PI3K inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-12478616-B2
Application number	US-201917282657-A
Country	US
Kind code	B2
Filing date	Oct 4, 2019
Priority date	Oct 5, 2018
Publication date	Nov 25, 2025
Grant date	Nov 25, 2025

Abstract

The development of a new, targeted drug delivery paradigm coupled to improved PI3K inhibitors (e.g., PI3Kα inhibitors) represents a significant advance in cancer therapy. Provided herein are compounds, such as compounds of Formula (I) and (II), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The compounds provided herein are PI3K (e.g., PI3Kα) inhibitors and are therefore useful for the treatment and/or prevention of various diseases (e.g., proliferative diseases such as cancer). Also provided herein are nanoparticles and nanogels (e.g., P-selectin targeting nanoparticles) comprising PI3K inhibitors, such a compound described herein. In certain embodiments, a nanoparticle or nanogel described herein encapsulates a compound described herein for targeting delivery to cancer cells or tumors.

First claim

What is claimed is:

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, halogen, —CN, —N 3 , —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR O , —N(R N ) 2 , or —SR S ;
R 2 is hydrogen, halogen, —CN, —N 3 , —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR O , —N(R N ) 2 , —SR S , or is of the formula:

each instance of R 3 is independently halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR O , —N(R N ) 2 , —SR S , or is of the formula:

each instance of R 4 is independently halogen, —CN, —N 3 , —NO 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR O , —N(R N ) 2 , or —SR S ;
each instance of R 5 is independently hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR O , —N(R N ) 2 , or —SR S , or two R 5 are joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
R 6 is hydrogen, halogen, haloalkyl, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR O , —N(R N ) 2 , or —SR S ;
R N1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or a nitrogen protecting group;
each instance of R N2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R N2 are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
each instance of R N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R N are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
each instance of R O and R O2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group;
each instance of R S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group;
p is 0, 1, or 2;
n is 0, 1, 2, 3, 4, 5, 6, or 7; and
m is 0, 1, or 2.

2 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

8 . The compound of claim 1 , wherein R 1 is optionally substituted C 1-6 alkyl.

9 . The compound of claim 4 , wherein at least one instance of R 5 is optionally substituted C 1-6 alkyl.

10 . The compound of claim 4 , wherein R 6 is haloalkyl.

11 . The compound of claim 1 , wherein R N1 is hydrogen.

12 . The compound of claim 1 , wherein at least one instance of R N2 is hydrogen.

13 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14 . A nanoparticle comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

15 . A nanogel comprising a plurality of nanoparticles of claim 14 .

16 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer is head and neck cancer, brain cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, bladder cancer, liver cancer, sarcoma, or a hematological cancer.

17 . A method of inhibiting PI3Kα enzymatic activity in vitro comprising contacting a PI3Kα enzyme with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

18 . A method of induc

Assignees

• Sloan Kettering Inst Cancer Res
• Tri Inst Therapeutics Discovery Inst Inc

Inventors

• Fushimi Makoto
• Scaltriti Maurizio
• Heller Daniel Alan
• Monterrubio Martinez Carles
• Arruabarrena Aristorena Amaia
• Meinke Peter T
• Foley Michael Andrew
• Asano Yasutomi
• Aso Kazuyoshi
• TAKAHAGI Hiroki
• Shamay Yosef
• Baselga Torres Jose Manuel
• Sasaki Yusuke
• Michino Mayako

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K49/0065

  the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle · CPC title

• A61K49/0034

  Indocyanine green, i.e. ICG, cardiogreen · CPC title

• A61K49/0032

  Methine dyes, e.g. cyanine dyes · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title