Small molecule antagonists of pf4

Patent metadata

Field	Value
Publication number	US-2025281424-A1
Application number	US-202118247216-A
Country	US
Kind code	A1
Filing date	Sep 29, 2021
Priority date	Sep 29, 2020
Publication date	Sep 11, 2025
Grant date	—

Abstract

The present application provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Y, R1, R2, R3 and R4 are described herein. The methods of using these compounds to inhibit tetramerization of PF4 and to treat the associated diseases and conditions, such as heparin-induced thrombocytopenia and thrombosis (HITT) and vaccine-induced immune thrombotic thrombocytopenia (VITT), methods of making these compounds, and pharmaceutical compositions containing these compounds are also disclosed.

First claim

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from O, C(═O), S(═O) 2 , C(R 5 )(R 6 ), C≡C, and a bond between the indane-1,3-dione rings of the compound of Formula (I);
R 1 and R 3 are each independently selected from H, halo, CN, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C(O)NH(R a1 ), and C(O)Cy 4 , wherein C 1-6 alkyl in the C 1-6 alkylcarbonyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 4 , amino, C 1-6 alkoxy, C 1-6 cycloalkoxy, C 6-10 arylcarbonyl, C 1-3 alkoxy-C 1-3 alkoxy, carboxy, C 1-3 alkoxycarbonyl, C 6-10 aryloxy, —N(C 1-3 alkyl)(C 1-6 alkoxycarbonyl), —NH(C 1-6 alkoxycarbonyl), and —NH(C 1-6 alkylcarbonyl), wherein C 1-6 alkoxy in any of said C 1-6 alkoxycarbonyl groups is optionally substituted with C 6-10 aryl, wherein C 6-10 arylcarbonyl may be optionally substituted with 1, 2, or 3 substituents independently selected from C 1-3 alkyl, and halo;
R 2 and R 4 are each independently selected from H, C 1-6 alkoxycarbonyl, and C 1-6 alkylcarbonyl;
R 5 and R 6 are each C 1-3 haloalkyl;
each R a1 is independently selected from C 1-6 alkyl, C 1-6 alkenyl, Cy 1 , C 1-6 alkoxycarbonyl, and S(O) 2 R a2 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , carboxyl, C 1-3 alkoxycarbonyl, C 1-3 alkoxy, C 1-3 alkoxy-C 1-3 alkoxy, and C 1-3 haloalkoxy;
each Cy 1 is independently selected from C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, NO 2 , C 1-6 alkyl, C 1-3 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, and Cy 3 ;
each Cy 2 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy;
each Cy 3 is independently selected from C 6-10 aryl and 5-10 membered heteroaryl;
each Cy 4 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, aryl, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylidene, and oxo; wherein C 1-6 alkoxy in said C 1-6 alkoxycarbonyl is optionally substituted with C 6-10 aryl; and
each R a2 is C 6-10 aryl, optionally substituted with C 1-3 alkyl,
with a proviso that the compound of Formula (I) is not any one of the compounds selected from:

2 . (canceled)

3 . The compound of claim 1 , wherein Y is C(═O).

4 .- 8 . (canceled)

9 . The compound of claim 1 , wherein:
R 2 and R 4 are each independently selected from C 1-6 alkoxycarbonyl and C 1-6 alkylcarbonyl; and R 1 and R 3 are each independently selected from C 1-6 alkoxycarbonyl and C 1-6 alkylcarbonyl.

10 . The compound of claim 1 , wherein:
R 1 and R 2 are each H; and R 3 and R 4 are each independently selected from C 1-6 alkoxycarbonyl and C 1-6 alkylcarbonyl.

11 .- 25 . (canceled)

26 . The compound of claim 1 , wherein the compound of Formula (I) has Formula (Ia):

or a pharmaceutically acceptable salt thereof.

27 .- 35 . (canceled)

36 . The compound of claim 26 , wherein R 1 and R 3 are each independently C 1-6 alkoxycarbonyl.

37 . The compound of claim 26 , wherein R 1 and R 3 are each independently an C 1-6 alkylcarbonyl, wherein C 1-6 alkyl in the C 1-6 alkylcarbonyl group is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 4 , amino, C 1-6 alkoxy, C 1-6 cycloalkoxy, C 6-10 arylcarbonyl, carboxy, C 1-3 alkoxycarbonyl, C 6-10 aryloxy, —N(C 1-3 alkyl)(C 1-6 alkoxycarbonyl), —NH(C 1-6 alkoxycarbonyl), and —NH(C 1-6 alkylcarbonyl), wherein C 1-6 alkoxy in any of said C 1-6 alkoxycarbonyl groups is optionally substituted with C 6-10 aryl, wherein C 6-10 arylcarbonyl may be optionally substituted with 1, 2, or 3 substituents independently selected from C 1-3 alkyl, and halo.

38 . The compound of claim 37 , wherein R 1 and R 3 are each independently selected from: —C(O)methyl, —C(O)ethyl, —C(O)propyl, —C(O)butyl, —C(O)hexyl, wherein said methyl, ethyl, propyl, butyl, and hexyl are each optionally substituted with 1, 2, or 3 substituents independently selected from: Cy 4 , amino, methoxy, t-butoxy, carboxy, (methoxy)carbonyl, phenoxy, —N(methyl)C(O)(t-butoxy), —NHC(O)(t-butoxy), —NHC(O)(benzoxy), —NH(acetyl), —NHC(O)(pentyl), and —NHC(O)(isopropyl).

39 . The compound of claim 26 , wherein R 1 and R 3 are each independently C(O)Cy 4 .

40 .- 42 . (canceled)

43 . The compound of claim 26 , wherein each Cy 4 is optionally substituted with 1, 2, or 3 substituents independently selected from (t-butoxy)carbonyl, fluoro, (methoxy)carbonyl, methyl, (benzyloxy)carbonyl, methylene, (isopropoxy)carbonyl, methoxy, carboxy, and oxo.

44 .- 65 . (canceled)

66 . The compound of claim 1 , wherein the compound of Formula (I) is selected from any one of the following compounds:

Assignees

• Zhou Yuhang
• New York Blood Center Inc
• Fox Chase Chemical Diversity Center Inc
• Univ Jefferson

Inventors

• Sachais Bruce
• Wrobel Jay E
• Reitz Allen B
• Mckenzie Steven E
• Mcdonnell Mark E
• Bian Haiyan
• Ford-Hutchinson Thomas A
• Rosano Robert J
• Zhou Yuhang
• Mandayam Nandan
• Clemens Jennifer
• Sausker Justin
• Tice Colin M

Classifications

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• C07D319/18

  Ethylenedioxybenzenes, not substituted on the hetero ring · CPC title

• C07D317/58

  Radicals substituted by nitrogen atoms (nitro radicals C07D317/52) · CPC title

• C07D309/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D307/52

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title