Thieno pyrimidines as ferroportin inhibitors

Patent metadata

Field	Value
Publication number	US-12559502-B2
Application number	US-202117921905-A
Country	US
Kind code	B2
Filing date	Apr 28, 2021
Priority date	Apr 28, 2020
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

The subject matter described herein is directed to ferroportin inhibitor compounds of Formula I and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of administering the compounds for prophylaxis and/or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload states, such as thalassemia, sickle cell disease and hemochromatosis, and also kidney injuries.

First claim

That which is claimed:

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein,
R A1 and R A2 are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl, halogen, and 5- or 6-membered heteroaryl;
Z is N or CH;
R 6 , in each instance, is selected from the group consisting of halogen, hydroxy, C 1 -C 3 alkoxy, hydroxy-C 1 -C 10 alkoxy, —O—(C 1 -C 6 alkyl) y -R bb , C 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl;
R bb is 4- to 7-membered monocyclic or bridged heterocyclyl, 5- or 6-membered monocyclic heteroaryl or —NR G R H ; wherein,
said heterocyclyl and heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 alkyl, and
R G and R H are each independently hydrogen or C 1 -C 3 alkyl;

y is 0 or 1;

n is 0, 1, 2, or 3;
Y 1 is absent or present,
Y 1 , if present, and Y 2 , and Y 3 are each independently selected from the group consisting of N, CH, and C (when R 6 is attached thereto);
R 3 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, and hydroxy-C 1 -C 3 alkyl;
R 4 is selected from the group consisting of

wherein,
R 4a is hydrogen or C 1 -C 6 alkyl;
R 4b is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 5 -C 10 cycloalkyl, 5- to 7-membered heterocyclyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; or
R 4a and R 4b taken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl;
R 4c is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, and hydroxy-C 1 -C 3 alkyl;
R 4d is hydrogen or C 1 -C 3 alkyl; or
R 4c and R 4d taken together with the atom to which each is attached form a C 3 -C 6 cycloalkyl or 5- to 7-membered heterocyclyl;
R 4e is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 5 -C 10 cycloalkyl, 5- to 7-membered heterocyclyl, and C 6 -C 10 aryl;
R 4f is hydrogen or C 1 -C 3 alkyl; or
R 4e and R 4f taken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl;
R 4g is selected from the group consisting of C 1 -C 6 alkyl, C 5 -C 10 cycloalkyl, 5- to 7-membered heterocyclyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl;
 wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 4b , R 4c , R 4e , and R 4g is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, hydroxy, and C 1 -C 3 alkoxy; and,

wherein the compound of Formula (I) is not:
N-(2-methoxyethyl)-5,6-dimethyl-2-(pyridin-2-yl) thieno[2,3-d]pyrimidin-4-amine;

or a salt thereof.

2 . The compound of claim 1 , wherein Z is N.

3 . The compound of claim 1 , wherein R 3 is C 1 -C 3 alkyl.

4 . The compound of claim 1 , wherein R 3 is methyl.

5 . The compound of claim 1 , wherein Y 1 , Y 2 , and Y 3 are each CH.

6 . The compound of claim 1 , wherein n is 0.

7 . The compound of claim 1 , wherein R A1 and R A2 are each independently C 1 -C 3 alkyl.

8 . The compound of claim 1 , wherein R A1 and R A2 are each methyl.

9 . The compound of claim 1 , wherein R 4 is

10 . The compound of claim 9 , wherein R 4g is C 1 -C 3 alkyl.

11 . The compound of claim 9 , wherein R 4g is methyl.

12 . The compound of claim 1 , wherein R 4 is

13 . The compound of claim 12 , wherein R 4a is hydrogen or C 1 -C 3 alkyl.

14 . The compound of claim 12 , wherein R 4a is hydrogen.

15 . The compound of claim 12 , wherein R 4a is methyl.

16 . The compound of claim 1 , wherein R 4b is C 1 -C 3 alkyl.

17 . The compound of claim 1 , wherein R 4b is methyl.

18 . The compound of claim 1 , wherein R 4b is phenyl or 5- or 6-membered heteroaryl, optionally substituted with one or two substituents each independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, and C 1 -C 3 alkoxy.

19 . The compound of claim 18 , wherein R 4b is phenyl, optionally substituted with C 1 -C 3 alkoxy.

20 . The compound of claim 18 , wherein R 4b is phenyl, substituted once with methoxy.

21 . The compound of claim 18 , wherein R 4b is 5- or 6-membered heteroaryl.

22 . The compound of claim 21 , wherein R 4b is pyridinyl.

23 . The compound of claim 1 , wherein R 4c and R 4d are each hydrogen.

24 . The compound of claim 1 , wherein R 4 is

25 . The compound of claim 24 , wherein R 4e and R 4f taken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl, optionally substituted with one or two substituents each independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, and C 1 -C 3 alkoxy.

26 . The compound of claim 24 , wherein R 4e and R 4f taken together with the atom to which each is attached form a pyrrolidonyl.

27 . The compound of claim 12 , wherein R 6 is —O—CH 2 CH 2 —OH.

28 . The compound of claim 27 , wherein
R 4a , R 4c , and R 4d are each hydrogen; and, R 4b is selected from the group consisting of pyridinyl, phenyl, cyclopropyl and C 1 -C 6 alkyl, wherein,
the pyridinyl, phenyl or cyclopropyl of R 4b is optionally substituted with one or two substitutents selected from the group consisting of fluoro, methyl, —CF 3 and methoxy.

29 . The compound of claim 12 , wherein R 6 is —O—CH 2 CH 2 —R bb .

30 . The compound of claim 28 , wherein R bb is selected from the group consisting of —N(CH 3 ) 2 , morpholinyl, piperazinyl, tetrahydropyrrolyl, imidazolyl, and

wherein, the morpholinyl, piperazinyl, imidazolyl or tetrahydropyrrolyl of R bb is optionally substituted with one or two substitutents selected from the group consisting of halogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl and C 1 -C 6 alkoxy.

31 . The compound of claim 30 , wherein
R 4a , R 4c , and R 4d are each hydrogen; and, R 4b is selected from the group consisting of pyridinyl, phenyl, cyclopropyl and C 1 -C 6 alkyl, wherein,
the pyridinyl, phenyl or cyclopropyl of R 4b is optionally substituted with one or two substitutents selected from the group consisting of fluoro, methyl, —CF 3 and methoxy.

32 . The compound of claim 28 , wherein Y 1 is absent.

33 . The compound of claim 32 , having the Formula Ia:

34 . The compound of claim 1 , or

Assignees

• Global Blood Therapeutics Inc

Inventors

• Xu Qing
• Li Zhe
• Nilar Shahul

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P13/00

  Drugs for disorders of the urinary system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title