IP Library › Granted Patent US 12,582,634
Granted Patent B2
US 12,582,634 · App. 17/782,617 · Granted Mar 24, 2026

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

Inventors: Andrew Becker (San Diego, CA); Scott Stirn (San Diego, CA); Joel Radisson (Paris, FR); Christina Marie Costa (San Diego, CA)
Assignees: Neurocrine Biosciences, Inc.; Sanofi
A61K31/426A61K9/0095A61K9/107A61K9/28A61K9/4833A61K45/06A61K47/10A61K47/14A61K47/22A61K47/26A61K47/32C07D277/42C07B2200/13
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Quick Facts
Patent No.
US 12,582,634
App. No.
17/782,617
Granted
Mar 24, 2026
Kind
B2
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).

Claims (179)

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: C 1 -C 4 alkylsulphonyloxy, C 6 -C 10 arylsulfonyloxy, halogen, and hydroxy; wherein C 1 -C 4 alkylsulphonyloxy and C 6 -C 10 arylsulfonyloxy are each optionally substituted with one or more groups selected from the group: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 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:

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;

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:

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;

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:

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;

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

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;

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

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;

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:

R 1c , R 2c , and R 3c are each independently selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1-6 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:

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.

52 . A Compound of Formula (g) or a salt thereof:

wherein:

R 1c , R 2c , and R 3c are each independently selected from: H, C 1-6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 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.

Assignments (4)
CONFIRMATORY GRANT OF SECURITY INTEREST IN UNITED STATES PATENTS Recorded May 26, 2026
From: NEUROCRINE BIOSCIENCES, INC.
To: JPMORGAN CHASE BANK, N.A.
Reel/Frame 075670/0001 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 23, 2022
From: PALMER, ANDREW; STIRN, SCOTT; COSTA, CHRISTINA MARIE
To: NEUROCRINE BIOSCIENCES, INC.
Reel/Frame 061190/0457 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 23, 2022
From: RADISSON, JOEL
To: SANOFI-AVENTIS RECHERCHE & DEVELOPPEMENT
Reel/Frame 061190/0664 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 23, 2022
From: SANOFI-AVENTIS RECHERCHE & DEVELOPPEMENT
To: SANOFI
Reel/Frame 061190/0830 →
Priority Claims (1)
WO PCT/IB2019/001325 · Dec 6, 2019 · international
Continuity (2)
Related Publication 20230018740A1 · Jan 19, 2023
Related Publication 20230286932A1 · Sep 14, 2023
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