Inhibitors of hif-2alpha and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2023159466-A1
Application number	US-202218050557-A
Country	US
Kind code	A1
Filing date	Oct 28, 2022
Priority date	Oct 29, 2021
Publication date	May 25, 2023
Grant date	—

Abstract

The present disclosure is directed to compounds that are inhibitors of HIF-2α having a structure according to Formula I, and compositions containing those compounds. Methods of using the compounds for the treatment of diseases, disorders, or conditions are also described.

First claim

What is claimed is:

1 . A compound, or a pharmaceutically acceptable salt thereof, having a structure according to Formula I:

wherein:
n is 1 or 2;
m is 2, 3, 4, 5, 6, 7, or 8, provided that when n is 1, m is 2, 3, 4, 5, or 6;
each R 1 is independently selected from the group consisting of halo, —OH, and —O—(C 1 -C 3 alkyl);
R 2 selected from the group consisting of —C 1 -C 6 alkyl, —CN, and —S(O) 2 —(C 1 -C 3 alkyl), wherein the —C 1 -C 6 alkyl and —S(O) 2 —(C 1 -C 3 alkyl) are substituted with 0-3 halo;
R 3 is selected from the group consisting of —C 1 -C 2 alkyl substituted with 1-3 R 4 , —C 3 -C 6 alkyl, —C 3 -C 8 cycloalkyl, -3- to 7-membered heterocycloalkyl having 1-3 heteroatom or heteroatom groups selected from N, O, S, S(═O), and S(═O) 2 , —Y—(C 3 -C 6 cycloalkyl), —Y—O—(C 3 -C 6 cycloalkyl), —Y-(3- to 6-membered heterocycloalkyl) having 1-3 heteroatom or heteroatom groups selected from N, O, S, S(═O), and S(═O) 2 , —X-(phenyl), and —Y-(5- to 6-membered heteroaryl) having 1-3 heteroatoms selected from N, O, and S, wherein the —C 3 -C 6 alkyl, —C 3 -C 6 cycloalkyl, -3- to 7-membered heterocycloalkyl, —Y—(C 3 -C 6 cycloalkyl), —Y—O—(C 3 -C 6 cycloalkyl), —Y-(3- to 6-membered heterocycloalkyl), —X-(phenyl), and —Y-(5- to 6-membered heteroaryl), are substituted with 0-3 R 4 ;

each R 4 is independently selected from halo, —C 1 -C 6 alkyl, —CN, —C 1 -C 6 haloalkyl, —OH, —O—(C 1 -C 6 alkyl), —Y—O—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl), —S(O)—(C 1 -C 6 alkyl), and —S(O) 2 —(C 1 -C 6 alkyl), wherein the —O—(C 1 -C 6 alkyl), —Y—O—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl), —S(O)—(C 1 -C 6 alkyl), and —S(O) 2 —(C 1 -C 6 alkyl) are substituted with 0-3 halo;
X is —C 2 -C 3 alkylene-; and
Y is —C 1 -C 3 alkylene-.

2 . The compound, or a pharmaceutically acceptable salt thereof, according to claim 1 wherein:
n is 1 or 2;
m is 2, 3, 4, 5, 6, 7, or 8, provided that when n is 1, m is 2, 3, 4, 5 or 6;
each R 1 is independently selected from the group consisting of halo, —OH, and —O—(C 1 -C 3 alkyl);
R 2 selected from the group consisting of —C 1 -C 6 alkyl, —CN, and —S(O) 2 —(C 1 -C 3 alkyl), wherein the —C 1 -C 6 alkyl and —S(O) 2 —(C 1 -C 3 alkyl) are substituted with 0-3 halo;
R 3 is selected from the group consisting of —C 1 -C 2 alkyl substituted with 1-3 R 4 , —C 3 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —Y—(C 3 -C 6 cycloalkyl), —Y—O—(C 3 -C 6 cycloalkyl), —Y-(3- to 6-membered heterocycloalkyl) having 1-3 heteroatom or heteroatom groups selected from N, O, S, S(═O), S(═O) 2 , and —Y-(5- to 6-membered heteroaryl) having 1-3 heteroatoms selected from N, O, and S, wherein the —C 3 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —Y—(C 3 -C 6 cycloalkyl), —Y—O—(C 3 -C 6 cycloalkyl), —Y-(3- to 6-membered heterocycloalkyl), and —Y-(5- to 6-membered heteroaryl) are substituted with 0-3 R 4 ;
each R 4 is independently selected from halo, —C 1 -C 6 alkyl, —CN, —C 1 -C 6 haloalkyl, —OH, —O—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl), and —S(O) 2 —(C 1 -C 6 alkyl), wherein the —O—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl), and —S(O) 2 —(C 1 -C 6 alkyl) are substituted with 0-3 halo; and
Y is —C 1 -C 3 alkylene-.

3 . The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound of Formula I has a structure according to Formula II:

4 . The compound, or pharmaceutically acceptable salt thereof, according to claim 3 , wherein the compound of Formula II has a structure according to Formula IIa:

wherein p is 0 or 1.

5 . The compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound of Formula I has a structure according to Formula III:

6 . The compound or pharmaceutically acceptable salt thereof, according to claim 5 , wherein the compound of Formula III has a structure according to Formula IIIa:

wherein p is 0 or 1.

7 . The compound, or pharmaceutically acceptable salt thereof, according to claim 5 , wherein the compound of Formula III has a structure according to Formula IIIc:

wherein p is 0 or 1.

8 . The compound, or pharmaceutically acceptable salt thereof, according to claim 5 , wherein the compound of Formula III has a structure according to Formula IIIe:

wherein p is 0 or 1.

9 . The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1 , and 3 - 8 , wherein:
each R 1 is independently halo or —OH; R 2 is —C 1 -C 6 alkyl substituted with 0-3 halo; R 3 is —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, tetrahydropyranyl, or —Y—(C 3 -C 6 cycloalkyl), each of which is substituted with 1-3 R 4 ; each R 4 is independently halo, —C 1 -C 6 haloalkyl, —O—(C 1 -C 6 alkyl), —Y—O—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl), or —S(O) 2 —(C 1 -C 6 alkyl), wherein the —O—(C 1 -C 6 alkyl), —Y—O—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl), and —S(O) 2 —(C 1 -C 6 alkyl) are substituted with 0-3 halo; and Y is —C 1 -C 3 alkylene-.

10 . The compound, or pharmaceutically acceptable salt thereof, according to claim 9 , wherein each R 4 is independently selected from the group consisting of halo, —CN, —O—(C 1 -C 3 alkyl), —S—(C 1 -C 3 alkyl), and —S(O) 2 —(C 1 -C 3 alkyl), wherein the —O—(C 1 -C 3 alkyl), —S—(C 1 -C 3 alkyl), and —S(O) 2 —(C 1 -C 3 alkyl) are substituted with 0-3 halo.

11 . The compound, or pharmaceutically acceptable salt thereof, according to claim 10 , wherein each R 4 is independently selected from —F, —CN, —OCH 3 , —OCF 2 H, —OCF 3 , —SCF 3 , and —S(O) 2 CF 3 .

12 . The compound, or pharmaceutically acceptable salt thereof, according to claim 9 , wherein each R 4 is independently halo, —C 1 -C 6 haloalkyl, —O—(C 1 -C 6 alkyl), or —Y—O—(C 1 -C 6 alkyl), wherein the —O—(C 1 -C 6 alkyl), or —Y—O—(C 1 -C 6 alkyl) are substituted with 0-3 halo.

13 . The compound, or pharmaceutically acceptable salt thereof, according to claim 12 , wherein each R 4 is independently —F, —CF 3 , —OCH 3 , —OCF 3 , or —CH(CH 3 )—O—CF 3 .

14 . The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 5 - 8 , wherein:
each R 1 is independently halo or —OH; R 2 is —C 1 -C 6 alkyl substituted with 0-3 halo, or —S(O) 2 —(C 1 -C 3 alkyl); R 3 is —C 1 -C 6 alkyl substituted with 1-3 R 4 , —C 3 -C 6 cycloalkyl, -6 to 7-membered heterocycloalkyl having one heteroatom or heteroatom group selected from O and S(═O) 2 , —C 1 -C 2 alkylene-(C 3 -C 4 cycloalkyl), —C 1 -C 2 alkylene-(4- to 5-membered heterocycloalkyl) having 1 heteroatom or heteroatom group selected from O and S(═O) 2 , —C 2 -C 3 alkylene-(phenyl), and —C 1 -C 2 alkylene-(5-membered heteroaryl) having 1-2 heteroatoms selected from N, O, and S, wherein the —C 3 -C 6 cycloalkyl, -6 to 7-membered heterocycloalkyl, —C 1 -C 2 alkylene-(C 3 -C 4 cycloalkyl), —C 1 -C 2 alkylene-(4- to 5-membered heterocycloalkyl), —C 2 -C 3 alkylene-(phen

Assignees

• Arcus Biosciences Inc

Inventors

• Beatty Joel Worley
• Drew Samuel Lawrie
• Epplin Matthew
• Fournier Jeremy
• Gal Balint
• Hardman Clayton
• Mailyan Artur Karenovich
• Lawson Kenneth Victor
• Leleti Manmohan Reddy
• Liu Dongdong
• Mata Guillaume
• Podunavac Masa
• Powers Jay Patrick
• Rosen Brandon Reid
• Yu Kai

Classifications

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D231/54

  condensed with carbocyclic rings or ring systems · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title