Granted Patent B2

US 12,679,815 · App. 19/323,862 · Granted Jul 14, 2026

Inventors: Adam J. Plaunt (Bridgewater, NJ); Gianpaolo Gobbo (Bridgewater, NJ); Byungchan Kim (Bridgewater, NJ); Yingxin Shi (Bridgewater, NJ)

Assignee: Insmed Incorporated

C07D263/58A61K31/397A61K31/423A61K31/427A61K31/4439C07D413/12C07D417/12C07D491/107

Abstract

Claims (94)

1 . A compound of Formula (IX),

or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:

R 1 is carbocyclyl, aryl, heterocyclyl or heteroaryl, wherein R 1 is optionally substituted with 1-5 groups independently selected from R 5 or R 6 ;

L is arylene, heterocyclylene, heteroarylene or cycloalkylene, wherein L is optionally substituted by 1-4 R 7 ;

each R 2 is independently H, halogen, —OH, —CN, —Oalkyl, -NH 2 , —SH, —C(═O)alkyl, -C(═O)NH 2 , alkyl, haloalkyl, -alkylene-OH, -alkylene-CH (COOH)(NH 2 ), alkenyl, alkynyl, -S(alkyl), —S(═O)alkyl, —S(═O) 2 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl, alkylene-heterocyclyl or alkylene-carbocyclyl, wherein R 2 is optionally substituted with 1-4 R 2a , provided that at least one R 2 is not H;

or two R 2 together form (═O);

R 3 is H, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -alkylene-OH, -alkylene-O-alkyl, -alkylene-carbocyclyl, -alkylene-heterocyclyl, -alkylene-aryl, -alkylene-heteroaryl, —C(═O)alkyl, —C(═O) cycloalkyl, —C(═O)aryl or -C(═O) heteroaryl, wherein R 3 is optionally substituted with 1-4 R 3a ;

R 4 is C 1-6 alkyl;

or R 3 and R 4 together with the nitrogen to which they are attached form a heterocyclyl, wherein the heterocyclyl is optionally substituted with 1-4 R 3a ;

each of R 2a and R 3a is independently alkyl, halogen, haloalkyl, —Oalkyl, —OH, —CN, -C(═O)OH, —NH 2 , —NH(alkyl), —NH(alkyl) 2 , cycloalkyl or heterocyclyl;

each R 5 is independently halogen, C 1-6 alkyl, —O (C 1-6 alkyl), C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CN, oxo, —OH, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , -COOH, -C(═O)(C 1-6 alkyl), —C(═O)O (C 1-6 alkyl), —C(═O)NH(C 1-6 alkyl), C(═O)N (C 1-6 alkyl) 2 , NHC(═O)(C 1-6 alkyl), —S(═O) 2 (C 1-6 alkyl), -(C 1-6 alkylene)-cycloalkyl, —S(═O) 2 -cycloalkyl, -(C 1-6 alkylene)-heterocyclyl, —S(═O) 2 -heterocyclyl, -heterocyclylene-heterocyclyl or heterocyclyl, wherein each R 5 is optionally substituted with 1-3 groups selected from halogen, —CN, —OH, —NH 2 , C 1-6 alkyl, —O (C 1-6 alkyl), -COOH, cycloalkyl or heterocyclyl;

each R 6 is independently H, C 1-6 alkyl, -(C 1-6 alkylene)-O-(C 1-6 alkyl), -(C 1-6 alkylene)-NH 2 , -(C 1-6 alkylene)-NH(C 1-6 alkyl) 2 , -C 1-6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-NH(C 1-6 alkylene-O-C 1-6 alkyl), -C 1-6 alkylene-N(C 1-6 alkylene-O-C 1-6 alkyl)(C 1-6 alkyl), -C 1-6 alkylene-heterocyclyl, C(═O)(C 1-6 alkyl), C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -heterocyclylene-heterocyclyl or heterocyclyl, wherein each R 6 is optionally substituted with 1-3 groups selected from halogen, —CN, —OH, C 1-6 alkyl, —O (C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , cycloalkyl, aryl, heterocyclyl, heteroaryl or -COOH; and

each R 7 is independently ═O, halogen, C 1-6 alkyl, —O (C 1-6 alkyl), —S(C 1-6 alkyl), C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CN, —OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , -COOH, -C(═O)(C 1-6 alkyl), —C(═O)O (C 1-6 alkyl), —C(═O)N (C 1-6 alkyl) 2 , or —NHC(═O)(C 1-6 alkyl);

or one R 7 and one R 5 together form a carbocyclyl, aryl, heterocyclyl or heteroaryl ring, wherein the carbocyclyl, aryl, heterocyclyl, heteroaryl is optionally substituted with 1-4 groups selected from C 1-6 alkyl, halogen, —OC 1-6 alkyl, haloalkyl, —OH, —CN, or heterocyclyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 1 is 8-10 membered fused bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the heteroaryl is optionally substituted with 1-4 groups independently selected from R 5 or R 6 .

3 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:

R 1 is

q is 0, 1, 2 or 3; and

Y is NH, O, S, CH 2 , CHF, or CF 2 .

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

5 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein L is arylene optionally substituted by 1-4 R 7 .

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

wherein p is 0, 1, 2, 3 or 4.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein L is

wherein R 7 is a halogen.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein one of R 2 is H, and the other R 2 is —F, —Cl, —Br, —OH, —CN, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —SH, —NH 2 , —CH 3 , —CH 2 CH 3 , —CH 2 (CH 3 ) 2 ,

—CH 2 F, —CHF 2 , —CH 2 Cl, —CH (COOH)NH 2 , —CH 2 CH 2 CH 2 F,

9 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein one of R 2 is H, and the other R 2 is —F, —Cl, —Br, —OH, —CN, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —SH, —NH 2 , —CH 3 , —CH 2 CH 3 , —CH 2 (CH 3 ) 2 ,

—CH 2 F, —CHF 2 , —CH 2 Cl, —CH (COOH)NH 2 , —CH 2 CH 2 CH 2 F,

10 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein one of R 2 is H, and the other R 2 is —OH or —OCH 3 .

11 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 3 is H or -C 1-6 alkyl.

12 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (IX-A),

or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:

q is 0, 1, 2 or 3;

Y is NR 6 , O, CR 8 R 9 , S, S(O) or S(O) 2 ; and

R 8 and R 9 are each independently H, halogen, C 1-6 alkyl, —O (C 1-6 alkyl), C 1-6 haloalkyl, C 3-6 cycloalkyl or heterocyclyl;

or R 8 and R 9 form-O.

13 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (IX-C),

or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:

p is 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3;

Y is NR 6 , O, CR 8 R 9 , S, S(O) or S(O) 2 ; and

R 8 and R° are each independently H, halogen, C 1-6 alkyl, —O (C 1-6 alkyl), C 1-6 haloalkyl, C 3-6 cycloalkyl or heterocyclyl;

or R 8 and R 9 form ═O.

14 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (IX-B),

or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein q is 0, 1, 2 or 3.

15 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (IX-D),

or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:

p is 0, 1, 2, 3 or 4; and

q is 0, 1, 2 or 3.

16 . The compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (X),

or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof.

17 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 1 is

18 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 1 is

19 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:

L is

R 7 is a halogen; and

p is 0 or 1.

20 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 2 is —F, —Cl, -Br, —OH, —CN, —OCH 3 , -OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —SH, —NH 2 , —CH 3 , —CH 2 CH 3 , —CH 2 (CH 3 ) 2 ,

—CH 2 F, —CHF 2 , —CH 2 Cl, —CH(COOH)NH 2 , —CH 2 CH 2 CH 2 F,

21 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 2 is —OH or —O(C 1-6 alkyl).

22 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 2 is —OH or —OCH 3 .

23 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 3 is H or —C 1-6 alkyl.

24 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein R 3 is H, CH 3 , CH 2 CH 3 or CH 2 CH 2 CH 3 and R 4 is CH 3 , CH 2 CH 3 or CH 2 CH 2 CH 3 .

25 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:

L is

wherein the asterisk (*) represents the point of attachment to R 1 ;

R 1 is

R 5 is halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, or —O(C 1-6 alkyl);

R 6 is H or C 1-6 alkyl;

R 7 is halogen;

Y is O or CH 2 ; and

q is 0, 1, 2 or 3.

26 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:

L is

wherein the asterisk (*) represents the point of attachment to R 1 ;

R 1 is

R 2 is —OH or —OCH 3 ;

R 3 is H or C 1-6 alkyl; and

R 7 is halogen.

27 . The compound of claim 16 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein the compound has the structure of Formula (X-A),

or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, wherein:

Y is O or CH 2 ;

R 2 is —OH or —OCH 3 ;

R 3 is H or C 1-6 alkyl;

R 5 is halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, or —O(C 1-6 alkyl);

R 6 is H or C 1-6 alkyl;

R 7 is halogen;

p is 0 or 1; and

q is 0 or 1.

28 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

29 . A compound selected from:

or a pharmaceutically acceptable salt, a stereoisomer, a racemic form, or a deuterated form thereof.

30 . A pharmaceutical composition comprising the compound of claim 29 , or a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

Assignments (5)

Priority Claims (3)

Continuity (2)

References Cited (400)