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US 2024/0197678 A1Published application
Inhibitors of the peptidyl-prolyl cis/trans isomerase (pin1) and uses thereof
AssigneesDana-Farber Cancer Institute, Inc., Yeda Research And Devlopment Co. Ltd.
InventorsInchul You, Nathanael S. Gray, Tinghu Zhang, Sirano Dhe-Paganon, Nir London, Christian Dubiella
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Abstract
Disclosed are compounds which inhibit Pin1 activity, methods of making the compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds to treat diseases or disorders characterized or mediated by dysregulated Pin1 activity.
Claims20
A compound having a structure represented by formula (PIN1-3 P1) or (PIN1-3 P2):
- or a pharmaceutically acceptable salt thereof.
(canceled)
A method of making a compound of formula PIN1-3 P1:
- the method comprising:
- a) forming a first reaction mixture comprising the compound of formula 1a:
- a non-nucleophilic base, a first solvent, and a compound of formula 3:
- wherein the molar ratio of the compound of formula 1a to the compound of formula 3 is greater than 1.4, wherein the reaction mixture is mixed for at least 1.5 hours at or above room temperature under conditions suitable to form an imine;
- wherein sodium triacetoxyborohydride (STAB) is added to the reaction mixture in one portion, wherein the molar ratio of STAB to the compound of formula 3 is greater than 2.0, wherein the reaction mixture is stirred for at least 12 hours at or above room temperature, thereby forming a compound of formula 2a:
- b) forming a second reaction mixture comprising a compound of formula 2a, a non-nucleophilic base, a second solvent, and a compound of formula 4:
- wherein the molar ratio of the compound of formula 4 to the compound of formula 2a is greater than 1.2, wherein the reaction mixture is mixed for at least 30 minutes at 0° C., thereby forming the compound of formula PIN1-3 P1, or
- a method of making a compound of formula PIN1-3 P2:
- the method comprising:
- a) forming a first reaction mixture comprising the compound of formula 1b:
- a non-nucleophilic base, a first solvent, and a compound of formula 3:
- wherein the molar ratio of the compound of formula 1b to the compound of formula 3 is greater than 1.4, wherein the reaction mixture is mixed for at least 1.5 hours at or above room temperature under conditions suitable to form an imine:
- wherein sodium triacetoxyborohydride (STAB) is added to the reaction mixture in one portion, wherein the molar ratio of STAB to the compound of formula 3 is greater than 2.0, wherein the reaction mixture is stirred for at least 12 hours at or above room temperature, thereby forming a compound of formula 2b:
- b) forming a second reaction mixture comprising a compound of formula 2b, a non-nucleophilic base, a second solvent, and a compound of formula 4:
- wherein the molar ratio of the compound of formula 4 to the compound of formula 2b is greater than 1.2. wherein the reaction mixture is mixed for at least 30 minutes at 0° C., thereby forming the compound of formula PIN1-3 P2.
12 more elements
(canceled)
Dependencies are inferred from the claim text.