Reversible DPP1 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-12479837-B2
Application number	US-202519088795-A
Country	US
Kind code	B2
Filing date	Mar 24, 2025
Priority date	Jan 6, 2023
Publication date	Nov 25, 2025
Grant date	Nov 25, 2025

Abstract

Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or deuterated forms thereof, wherein R 0 , L and R 1 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of Formula (I) or pharmaceutically acceptable salt or deuterated form thereof, e.g., in the treatment of a disease that is treatable by administration of a DPP1 inhibitor.

First claim

The invention claimed is:

1 . A compound of formula (I)

or a pharmaceutically acceptable salt or deuterated form thereof,
wherein:
R 0 is

X 1 and X 2 are independently O, S, NH, N(C 1-6 alkyl), or CR 12 R 13 , wherein at least one of X 1 and X 2 are not CR 12 R 13 ;
L is aryl, heterocyclyl, heteroaryl, or

wherein L is independently substituted by 0-4 R 10 and wherein ring B is a carbocycle, or a heterocycle;
R 1 is

R 2 is H, F, Cl, Br, OSO 2 C 1-6 alkyl, or C 1-6 alkyl;
R 3 is H, F, Cl, Br, CN, C 1-6 haloalkyl, SO 2 C 1-6 alkyl, CONH 2 , or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclyl;
X is O, S, CHF, or CF 2 ;
Y is O, S, or CH 2 ;
Q is CH or N;
R 6 is C 1-6 alkyl optionally substituted by 1, 2 or 3 F, or optionally substituted by OH, OC 1-6 alkyl, N(C 1-6 alkyl) 2 , N(C 1-6 alkyl)(C 1-6 alkylene-O—C 1-6 alkyl), cycloalkyl, or heterocyclyl;
R 7 is H, F, Cl, Br, or C 1-6 alkyl;
each R 8 and R 12 are independently H, OH, halogen, NH 2 , COOH, C 1-6 alkyl, C 1-6 alkyl-OH, C 2-6 alkenyl, C 1-6 alkoxy, O-cycloalkyl, cycloalkyl, C 1-6 alkylene-carbocyclyl, C 1-6 alkylene-heteroaryl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, heteroaryl, or carbocyclyl;
each R 13 is independently H, F, Cl, Br, I, or C 1 -C 6 alkyl;
each R 10 is independently oxo, halogen, C 1-6 alkyl, C 1-6 alkoxy, S-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, cyano, hydroxy, NH 2 , —NH—C 1-6 alkyl, N(C 1-6 alkyl) 2 , COOH, COC 1-6 alkyl, COOC 1-6 alkyl, CON 1-6 alkyl, CON(C 1-6 alkyl) 2 , NHCOC 1-6 alkyl, or heterocycle; wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxy, NH 2 , and COOH;
W, X 4 , and Y 2 are each independently CH or N, provided that a maximum of one of W, X 4 , and Y 2 can be N;
D-E is N(H)—C(O), N(C 1-6 alkyl)-C(O), CH 2 CH 2 , C(O)—O, or CH 2 —O;
R 11 is H, C 1-6 alkyl, alkylene-O-alkyl, or heterocyclyl; and
i and j are each independently 1, 2 or 3, provided that the sum of i+j is 2, 3, or 4.

2 . The compound of claim 1 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, 1, or 2, and R 10 is halogen.

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof or deuterated form thereof, wherein the halogen is F.

4 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof or deuterated form thereof, wherein n is 0 or 1.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein,
R 1 is

X is O, S, or CF 2 ;
Y is O or S;
Q is CH or N;
R 6 is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2, or 3 F, OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , N(C 1-3 alkyl)(C 1-3 alkylene-O—C 1-3 alkyl), cyclopropyl, or tetrahydropyran;
R 7 is H, F, C 1 , or CH 3 ; and
R 11 is H, C 1-6 alkyl, alkylene-O-alkyl, or heterocyclyl.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein,
R 1 is

X is O;
R 6 is C 1-3 alkyl; and
R 7 is H.

7 . The compound of claim 2 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 6 is methyl.

8 . The compound of claim 2 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 6 is ethyl.

9 . The compound of claim 2 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 1 is

10 . The compound of claim 1 , wherein the compound is of Formula (III):

or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1.

11 . The compound of claim 1 , wherein the compound is of Formula (III-B):

or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 10 is —F.

12 . The compound of claim 11 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O.

13 . The compound of claim 2 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 is

14 . The compound of claim 13 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 is

15 . The compound of claim 14 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 is

16 . The compound of claim 15 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein X 1 is O and X 2 is NH.

17 . The compound of claim 15 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein X 1 is CH 2 and X 2 is NH.

18 . The compound of claim 15 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein one R 8 is OH, unsubstituted C 1-6 alkoxy, or O-cycloalkyl.

19 . The compound of claim 2 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein each occurrence of R 8 is methoxy, ethoxy, or OH.

20 . The compound of claim 15 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 8 is H.

21 . The compound of claim 1 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 0 is

22 . The compound of claim 21 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein:
R 0 is

X 1 is O and X 2 is NH, or X 1 is CH 2 and X 2 is NH; and
each R 8 is independently H, OH, halogen, NH 2 , COOH, C 1-6 alkyl, C 1-6 alkyl-OH, C 2-6 alkenyl, C 1-6 alkoxy, O-cycloalkyl, cycloalkyl, C 1-6 alkylene-heteroaryl, halogenated C 1-6 alkyl, or halogenated C 1-6 alkoxy, pro

Assignees

• Insmed Inc

Inventors

• Plaunt Adam J
• Cerdan Adrien
• Ciapetti Paola
• Goegan Bastien

Classifications

• A61P11/08

  Bronchodilators · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P29/00

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

• A61P35/04

  specific for metastasis · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title