase transfer catalyst is from 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 from about 1:0.05 to about 1:0.4. In some embodiments, the molar ratio of Compound 9A to the phase transfer catalyst is from 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 the phase transfer catalyst to the base in the alkylation step is from about 1:0.05:5 to about 1:0.4:25. In some embodiments, the molar ratio of Compound 9A to the phase transfer catalyst to the base in the alkylation step is from about 1:0.1:10 to about 1:0.2:20. In some embodiments, the molar ratio of Compound 9A to the phase transfer catalyst to the 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 the solvents 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 referred to 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 referred to 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 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 a quaternary ammonium salt selected from 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 the bases described herein or mixtures thereof.

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

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

Claims

1. 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-thiazole-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof 【Chemical Formula 78】 A method for preparing the same, comprising (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazole-2-amine (Compound 9A) or a salt thereof 【Chemical Formula 79】 Reacting the compound of formula (Ii) 【Chemical Formula 80】 [wherein, LG is a leaving group] in the presence of a solvent for the alkylation step, a phase transfer catalyst, a base for the alkylation step, and water to effect alkylation 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-thiazole-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof, wherein the solvent for the alkylation step is methyl tert-butyl ether (MTBE) or a mixture of MTBE and toluene, and the base for the alkylation step is an alkali metal hydroxide, A method.

2. The method according to claim 1, wherein the compound of formula (Ii) and Compound 9A are present in equimolar amounts.

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

4. The method according to claim 1, wherein the compound of formula (Ii) is present in a 30% ± 5% molar excess compared to compound 9A.

5. The method according to claim 1, wherein the compound of formula (Ii) is present in a 25% ± 5% molar excess compared to compound 9A.

6. The method according to claim 1, wherein the compound of formula (Ii) is present in a 20% ± 5% molar excess compared to compound 9A.

7. The method according to any one of claims 1 to 6, wherein compound 9A and the phase transfer catalyst are present in equimolar amounts.

8. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst is from 1:0.05 to 1:0.

9.

9. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst is from 1:0.05 to 1:0.

8.

10. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst is from 1:0.05 to 1:0.

7.

11. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst is from 1:0.05 to 1:0.

6.

12. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst is from 1:0.05 to 1:0.

5.

13. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst is from 1:0.05 to 1:0.

4.

14. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst is from 1:0.1 to 1.3:0.

2.

15. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst is 1:0.

15.

16. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst to the base in the alkylation step is 1:0.05:5 to 1:0.4:

25.

17. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst to the base in the alkylation step is 1:0.1:10 to 1:0.2:

20.

18. The method according to any one of claims 1 to 6, wherein the molar ratio of compound 9A to the phase transfer catalyst to the base in the alkylation step is 1:0.15:

16.

19. The method according to any one of claims 1 to 18, wherein the phase transfer catalyst is a quaternary ammonium salt.

20. The method according to any one of claims 1 to 18, wherein the phase transfer catalyst is a quaternary ammonium salt selected from tricaprylylmethylammonium chloride (Aliquat 336), tetra-n-butylammonium bromide (TBAB), benzyltriethylammonium chloride (BTAC), 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.

21. The method according to any one of claims 1 to 18, wherein the phase transfer catalyst is tetra-n-butylammonium bromide (TBAB).

22. The method according to any one of claims 1 to 21, wherein the alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide.

23. The method according to any one of claims 1 to 21, wherein the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide.

24. The method according to any one of claims 1 to 21, wherein the alkali metal hydroxide is potassium hydroxide.

25. Alkylation is forming a first alkylation mixture at a first alkylation temperature, comprising a solvent for the alkylation step, the alkylation catalyst, and Compound 9A; adding the base for the alkylation step and the compound of formula (Ii) to the first alkylation mixture at the first alkylation temperature to form a biphasic alkylation mixture at a second alkylation temperature The method according to any one of claims 1 to 24, further comprising.

26. The method according to claim 25, further comprising heating the first alkylation mixture comprising a solvent for the alkylation step, the alkylation catalyst, and Compound 9A to a temperature of 40°C to 75°C and then cooling to the first alkylation temperature.

27. The method according to claim 25, further comprising heating the first alkylation mixture comprising a solvent for the alkylation step, the alkylation catalyst, and Compound 9A to a temperature of 55°C to 65°C and then cooling to the first alkylation temperature.

28. The method according to claim 25, further comprising heating the first alkylation mixture comprising a solvent for the alkylation step, the alkylation catalyst, and Compound 9A to a temperature of 60°C and then cooling to the first alkylation temperature.

29. The method according to any one of claims 25 to 28, wherein the addition of the base in the alkylation step to the first alkylation mixture is carried out as an aqueous solution of the base in the alkylation step.

30. The method according to any one of claims 25 to 28, wherein the addition of the base in the alkylation step to the first alkylation mixture is carried out as an aqueous solution of the base in the alkylation step, and the concentrations of the base and water in the alkylation step are 40 to 60 in units of weight / weight percent (% w / w).

31. The method according to any one of claims 25 to 28, wherein the addition of the base in the alkylation step to the first alkylation mixture is carried out as an aqueous solution of the base in the alkylation step, and the concentrations of the base and water in the alkylation step are 45 to 55 in units of weight / weight percent (% w / w).

32. The method according to any one of claims 25 to 28, wherein the addition of the base in the alkylation step to the first alkylation mixture is carried out as an aqueous solution of the base in the alkylation step, and the concentrations of the base and water in the alkylation step are 52 to 53 in units of weight / weight percent (% w / w).

33. The method according to any one of claims 25 to 28, wherein the addition of the base in the alkylation step to the first alkylation mixture is carried out as an aqueous solution of the base in the alkylation step, and the concentration of the base and water in the alkylation step is 52.4 in units of weight / weight percent (% w / w).

34. The method according to any one of claims 25 to 33, wherein 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 solvent of the alkylation step.

35. 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 solvent of the alkylation step, and the concentration of the compound of formula (Ii) in the solvent of the alkylation step is 65 to 90 in units of weight / weight percent (% w / w). The method according to any one of claims 25 to 33.

36. 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 solvent of the alkylation step, and the concentration of the compound of formula (Ii) in the solvent of the alkylation step is 75 to 85 in units of weight / weight percent (% w / w). The method according to any one of claims 25 to 33.

37. 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 solvent of the alkylation step, and the concentration of the compound of formula (Ii) in the solvent of the alkylation step is 80 in units of weight / weight percent (% w / w). The method according to any one of claims 25 to 33.

38. The addition of the base of the alkylation step and the compound of formula (Ii) to the first alkylation mixture is carried out simultaneously at a rate that maintains the first alkylation temperature. The method according to any one of claims 25 to 37.

39. The addition of the base of the alkylation step and the compound of formula (Ii) to the first alkylation mixture is carried out sequentially at a rate that maintains the first alkylation temperature. The method according to any one of claims 25 to 37.

40. During each addition, at a rate that maintains the first alkylation temperature, the base of the alkylation step is added to the first alkylation mixture, and subsequently the compound of formula (Ii) is added, thereby being carried out sequentially. The method according to claim 39.

41. The method according to any one of claims 25 to 40, wherein the first alkylation temperature is -15°C to 15°C.

42. The method according to any one of claims 25 to 40, wherein the first alkylation temperature is -10°C to 10°C.

43. The method according to any one of claims 25 to 40, wherein the first alkylation temperature is -5°C to 7°C.

44. The method according to any one of claims 25 to 40, wherein the first alkylation temperature is 0°C to 5°C.

45. The method according to any one of claims 25 to 44, wherein the second alkylation temperature is -10°C to 20°C.

46. The method according to any one of claims 25 to 44, wherein the second alkylation temperature is -5°C to 15°C.

47. The method according to any one of claims 25 to 44, wherein the second alkylation temperature is 0°C to 10°C.

48. The method according to any one of claims 25 to 44, wherein the second alkylation temperature is 4°C to 6°C.

49. The LG is C １ to C ４ alkylsulfonyloxy, C ６ to C １０ arylsulfonyloxy, halogen, and hydroxy, where C １ to C ４ alkylsulfonyloxy and C ６ to C １０ arylsulfonyloxy are each C １ to C ４ alkyl, C １ to C ４ alkoxy, halogen, C １ to C ４ haloalkyl, C １ to C ４The method according to any one of claims 1 to 48, optionally substituted with one or more groups selected from the group consisting of haloalkoxy and nitro.

50. The compound of formula (Ii) is a compound of the following formula 【Chemical formula 81】 [wherein the alkyl group is C １ ~C ４ alkoxy, halogen, C １ ~C ４ haloalkyl, C １ ~C ４ haloalkoxy, and optionally substituted with one or more groups selected from the group consisting of nitro] The method according to any one of claims 1 to 48.

51. The method according to claim 50, wherein the alkyl group is optionally substituted with one or more fluoro groups.

52. The method according to claim 50, wherein the alkyl group is optionally substituted with three fluoro groups.

53. The compound of formula (Ii) is a compound of the following formula 【Chemical formula 82】 [wherein R １ａ 、R ２ａ 、and R ３ａ are each independently H, C １ ~C ４ alkyl, C １ ~C ４ alkoxy, halogen, C １ ~C ４ haloalkyl, C １ ~C ４ haloalkoxy, and selected from the group consisting of nitro] The method according to any one of claims 1 to 48.

54. R １ａ 、R ２ａ 、and R ３ａThe method according to claim 53, wherein each is independently selected from the group consisting of H, methyl, methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, trifluoromethoxy, and nitro.

55. R １ａ R ２ａ and R ３ａ The method according to claim 53, wherein each is independently selected from the group consisting of H, methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, and nitro.

56. R １ａ R ２ａ and R ３ａ The method according to claim 53, wherein each is independently selected from the group consisting of H, methyl, fluoro, trifluoromethyl, trifluoromethoxy, and nitro.

57. R １ａ R ２ａ and R ３ａ The method according to claim 53, wherein each is independently selected from the group consisting of H and methyl.

58. The method according to any one of claims 1 to 48, wherein LG is halogen.

59. The method according to any one of claims 1 to 48, wherein LG is Cl, Br, or I.

60. The method according to any one of claims 1 to 48, wherein LG is Br.

61. The method according to any one of claims 1 to 48, wherein the compound of formula (Ii) is selected from the group consisting of propargyl bromide, propargyl chloride, propargyl alcohol, propargyl methanesulfonate, propargyl trifluoromethanesulfonate, propargyl benzenesulfonate, and propargyl p-toluenesulfonate.

62. The method according to any one of claims 1 to 48, wherein the compound of formula (Ii) is selected from the group consisting of propargyl bromide, propargyl methanesulfonate, propargyl trifluoromethanesulfonate, propargyl benzenesulfonate, and propargyl p-toluenesulfonate.

63. The method according to any one of claims 1 to 48, wherein the compound of formula (Ii) is propargyl bromide.

64. The method according to any one of claims 1 to 63, wherein the alkylation is carried out under stirring.

65. The method according to any one of claims 1 to 63, wherein the alkylation is carried out under vigorous stirring.

66. (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof 【Chemical Formula 83】 with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) or a tautomeric form thereof 【Chemical Formula 84】 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, by the step of The method according to any one of claims 1 to 65, further comprising 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.

67. A compound of formula (Ig) or a salt thereof 【Chemical Formula 85】 [wherein, R １ｃ 、R ２ｃ 、and R ３ｃ are each independently selected from H, C １ to C ６ alkoxy, C １ to C ６ alkyl, C １ to C ６ haloalkyl, and halogen] is deprotected 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, The method according to claim 66, further comprising the preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof.

68. A compound of formula (Ie) 【Chemical Formula 86】 [wherein, R １ｃ 、R ２ｃ 、and R ３ｃ are each independently selected from H, C １ to C ６ alkoxy, C １ to C ６ alkyl, C １ to C ６ haloalkyl, and halogen] is reduced 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 method according to claim 67, further comprising the preparation of a compound of formula (Ig) or a salt thereof.

69. 2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A) 【Chemical Formula 87】 with a compound of formula (Ic) or a salt thereof 【Chemical Formula 88】 [wherein, R １ｃ , R ２ｃ , and R ３ｃ are each independently selected from H, C １ ~C ６ alkoxy, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, and halogen] and condensing in the presence of an acid of the condensation step and a solvent of the condensation step to form a compound of formula (Ie), The method according to claim 68, further comprising the preparation of a compound of formula (Ie).

70. 2-Cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A) 【Chemical Formula 89】 Reacting in the presence of a solvent for the reaction step with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene to form 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), The method according to claim 69, further comprising the preparation of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A).

71. 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-thiazole-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof, the method according to any one of claims 1 to 70.

72. A method for forming a pharmaceutical composition comprising 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-thiazole-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof, comprising the method according to any one of claims 1 to 71, and further comprising the step of formulating said 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-thiazole-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof, to form said pharmaceutical composition.

73. The method according to claim 72, wherein the step of formulating comprises mixing 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-thiazole-2-amine, or a pharmaceutically acceptable salt thereof, with a pharmaceutical excipient.

74. The method according to any one of claims 1 to 73, wherein 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-thiazole-2-amine (Compound 1) is a free base.

75. The method according to claim 74, wherein 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-thiazole-2-amine (Compound 1) is crystalline.

76. The method according to claim 75, wherein 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-thiazole-2-amine (Compound 1) is in anhydrous crystalline Form I.

Images