Ferroportin inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-11286243-B2
Application number	US-201916712628-A
Country	US
Kind code	B2
Filing date	Dec 12, 2019
Priority date	Dec 13, 2018
Publication date	Mar 29, 2022
Grant date	Mar 29, 2022

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. The compounds of Formula I and pharmaceutical salts thereof have the following structure:wherein R1, R2, R3, X1, X2, X3, X4, Y1, Y2, and Y3 are as described herein.

First claim

That which is claimed:

1. A compound of Formula I:

wherein
R 1 is phenyl or a 6-membered heteroaryl, wherein the heteroaryl contains up to two ring heteroatoms, wherein the phenyl and heteroaryl are optionally substituted with one, two, three, or four substituents, each of which is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —OR 1a , —NR 1b R 1c , —N 3 , and —CN;
wherein R 1a , R 1b , and R 1c are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

R 2 and R 3 are each independently hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 taken together with the carbon to which they are attached form a C 3 -C 6 cycloalkyl;
X 1 is CR 10 and X 2 is N or CR 10 ; wherein
R 10 is selected from the group consisting of hydrogen, halogen, —CN, C 1 -C 3 alkyl, —OR 15 , and —NR 16 R 17 ; wherein
R 15 , R 16 , and R 17 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, optionally substituted C 3 -C 7 cycloalkyl, and —NR g (CO)R h ; wherein
R g and R h are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl;

X 3 and X 4 are each independently C;
Y 1 is N or NR 18 ;
Y 2 is CJ 1 ; and
Y 3 is N, O, S, CR 18 , or NR 18 ;
wherein
R 18 is hydrogen or C 1 -C 3 alkyl; and
J 1 is

wherein
R 20 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
m, n, and o are each independently 0 or 1, provided that the sum of m, n, and o is at least 1;
p, q, and r are each independently 0 or 1, provided that the sum of p, q, and r is at least 1;
each R J1a , R J1b , R J2a , R J2b , R J3a , R J3b , R J4a , R J4b , R J5a , R J5b , R J6a , and R J6b is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, and a 4- to 6-membered heterocycle; or
wherein two of R J1a , R J2a , R J3a , and R 20 or two of R J4a , R J5a , R J6a , and R 20 or on of R J1a , R J2a , and R J3a , and one of R J4a , R J5a , and R J6a take together with the atom to which they are attached form a C 3 -C 6 cycloalkyl or a 4- to 6-membered heterocycle; and

R 4 is C 6 -C 10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 15 , R 16 , and R 17 are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
Y 1 is N;
each R J1a , R J1b , R J2a , R J2b , R J3a , R J3b , R J4a , R J4b , R J5a , R J5b , R J6a , and R J6b is independently selected from the group consisting of hydrogen, fluorine, methyl, and hydroxy; or
wherein two of R J1a , R J2a , R J3a , and R 20 or two of R J4a , R J5a , R J6a , and R 20 taken together with the atom to which they are attached form a C 3 -C 6 cycloalkyl or a 4- to 6-membered heterocycle; and

R 4 is C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one, two, three, or four substituents, each of which is independently selected from the group consisting of hydrogen, C 3 -C 6 cycloalkyl, phenyl, benzyl, halo-C 1 -C 3 alkyl, 5- to 7-membered heteroaryl, (C 3 -C 6 cycloalkyl)-C 1 -C 3 alkyl, C 1 -C 6 alkyl, —C(O)O—C 1 -C 6 alkyl, halogen, —OR 4a , —CN, —C(O)NR 4b R 4c , and —NR 4b (CO)R 4c ;
wherein said phenyl or 5- to 7-membered heteroaryl is optionally substituted with one, two, or three substituents, each of which is independently selected from the group consisting of halogen, halo-C 1 -C 3 alkyl, and C 1 -C 6 alkyl;
wherein R 4a is hydrogen; and
R 4b and R 4c are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl.

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

wherein Y 3 is NR 18 , O or S.

4. The compound of claim 1 , wherein Y 3 is S or O.

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

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

7. The compound of claim 1 , wherein the compound is of Formula Ie:

8. The compound of claim 1 , wherein the compound is of Formula If:

9. The compound of claim 1 , wherein the compound is of Formula Ig:

wherein Y 1 is NR 18 , O, or S.

10. The compound of claim 1 , wherein R 1 is an optionally substituted, 6-membered heteroaryl containing one or two ring heteroatoms.

11. The compound of claim 1 , wherein R 1 is optionally substituted pyridinyl.

12. The compound of claim 1 , wherein R 2 and R 3 are each hydrogen.

13. The compound of claim 1 , wherein X 2 is N.

14. The compound of claim 13 , wherein R 10 is hydrogen.

15. The compound of claim 14 , wherein R 20 is hydrogen.

16. The compound of claim 1 , wherein the sum of m, n, and o is 2, and the sum of p, q, and r is 2.

17. The compound of claim 16 , wherein n, o, p, and q, in each instance is 1.

18. The compound of claim 1 , wherein each of R J1a , R J1b , R J2a , R J2b , R J3a , R J3b , R J4a , R J4b , R J5a , R J5b , R J6a , and R J6b , if present, is hydrogen.

19. The compound of claim 1 , wherein m is 1; R J1a is fluorine; R J1b is hydrogen or fluorine; and each of R J2a , R J2b , R J3a , R J3b , R J4a , R J4b , R J5a , R J5b , R J6a , and R J6b , if present, is hydrogen.

20. The compound of claim 1 , wherein R 4 is a 5- to 10-membered heteroaryl.

21. The compound of claim 1 , wherein R 4 is a 9-membered bicyclic heteroaryl.

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

wherein R 4d and R 4e are independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl, halo-C 1 -C 3 alkyl, 5- to 7-membered heteroaryl, (C 3 -C 6 cycloalkyl)-C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, phenyl, and benzyl, and
wherein said phenyl or 5- to 7-membered heteroaryl is optionally substituted with one, two, or three substituents, each of which is independently selected from the group consisting of halogen, halo-C 1 -C 3 alkyl, and C 1 -C 6 alkyl.

23. The compound of claim 1 , wherein the compound has one of the following structures:

Compound

No.
Structure

Assignees

• Global Blood Therapeutics Inc

Inventors

• Li Zhe
• Xu Qing
• Metcalf Brian Walter
• Yee Calvin Wesley
• Rademacher Peter Michael
• Alt Carsten

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D277/62 Primary

  Benzothiazoles · CPC title

• C07D233/96

  having three double bonds between ring members or between ring members and non-ring members · CPC title

• 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