Synthesis of nirogacestat

Patent metadata

Field	Value
Publication number	US-2025361212-A1
Application number	US-202519061962-A
Country	US
Kind code	A1
Filing date	Feb 24, 2025
Priority date	Sep 1, 2021
Publication date	Nov 27, 2025
Grant date	—

Abstract

The present disclosures are directed to processes for synthesizing(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide (“nirogacestat”).

First claim

1 - 87 . (canceled)

88 . A composition comprising: 98.0% to 99.9% of a Compound 1:

or a pharmaceutically acceptable salt thereof; and one or more of the following:
(1) 0.7% to 0.01% of a compound of Formula II:

wherein:
R 1 is selected from the group consisting of hydrogen, fluoro, or chloro;
R 2 is selected from the group consisting of hydrogen or chloro;
R 3 is selected from the group consisting of fluoro, or chloro; and
R 4 is selected from the group consisting of −OH and −N(H)CH 2 C(CH 3 ) 3 ,

or a pharmaceutically acceptable salt thereof;
(2) 0.05% to 0.005% of imidazole, or a pharmaceutically acceptable salt thereof; or
(3) 0.7% to 0.01% of a compound of Formula II, or a pharmaceutically acceptable salt thereof, and 0.05% to 0.005% of imidazole, or a pharmaceutically acceptable salt thereof,
wherein the compound of Formula II is not Compound 1, and the percentages of Compound 1, the compound of Formula II, and/or imidazole are determined by high performance liquid chromatography.

89 . The composition of claim 88 , wherein the compound of Formula II is a hydrobromide salt.

90 . The composition of claim 88 , wherein the compound of Formula II is a compound of Formula II-A:

or a pharmaceutically acceptable salt thereof.

91 . The composition of claim 90 , wherein the compound of Formula II-A is a hydrobromide salt.

92 . The composition of claim 88 , wherein the compound of Formula II is a compound of Formula II-B:

or a pharmaceutically acceptable salt thereof.

93 . The composition of claim 92 , wherein the compound of Formula II-B is a hydrobromide salt.

94 . The composition of claim 88 , wherein the compound of Formula II is a compound of Formula II-C:

or a pharmaceutically acceptable salt thereof.

95 . The composition of claim 94 , wherein the compound of Formula II-C is a hydrobromide salt.

96 . The composition of claim 88 , wherein the compound of Formula II is a compound of Formula II-D:

or a pharmaceutically acceptable salt thereof.

97 . The composition of claim 96 , wherein the compound of Formula II-D is a hydrobromide salt.

98 . The composition of claim 88 , wherein R 4 is —N(H)CH 2 C(CH 3 ) 3 .

99 . The composition of claim 88 , wherein R 4 is —OH.

100 . The composition of claim 88 , wherein R 1 is fluoro; R 2 is hydrogen; and R 3 is chloro.

101 . The composition of claim 88 , wherein R 1 is chloro; R 2 is hydrogen; and R 3 is fluoro.

102 . The composition of claim 88 , wherein R 1 is hydrogen; R 2 is chloro; and R 3 is fluoro.

103 . The composition of claim 88 , wherein R 1 is fluoro, R 2 is hydrogen, and R 3 is fluoro.

104 - 139 . (canceled)

140 . A method of treating tumors or cancer in a subject in need thereof comprising administering to the subject a composition of claim 88 .

141 . The method of claim 140 , wherein the tumors are desmoid tumors.

142 . The method of claim 140 , wherein the cancer is multiple myeloma, a cancer having a mutation in a Notch pathway gene, adenoid cystic carcinoma, or T-cell acute lymphoblastic leukemia.

Assignees

• Springworks Therapeutics Inc

Inventors

• Patterson Kristin
• Hatcher Mark

Classifications

• C07D263/44 Primary

  Two oxygen atoms · CPC title

• C07C227/26

  from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles · CPC title

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• C07B2200/07

  Optical isomers · CPC title

• A61K31/417

  Imidazole-alkylamines, e.g. histamine, phentolamine · CPC title