Claims for Patent: 12,582,634

Summary for Patent: 12,582,634

Title:	Synthetic methods for preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-n-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-n-prop-2-ynyl-1,3-thiazol-2-amine
Abstract:	The present disclosure relates to the fields of chemistry and medicine, more particularly to processes for making 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), pharmaceutically acceptable salts, and crystalline forms thereof, for the treatment of congenital adrenal hyperplasia (CAH).
Inventor(s):	Andrew Becker, Scott Stirn, Joel Radisson, Christina Marie COSTA
Assignee:	Sanofi SA , Neurocrine Biosciences Inc
Application Number:	US17/782,617
Patent Claims:	1. A process for preparing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof: comprising: alkylating (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof: with a Compound of Formula (Ii): wherein: LG is a leaving group; in the presence of an alkylating-step solvent, a phase-transfer catalyst, an alkylating-step base, and water to form 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof. 2. The process according to claim 1, wherein the Compound of Formula (Ii) is present in a molar excess compared to Compound 9A. 3. The process according to claim 1, wherein the Compound of Formula (Ii) is present in about 20% molar excess compared to Compound 9A. 4. The process according to claim 1, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.05 to about 1:0.5. 5. The process according to claim 1, wherein the molar ratio between Compound 9A and the phase-transfer catalyst is about 1:0.1 to about 1.3:0.2. 6. The process according to claim 1, wherein the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.05:5 to about 1:0.4:25. 7. The process according to claim 1, wherein the molar ratio between Compound 9A, the phase-transfer catalyst, and the alkylating-step base is about 1:0.1:10 to about 1:0.2:20. 8. The process according to claim 1, wherein the alkylating-step solvent is selected from a halogenated solvent, an ether solvent, an aprotic solvent, and mixtures thereof. 9. The process according to claim 1, wherein the alkylating-step solvent 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, heptanes, n-heptane, ethylbenzene, o-xylene, m-xylene, p-xylene, mixtures of xylenes, octane, and mixtures thereof. 10. The process according to claim 1, wherein the alkylating-step solvent is selected from: methyl tert-butyl ether (MTBE), toluene, and mixtures thereof. 11. The process according to claim 1, wherein the phase-transfer catalyst is a quaternary ammonium salt. 12. The process according to claim 1, wherein the phase-transfer catalyst is a quaternary ammonium salt selected from: tricaprylyl methyl ammonium chloride (Aliquat 336), tetra-n-butylamnmonium bromide (TBAB), benzyltriethylammonium chloride (BTEAC), cetyltrimethylammonium bromide (CTAB), tetra-n-butylammonium chloride (TBAC), tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride (TEAC), benzyltributylammonium chloride (BTBAC), cetyltrimethylammonium chloride (CTAC), tetramethylammonium chloride, cetyltrimethylammonium chloride (CTAC), octyltrimethylammonium chloride, and combinations thereof. 13. The process according to claim 1, wherein the phase-transfer catalyst is tetra-n-butylammonium bromide (TBAB). 14. The process according to claim 1, wherein the alkylating-step base is an alkali metal hydroxide. 15. The process according to claim 1, wherein the alkylating-step base is potassium hydroxide. 16. The process according to claim 1, wherein alkylating further comprises the steps of: forming a first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A at a first-alkylating temperature; and adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture at the first-alkylating temperature to form an alkylating-biphasic mixture at a second-alkylating temperature. 17. The process according to claim 16, further comprising heating first-alkylating mixture comprising the alkylating-step solvent, the alkylating-catalyst, and Compound 9A to a temperature of about 55° C. to about 65° C. and subsequently cooling to the first-alkylating temperature. 18. The process according to claim 16, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water. 19. The process according to claim 16, wherein adding the alkylating-step base to the first-alkylating mixture is conducted as a solution of the alkylating-step base in water and the concentration in terms of percent weight/weight (% w/w) of the alkylating-step base and water is about 52 to about 53. 20. The process according to claim 16, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent. 21. The process according to claim 16, wherein adding the Compound of Formula (Ii) to the first-alkylating mixture is conducted as a solution of the Compound of Formula (Ii) in the alkylating-step solvent and the concentration in terms of percent weight/weight (% w/w) of the Compound of Formula (Ii) in the alkylating-step solvent is about 75 to about 85. 22. The process according to claim 16, wherein adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture is conducted concurrently at a rate to maintain the first-alkylating temperature. 23. The process according to claim 16, wherein adding the alkylating-step base and the Compound of Formula (Ii) to the first-alkylating mixture is conducted serially at a rate to maintain the first-alkylating temperature. 24. The process according to claim 16, wherein the first-alkylating temperature is about −5° C. to about 7° C. 25. The process according to claim 16, wherein the second-alkylating temperature is about 0° C. to about 10° C. 26. The process according to claim 1, wherein the LG is selected from the group: C1-C4 alkylsulphonyloxy, C6-C10 arylsulfonyloxy, halogen, and hydroxy; wherein C1-C4 alkylsulphonyloxy and C6-C10 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. 27. The process according to claim 1, wherein LG is halogen. 28. The process according to claim 1, 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. 29. The process according to claim 1, wherein the Compound of Formula (Ii) is propargyl bromide. 30. The process according to claim 1, wherein alkylating is conducted with stirring. 31. The process according to claim 1, further comprising preparing (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof, by the step of: cyclizing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof: with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) or a tautomeric form thereof: in the presence of a cyclizing-step solvent to form (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof. 32. The process according to claim 31, further comprising preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof, comprising: deprotecting a Compound of Formula (Ig), or a salt thereof: wherein: R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen; in the presence of a deprotecting-catalyst, hydrogen, and a deprotecting-step solvent to form (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof. 33. The process according to claim 32, further comprising preparing a Compound of Formula (Ig), or a salt thereof, comprising: reducing a Compound of Formula (Ie): wherein: R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen; in the presence of a reducing-catalyst, hydrogen, and a reducing-step solvent to form the Compound of Formula (Ig), or a salt thereof. 34. The process according to claim 33, further comprising preparing a Compound of Formula (Ie), comprising: condensing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A): with a Compound of Formula (Ic), or salt thereof: wherein: R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen; in the presence of a condensing-step acid and a condensing-step solvent to form the Compound of Formula (Ie). 35. The process according to claim 34, further comprising preparing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A), by the step of: reacting 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A): with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a reacting-step solvent to form 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A). 36. The process according to claim 1, further comprising the step of isolating 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof. 37. The process according to claim 1, further comprising the step of formulating 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof, to form a pharmaceutical composition. 38. The process according to claim 37, wherein the step of formulating comprises admixing 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, with a pharmaceutical excipient. 39. The process according to claim 1, 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-thiazol-2-amine (Compound 1) is the free base. 40. The process according to claim 1, 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-thiazol-2-amine (Compound 1) is crystalline. 41. The process according to claim 1, 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-thiazol-2-amine (Compound 1) is anhydrous crystalline Form I. 42. A process for preparing (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof: comprising: cyclizing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof: with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound 8A) or a tautomeric form thereof: in the presence of a cyclizing-step solvent to form (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A) or a salt thereof. 43. A process for preparing (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof: comprising: deprotecting a Compound of Formula (Ig), or a salt thereof: wherein R1c, R2c and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen; in the presence of a deprotecting-catalyst, hydrogen, and a deprotecting-step solvent to form (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) or a salt thereof. 44. A process for preparing a Compound of Formula (Ig), or a salt thereof: wherein R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen; comprising: reducing a Compound of Formula (Ie): in the presence of a reducing-catalyst, hydrogen, and a reducing-step solvent to form the Compound of Formula (Ig), or a salt thereof. 45. A process for preparing a Compound of Formula (Ie): wherein: R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-6 haloalkyl, and halogen; comprising: condensing 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A): with a Compound of Formula (Ie), or a salt thereof: in the presence of a condensing-step acid and a condensing-step solvent to form the Compound of Formula (Ie). 46. An anhydrous crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base), wherein the anhydrous crystalline form has an X-ray powder diffraction (XRPD) pattern comprising at least three peaks, in terms of 2θ, 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°. 47. A crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, tosylate salt) wherein the anhydrous crystalline form has an X-ray powder diffraction XRPD pattern comprising at least three peaks in terms of 2θ, 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°. 48. A pharmaceutical composition comprising a crystalline form (Compound 1, free base) according to claim 46, and a pharmaceutically acceptable carrier. 49. A pharmaceutical composition comprising a crystalline form (Compound 1, tosylate salt) according to claim 47, and a pharmaceutically acceptable carrier. 50. A composition comprising: a. 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof; and b. at least one compound selected from: (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa); (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb); and ethanol; wherein the compound in the composition contains no more than: 0.8% of Compound IIa; 0.15% of Compound IIb; and 500 ppm of ethanol. 51. A Compound of Formula (Ie): wherein: R1c, R2c, and R3c are each independently selected from: H, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. 52. A Compound of Formula (g) or a salt thereof: wherein: R1c, R2c, and R3c are each independently selected from: H, C1-6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and halogen. 53. A process for preparing a pharmaceutical composition comprising admixing a crystalline form (Compound 1, free base) according to claim 46; a crystalline form (Compound 1, tosylate base) according to claim 47; or a composition according to claim 50; and a pharmaceutically acceptable carrier. 54. The composition according to claim 50, 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-thiazol-2-amine (Compound 1) is a free base. 55. The composition according to claim 50, wherein the composition contains at least 97% 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). 56. The composition according to claim 50, wherein the composition contains at least 98% 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). 57. The composition according to claim 50, wherein the composition contains at least 99% 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). 58. The composition according to claim 50, wherein Compound IIa is present, and the composition contains no more than 0.7% of Compound IIa. 59. The composition according to claim 50, wherein Compound IIa is present, and the composition contains no more than 0.6% of Compound IIa. 60. The composition according to claim 50, wherein Compound IIb is present, and the composition contains no more than 0.1% of Compound IIb. 61. The composition according to claim 50, wherein Compound IIb is present, and the composition contains no more than 0.05% of Compound IIb. 62. The composition according to claim 50, wherein ethanol is present, and the composition contains no more than 3000 ppm of ethanol. 63. The composition according to claim 50, wherein ethanol is present, and the composition contains no more than 1000 ppm of ethanol. 64. The composition according to claim 50, 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-thiazol-2-amine (Compound 1) is an anhydrous crystalline form. 65. The composition according to claim 50, further comprising a pharmaceutically acceptable excipient. 66. The composition according to claim 54, further comprising a pharmaceutically acceptable excipient. 67. A 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-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof; and (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-A-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa). 68. The composition according to claim 67, 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-thiazol-2-anine (Compound 1) is a free base. 69. The composition according to claim 67, wherein the composition contains at least 97% 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). 70. The composition according to claim 67, wherein the composition contains at least 98% 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). 71. The composition according to claim 67, wherein the composition contains at least 99% 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). 72. The composition according to claim 67, wherein the composition contains no more than 0.8% of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa). 73. The composition according to claim 67, wherein the composition contains no more than 0.7% of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa). 74. The composition according to claim 67, wherein the composition contains no more than 0.6% of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa). 75. The composition according to claim 67, wherein the composition further comprises Compound 9A. 76. The composition according to claim 75, wherein the composition comprises no more than 0.3% of Compound 9A. 77. The composition according to claim 75, wherein the composition comprises no more than 0.2% of Compound 9A. 78. The composition according to claim 75, wherein the composition comprises no more than 0.1% of Compound 9A. 79. The composition according to claim 67, wherein the composition further comprises Compound IIb. 80. The composition according to claim 79, wherein the composition comprises no more than 0.15% of Compound IIb. 81. The composition according to claim 79, wherein the composition comprises no more than 0.1% of Compound IIb. 82. The composition according to claim 79, wherein the composition comprises no more than 0.05% of Compound IIb. 83. The composition according to claim 67, wherein the composition further comprises Compound IIc. 84. The composition according to claim 83, wherein the composition comprises no more than 0.3% of Compound IIc. 85. The composition according to claim 83, wherein the composition comprises no more than 0.2% of Compound IIc. 86. The composition according to claim 83, wherein the composition comprises no more than 0.1% of Compound IIc. 87. The composition according to claim 67, wherein the composition further comprises ethanol. 88. The composition according to claim 87, wherein the composition comprises no more than 5000 ppm of ethanol. 89. The composition according to claim 87, wherein the composition comprises no more than 3000 ppm of ethanol. 90. The composition according to claim 87, wherein the composition comprises no more than 1000 ppm of ethanol. 91. The composition according to claim 67, wherein the composition further comprises propargyl bromide. 92. The composition according to claim 91, wherein the composition comprises no more than 200 ppm of propargyl bromide. 93. The composition according to claim 91, wherein the composition comprises no more than 100 ppm of propargyl bromide. 94. The composition according to claim 91, wherein the composition comprises no more than 30 ppm of propargyl bromide. 95. The composition according to claim 67, 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-thiazol-2-amine (Compound 1) is an anhydrous crystalline form. 96. The composition according to claim 67, wherein the composition further comprises a pharmaceutically acceptable excipient. 97. The composition according to claim 68, wherein the composition further comprises a pharmaceutically acceptable excipient. 98. The composition according to claim 67, comprising: a. 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), or a pharmaceutically acceptable salt thereof; and (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(p-tolyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIa); and b. at least one compound selected from: (S)-4-(2-Chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A); (S)-4-(2-chloro-5-methyl-4-(prop-2-yn-1-yloxy)phenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(prop-2-yn-1-yl)thiazol-2-amine (Compound IIb); 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1R)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-(2-propyn-1-yl)-2-thiazolamine (Compound IIc); ethanol; and propargyl bromide; wherein the compound in the composition, when present, contains no more than: 0.8% of Compound IIa; 0.2% of Compound 9A; 0.15% of Compound IIb; 0.2% of Compound IIc; 5000 ppm of ethanol; and 30 ppm of propargyl bromide. 99. The composition according to claim 98, 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-thiazol-2-amine (Compound 1) is a free base. 100. The composition according to claim 98, 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-thiazol-2-amine (Compound 1) is an anhydrous crystalline form. 101. The composition according to claim 98, wherein the composition further comprises a pharmaceutically acceptable excipient.