Macrocyclic compound

Patent metadata

Field	Value
Publication number	US-12577258-B2
Application number	US-202018028578-A
Country	US
Kind code	B2
Filing date	Sep 30, 2020
Priority date	Sep 30, 2020
Publication date	Mar 17, 2026
Grant date	Mar 17, 2026

Abstract

A compound represented by the general formula (1) or a salt thereof, which has a superior IRAK-4 inhibitory activity, and is useful as active ingredients of medicaments for prophylactic treatment and/or therapeutic treatment of diseases relating to IRAK-4 inhibition.

First claim

The invention claimed is:

1 . A compound represented by the following formula (1):

in the formula (1),
R 1 is —H, C 1-6 alkyl, halogeno-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, —C(O)R 12 , —S(O 2 )R 12 , —C(O)NR 11 R 12 , —C(O) OR 12 , or a 3- to 7-membered saturated ring group, R 1 may be substituted with the same or different 1 to 3 substituents selected from a group G 1 ;
the group G 1 is a group consisting of —F, hydroxy, cyano, halogeno-C 1-6 alkyl, C 1-4 alkoxy, phenyl, 5- to 6-membered heteroaryl, and a 3- to 7-membered saturated ring group, the phenyl and 5- to 6-membered heteroaryl included in the group G 1 may be substituted with the same or different 1 to 3 substituents selected from a group G Ar ;
the group G Ar is a group consisting of —F, —Cl, hydroxy, cyano, C 1-6 alkyl, halogeno-C 1-6 alkyl, and —NH 2 ;
R 11 is —H, C 1-6 alkyl, halogeno-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, halogeno-C 1-6 alkoxy-C 1- alkyl, or a 3- to 7-membered saturated ring group;
R 12 is C 1-6 alkyl, halogeno-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, halogeno-C 1-6 alkoxy-C 1-6 alkyl, a 3- to 7-membered saturated ring group, phenyl, or 5- or 6-membered heteroaryl, the phenyl and 5- or 6-membered heteroaryl as R 12 may be substituted with the same or different 1 to 3 substituents selected from the group G Ar ;
R 2 is —H, C 1-6 alkyl, halogeno-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, or a 3- to 7-membered saturated ring group;
R 3 is —H, C 1-6 alkyl, halogeno-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, or a 3- to 7-membered saturated ring group;
Ar is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, Ar may be substituted with the same or different 1 to 3 substituents selected from the group G 2 ;
the group G 2 is a group consisting of —F, —Cl, hydroxy, cyano, C 1-6 alkyl, halogeno-C 1-6 alkyl, hydroxy-C 1-6 alkyl, R Ar1 —O—C 1-3 alkyl, R Ar1 —NR 13 —C 1-3 alkyl, —NR 13 C(O)R 14 , —C(O)NR 13 R 14 , —C(O)NH 2 , —NR 13 S(O 2 )R 14 , —S(O 2 ) NR 13 R 14 , —NH 2 , —S(O 2 )NH 2 , —NR 13 R 14, and —NHC(O)NHR 15 ;
R Ar1 is —H, C 1-6 alkyl, halogeno-C 1-6 alkyl, or a 3- to 7-membered saturated ring group, R Ar1 may be substituted with the same or different 1 to 3 substituents selected from the group G 3 ;
the group G 3 is a group consisting of —F, hydroxy, C 1-3 alkyl, halogeno-C 1-3 alkyl, oxo, C 1-3 alkoxy, halogeno-C 1-3 alkoxy, and a 3- to 7-membered saturated ring group;
R 13 is —H, C 1-3 alkyl, halogeno-C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, halogeno-C 1-3 alkoxy-C 1 -3 alkyl, or a 3- to 7-membered saturated ring group;
R 14 is C 1-3 alkyl, halogeno-C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, halogeno-C 1-3 alkoxy-C 1-3 alkyl, or a 3- to 7-membered saturated ring group;
R 15 is —H, phenyl, or 5- or 6-membered heteroaryl, R 15 may be substituted with the same or different 1 to 3 substituents selected from the group G 4 ;
the group G 4 is a group consisting of halogen, cyano, C 1-3 alkyl, and halogeno-C 1-3 alkyl;
X 1 is N or CH;
X 2 is NH or O;
X 3 is a group represented by the following formula (1-1):

the following formula (1-2):

or
the following formula (1-3):

a and b represent direction of bonding:
R 21 and R 22 are independently —H, C 1-3 alkyl, or halogeno-C 1-3 alkyl;
X 4 is a group represented by the following formula (2-1):

b and c represent direction of bonding;
in the formula (2-1),
n is an integer of 1 to 3;
Y is NR 51 or O;
R 31 and R 32 are independently —H, C 1-3 alkyl, or halogeno-C 1-3 alkyl; or
R 31 and R 32 may combine to form a 3- to 6-membered saturated ring;
R 41 and R 42 are independently —H, —F, hydroxy, C 1-3 alkyl, halogeno-C 1-3 alkyl, C 1-3 alkoxy, or halogeno-C 1-3 alkoxy; or
R 41 and R 42 may combine to form a 3- to 6-membered saturated ring;
R 51 is —H, C 1-3 alkyl, or halogeno-C 1-3 alkyl; or
R 51 and R 31 may combine to form a 4- to 6-membered saturated ring;
X 4 may be substituted with the same or different 1 to 3 substituents selected from the group G 5 ; and
the group G 5 is a group consisting of —F, hydroxy, C 1-3 alkyl, halogeno-C 1-3 alkyl, C 1-3 alkoxy, and halogeno-C 1-3 alkoxy,

or a salt thereof.

2 . The compound or a salt thereof according to claim 1 , wherein Ar is 5- or 6-membered heteroaryl.

3 . The compound or a salt thereof according to claim 1 , wherein R 1 is —H, C 1-6 alkyl, halogeno-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, or a 3- to 7-membered saturated ring group, and R 1 may be substituted with the same or different 1 to 3 substituents selected from the group G 1 .

4 . The compound or a salt thereof according to claim 1 , wherein X 2 is NH.

5 . The compound or a salt thereof according to claim 1 , wherein:
X 3 is a group represented by the following formula (1-1):

6 . The compound or a salt thereof according to claim 1 , wherein:
X 3 is a group represented by the following general formula (1-1-1):

7 . The compound or a salt thereof according to claim 1 , wherein:
in the formula (2-1) for X 4 , n is 1.

8 . The compound or a salt thereof according to claim 1 , wherein:
Ar is a group represented by the following formula (3-1):

and
in the formula (3-1),
R Ar2 is —H, —F, —Cl, hydroxy, cyano, C 1-6 alkyl, halogeno-C 1-6 alkyl, hydroxy-C 1-6 alkyl, R Ar1 —O—C 1-3 alkyl, or—NR 13 R 14 .

9 . The compound or a salt thereof according to claim 8 , wherein:
Ar is a group represented by the formula (3-1), and in the formula (3-1), R Ar2 is —H, methyl, hydroxymethyl, or—CH 2 —O—R Ar1 .

10 . The compound or a salt thereof according to claim 1 , wherein R 3 is —H.

11 . The compound or a salt thereof according to claim 1 , wherein R 2 is —H or methyl.

12 . The compound or a salt thereof according to claim 1 , wherein R 1 is —H or C 1-3 alkyl.

13 . A compound represented by the following formula:

or a salt thereof.

14 . A compound represented by the following formula:

or a salt thereof.

15 . A compound represented by the following formula:

or a salt thereof.

16 . A compound represented by the following formula:

or a salt thereof.

17 . A compound rep

Assignees

• Asahi Kasei Pharma Corp
• Vernalis R&D Ltd

Inventors

• Ito Takahiko
• Takashima Misato
• Atobe Masakazu
• Arai Koichiro
• Toyama Tomohisa
• Yoshii Yu
• Potter Andrew John
• MADDOX Daniel Paul
• Ray Stuart
• Foloppe Nicolas

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00 Primary

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D498/18 Primary

  Bridged systems · CPC title