PIKfyve inhibitors

Patent metadata

Field	Value
Publication number	US-12030896-B2
Application number	US-201917255810-A
Country	US
Kind code	B2
Filing date	Jul 1, 2019
Priority date	Jul 5, 2018
Publication date	Jul 9, 2024
Grant date	Jul 9, 2024

Abstract

The present application provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein Y, Ar, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described herein. Methods of making these compounds and methods of using these compound for treating diseases such as cancer are also provided.

First claim

What is claimed is:

1. A compound selected from:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from H and C 1-6 alkyl optionally substituted with OR a2 ;
R 2 is C 1-6 alkyl optionally substituted with OR a2 ; or
R 1 and R 2 together form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected R 8 ;
each R 8 is selected from C 1-6 alkyl and OR a2 ;
R a2 is selected from H and C 1-6 alkyl;
R 3 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R 7 is selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 S(O) 2 R b1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;
R a1 , R c1 , and R d1 are each independently selected from H, C 1-6 alkyl, and C 1-4 haloalkyl;
each R b1 is independently selected from C 1-6 alkyl and C 1-4 haloalkyl;
R A is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
R B is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
R C is selected from C 6-10 aryl, 5-membered heteroaryl, and 7-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, OR a3 , NR c3 R d3 NR c3 C(O)R b3 , and NR c3 S(O) 2 R b3 ;
R a3 , R c3 , and R d3 are each independently selected from H, C 1-6 alkyl, and C 1-4 haloalkyl; and
each R b3 is independently selected from C 1-6 alkyl and C 1-4 haloalkyl.

2. The compound of claim 1 , wherein:
R 1 and R 2 together with N to which they are attached form a ring selected from morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, and 3-oxa-8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1, 2, or 3 independently selected R 8 ;
R 3 and R 4 are each H;
R 7 is selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, OR a1 , NR c1 R d1 NR c1 C(O)R b1 , and NR c1 S(O) 2 R b1 ;
R A is H;
R B is H; and
R C is selected from phenyl, indolyl, pyrrolyl, benzofuranyl, and thiophenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from methyl, trifluoromethyl, methoxy, fluoro, chloro, bromo, CN, NO 2 , amino, dimethylamino, NHC(O)CH 3 , and NHS(O) 2 CH 3 .

3. The compound of claim 1 , wherein:
R 1 is selected from H and C 1-6 alkyl optionally substituted with OR a2 ;
R 2 is C 1-6 alkyl optionally substituted with OR a2 ; R 3 and R 4 are each H;
each R 7 is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , and NR c1 S(O) 2 R b1 ; R A is H;
R B is H; and
R C is selected from phenyl, indolyl, pyrrolyl, benzofuranyl, and thiophenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from methyl, trifluoromethyl, methoxy, fluoro, chloro, bromo, CN, NO 2 , amino, dimethylamino, NHC(O)CH 3 , and NHS(O) 2 CH 3 .

4. The compound of claim 1 , wherein:
R 1 and R 2 together with N to which they are attached form a ring selected from morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, and 3-oxa-8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with 1, 2, or 3 independently selected R 8 ;
R 3 and R 4 are each H;
each R 7 is selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, OR a1 , NR c1 R d1 , NR c1 C(O)R b1 , and NR c1 S(O) 2 R b1 ;
R A is H;
R B is H; and
R C is selected from phenyl, indolyl, pyrrolyl, benzofuranyl, and thiophenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from methyl, trifluoromethyl, methoxy, fluoro, chloro, bromo, CN, NO 2 , amino, dimethylamino, NHC(O)CH 3 , and NHS(O) 2 CH 3 .

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

Ex

No.
Structure

 3

or a pharmaceutically acceptable salt thereof.

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

7. A method of:
inhibiting phosphatidylinositol-3-phosphate 5-kinase type III (PIKfyve) in a glioblastoma, malignant peripheral nerve sheath tumor (MPNST) or colorectal cancer cell; and/or
inducing cytoplasmic vacuolization in a glioblastoma, malignant peripheral nerve sheath tumor (MPNST) or colorectal cancer cell; and/or
blocking secretion of IL12/23 in a cell; and/or
inhibiting phosphatidylinositol-3-phosphate 5-kinase type III (PIKfyve) in a subject; and/or
inducing cytoplasmic vacuolization in a glioblastoma, malignant peripheral nerve sheath tumor (MPNST) or colorectal cancer cell of a subject; and/or
treating a cancer in a subject; and/or
treating an inflammatory disease or condition in a subject;
the method comprising contacting the cell with an effective amount of, or administering to a subject in need thereof a therapeutically effective amount of, a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R B is H; and R C is selected from indolyl, pyrrolyl, and benzofuranyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, OR a3 , NR c3 R d3 , and NR c3 C(O)R b3 .

9. The compound of claim 1 , wherein R B is H; and R C is indolyl.

10. The compound of claim 1 , wherein R B is H; and R C is selected from indolyl, pyrrolyl, and benzofuranyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, OR a3 , NR c3 R d3 , and NR c3 C(O)R b3 .

11. The compound of claim 8 , wherein R B is H; and R C is selected from indolyl, pyrrolyl, and benzofuranyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, and OR a3 .

12. The compound of claim 11 , wherein R B is H; and R C is selected from indolyl, and pyrrolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

13. The compound of claim 12 , wherein R B is H; and R C is selected from indolyl, and pyrrolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, and C 1-6 alkyl.

14. The compound of claim 13 , wherein R B is H; and R C is indolyl optionally subst

Assignees

• Mayo Found Medical Education & Res
• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Bram Richard J
• Pinkerton Anthony B
• Serguienko Eduard

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title