Granted Patent B2

US 12,479,837 · App. 19/088,795 · Granted Nov 25, 2025

Inventors: Adam J. Plaunt (Bridgewater, NJ); Adrien Cerdan (Strasbourg, FR); Paola Ciapetti (Strasbourg, FR); Bastien Goegan (Strasbourg, FR)

Assignee: Insmed Incorporated

C07D413/12C07D267/22C07D413/14C07D417/14C07D491/107C07D498/10

Abstract

Claims (95)

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, provided that one R 8 is not H.

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

24 . A compound having the structure:

or a pharmaceutically acceptable salt thereof.

25 . The compound of claim 24 , having the structure:

or a pharmaceutically acceptable salt thereof.

26 . The compound of claim 10 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0.

27 . The compound of claim 26 , or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O.

28 . The compound of claim 24 , having the structure:

or a pharmaceutically acceptable salt thereof.

29 . The compound of claim 24 , having the structure:

or a pharmaceutically acceptable salt thereof.

30 . The compound of claim 24 , having the structure:

or a pharmaceutically acceptable salt thereof.

31 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

32 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

33 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

34 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

35 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

36 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

37 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

38 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

39 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

40 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

41 . The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

Assignments (3)

Continuity (4)

References Cited (400)

Cited By (1)

US 12,679,815