Cycloalkyl pyrimidines as ferroportin inhibitors

Patent metadata

Field	Value
Publication number	US-11746100-B2
Application number	US-202117242731-A
Country	US
Kind code	B2
Filing date	Apr 28, 2021
Priority date	Apr 28, 2020
Publication date	Sep 5, 2023
Grant date	Sep 5, 2023

Abstract

The subject matter described herein is directed to ferroportin inhibitor compounds of Formula I or 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,
Z is N;
Ring B is

 wherein indicates the point of attachment to the remainder of the molecule;
R 6 , in each instance, is selected from the group consisting of halogen, hydroxy, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy-C 1 -C 3 alkyl, hydroxy-C 1 -C 10 alkoxy, hydroxy-C 1 -C 10 -alkyl, cyano, —NR G R H , halo-C 1 -C 3 alkoxy, —O—(C 1 -C 6 alkyl)-R bb , —O—R bb , —(C 1 -C 6 alkyl)-NR GI R HI , —S—C 1 -C 3 alkyl, —S—C 1 -C 3 alkyl-NR G1 R H1 , halo-C 1 -C 3 alkyl, —O—R cc —O—R dd , 5- to 7-membered monocyclic heteroaryl, and C 3 -C 6 cycloalkyl; wherein,
the alkyl moiety in hydroxy-C 1 -C 10 alkoxy or —O—(C 1 -C 6 alkyl)-R bb is optionally substituted with cyano, hydroxy, hydroxy-C 1 -C 3 -alkyl, halogen, or C 1 -C 3 alkoxy;
R bb is 4- to 7-membered monocyclic or bridged heterocyclyl, C 3 -C 7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, —SO 2 —C 1 -C 3 alkyl, —S—C 1 -C 3 alkyl, —C(O)NR G1 R H1 , or —NR G R H ;
R cc is C 1 -C 3 alkyl; and
R dd is C 1 -C 3 alkyl or a 6-membered heteroaryl;
 wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R 6 , R bb , or R dd is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C 1 -C 3 alkyl, oxo, C 1 -C 3 alkoxy, and C 1 -C 3 alkyl;
R G1 and R H1 are each independently hydrogen or C 1 -C 3 alkyl;

and,
R G and R H are each independently hydrogen, —C(O)R Ga , or optionally deuterated C 1 -C 3 alkyl; wherein,
R Ga is C 1 -C 3 alkyl or hydrogen;

or,
two R 6 groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C 4 -C 7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein,
said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C 1 -C 3 alkoxy, hydroxy, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl;

n is 0, 1, 2, or 3;
Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from the group consisting of CH, N, NH, O, S, SH, S—R 6 , N—R 6 , and C—R 6 , provided that 1 or 2 of Y 1 , Y 2 , Y 3 , and Y 4 can be N, N—R 6 , NH, O, SH or S—R 6 ;
f is 0 or 1;

p is 1 or 2;
R X , in each instance, is halogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, hydroxy, oxo, or cyano;
m is 0, 1, or 2;
R 3 is selected from the group consisting of hydrogen, optionally deuterated C 1 -C 3 alkyl, hydroxy-C 1 -C 3 alkyl, halo-C 1 -C 3 alkyl, cyclopropyl, and phenyl;
R 4 is

wherein,
R 4a and R 4b are each independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, hydroxy-C 1 -C 6 alkyl, halo-C 1 -C 3 alkyl, C 1 -C 3 alkoxy-C 1 -C 6 alkyl, —C 1 -C 6 alkyl-NR J1 R J2 , C 3 -C 7 cycloalkyl, 4- to 10-membered monocyclic, fused bicyclic, bridged bicyclic, or spiro heterocyclyl, C 6 -C 10 monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (C 6 -C 10 monocyclic or fused bicyclic aryl)-C 1 -C 3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C 1 -C 3 alkyl;
 R J1 and R J2 are independently hydrogen or C 1 -C 3 alkyl;
 wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl of R 4a or R 4g is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, C 1 -C 6 alkyl, halo-C 1 -C 3 alkyl, hydroxy, C 1 -C 3 alkoxy, halo-C 1 -C 3 alkoxy, oxo, C 3 -C 7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl;
 R 4b is hydrogen or C 1 -C 6 alkyl; or
 R 4a and R 4b taken together with the atom to which each is attached form a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, 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 3 alkyl, hydroxy, and C 1 -C 3 alkoxy; or
 R 4b and R 4c taken together with the atom to which each is attached form a 5- to 7-membered monocyclic heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of hydroxy, halogen, and C 1 -C 3 alkyl; or
 R 4c and R 4d are each independently selected from the group consisting of hydrogen, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 alkyl-thio-C 1 -C 3 alkyl, hydroxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, and 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 7 cycloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein p is 1.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 , Y 3 , and Y 4 are each CH or C—R 6 .

4. The compound of claim 3 , a pharmaceutically acceptable salt thereof, wherein Y 1 is CH, Y 2 is C—R 6 , Y 3 is CH, and Y 4 is CH.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 3 is N and Y 1 , Y 2 , and Y 4 are each CH or C—R 6 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is N and Y 1 , Y 3 , Y 4 are each CH or C—R 6 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 , in each instance, is selected from the group consisting of halogen, hydroxy, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy-C 1 -C 3 alkyl, hydroxy-C 1 -C 10 alkoxy, hydroxy-C 1 -C 10 -alkyl, —O—(C 1 -C 6 alkyl)-R bb , halo-C 1 -C 3 alkoxy, —O—R cc —O—R dd , halo-C 1 -C 3 alkyl, —(C 1 -C 6 alkyl)- NR GI R HI , —S—CH 3 , —S(CH 2 ) 2 N(CH 3 ) 2 , and —NR G R H ; wherein,
R bb is —NR G R H , —C(O)N(CH 3 ) 2 , —S(O) 2 CH 3 , or —SCH 3 ;
R G and R H are each independently hydrogen, optionally deuterated C 1 -C 3 alkyl, or —C(O)R G a, wherein R Ga is C 1 -C 3 alkyl;
R GI and R HI are each independently hydrogen or C 1 -C 3 alkyl;
R cc and R dd are each independently C 1 -C 3 alkyl; and,
wherein the alkyl moiety in hydroxy-C 1 -C 10 alkoxy is optionally substituted with hydroxy, halogen, or C 1 -C 3 alkoxy.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 6 , in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, —N(CH 3 ) 2 , hydroxy, —OCH 2 CH 2 OH, —CH 2 OH, —CH 2 OCH 3 , —OCH 2 CH 2 NH 2 , OCH 2 CH 2 N(CH 3 ) 2 , —OCH 2 C(CH 3 ) 2 OH, —OCH 2 CF 3 , —OCHF 2 , —OCF 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 C H 2 F, —OC(CH 3 ) 2 CH 2 OH, —OCH 2 CH(CH 3 )OH, —OCH 2 CH 2 NHC(O)CH 3 , —OC(CH 3 ) 2 CH 2 N(CH 3 ) 2 , —OCH(CH 3 )CH 2 OH, —OCH 2 CH(CH(CH 3 ) 2 )OH, —OCH 2 CH(CH 2 CH 3 )OH, —OCH 2 C(CH 2 CH 3 ) 2 OH, —OCH 2 CH 2 N(CH 2 CH 3 ) 2 , —OCH(CH 3 )CH 2 N(CH 3 ) 2 , —OCH 2 C(O)N(CH 3 ) 2 , —OCH 2 C(CH 3 ) 2 N(CH 3 ) 2 , —OCH 2 CH(CH 2 OH)OH, —OCH 2 CH 2 NH(CH 3 ), —OCH 2 CH(CF 3 )OH, —OCH 2 C(CH 3 )(

Assignees

• Global Blood Therapeutics Inc

Inventors

• Xu Qing
• Alt Carsten
• Li Zhe
• Nilar Shahul
• Rademacher Peter Michael
• Yee Calvin Wesley

Classifications

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D239/70

  condensed with carbocyclic rings or ring systems · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61P13/12

  of the kidneys · CPC title