Heterocyclic compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-11547697-B2
Application number	US-201816211803-A
Country	US
Kind code	B2
Filing date	Dec 6, 2018
Priority date	Aug 17, 2009
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the heterocyclic entities, and methods of using these chemical entities for treating diseases and conditions associated with PI3 kinase activity are described herein.

First claim

What is claimed is:

1. A method of inhibiting a phosphatidyl inositol-3 kinase (PI3 kinase), comprising: contacting the PI3 kinase with a therapeutically effective amount of a compound of the following formula:

or a pharmaceutically acceptable salt thereof, wherein
W 1 is CR 3 ,
W 2 is CR 4 ,
W 3 is N;
W 4 is N;
W 5 is CR 7 ;
W 6 is CR 8 ;
R 1 and R 2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
R 3 is amido of formula —C(O)N(R) 2 or —NHC(O)R, wherein R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heteroalicyclic; or wherein said (R) 2 may be taken together with the nitrogen to which they are attached to form an optionally substituted 4-, 5-, 6-, 7-, or 8-membered ring;
R 4 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
or R 3 and R 4 taken together form a cyclic moiety; and
R 5 , R 7 , and R 8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.

2. The method of claim 1 , wherein the contacting of the PI3 kinase with the compound comprises contacting a cell that expresses the PI3 kinase.

3. The method of claim 1 , wherein the PI3 kinase is PI3 kinase alpha.

4. The method of claim 2 , further comprising administering a second therapeutic agent to the cell.

5. The method of claim 1 ,
wherein the contacting of the PI3 kinase with the compound is in a subject suffering from a cancer selected from the group consisting of: breast invasive carcinoma, prostate adenocarcinoma, colon adenocarcinoma, thyroid carcinoma, bladder urothelial carcinoma, lung adenocarcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, testicular germ cell tumors, lung squamous cell carcinoma, stomach adenocarcinoma, glioblastoma multiforme, liver hepatocellular carcinoma, pancreatic adenocarcinoma, esophageal carcinoma, brain lower grade glioma, head and neck squamous cell carcinoma, rectum adenocarcinoma, cholangiocarcinoma, mesothelioma, breast cancer, lung cancer, gastric cancer, and uterine cancer.

6. The method of claim 1 , wherein
W 1 is CR 3 ;
W 2 is CR 4 ;
W 3 is N;
W 4 is N;
W 5 is CR 7 ;
W 6 is CR 8 ;
R 1 and R 2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
R 3 is amido of formula —C(O)N(R) 2 or —NHC(O)R, wherein R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heteroalicyclic; or wherein said (R) 2 may be taken together with the nitrogen to which they are attached to form an optionally substituted 4-, 5-, 6-, or 7-membered ring, and
R 4 , R 7 , and R 8 are each hydrogen.

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

or a pharmaceutically acceptable salt thereof.

8. The method of claim 5 , wherein
W 1 is CR 3 ;
W 2 is CR 4 ;
W 3 is N;
W 4 is N;
W 5 is CR 7 ;
W 6 is CR 8 ;
R 1 and R 2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
R 3 is amido of formula —C(O)N(R) 2 or —NHC(O)R, wherein R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heteroalicyclic; or wherein said (R) 2 may be taken together with the nitrogen to which they are attached to form an optionally substituted 4-, 5-, 6-, or 7-membered ring, and
R 4 , R 7 , and R 8 are each hydrogen.

9. The method of claim 5 , wherein the compound is selected from the group consisting of:

Assignees

• Millennium Pharm Inc

Inventors

• Ren Pingda
• Liu Yi
• Li Liansheng
• Chan Katrina
• Wilson Troy Edward
• Campbell Simon Fraser

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title