Granted Patent B2

US 12,552,826 · App. 17/266,515 · Granted Feb 17, 2026

Inventors: Michelle Machacek (Belmont, MA); David Witter (Norfolk, MA); Chunhui Huang (Arlington, MA); Shuhei Kawamura (Cambridge, MA); Sebastian Schneider (Boston, MA); Murray Wan (Watertown, MA)

Assignee: Merck Sharp & Dohme LLC

C07H19/14A61P35/00

Abstract

Claims (132)

1 . A compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein

X is O;

Y is —CH(CH 3 ), CH(OH), or C(CH 3 )(OH) or C═CH 2 ;

A 1 is CH;

A 2 is CH;

Z 1 is N, or CR 4 ;

Z 2 is N, or CR 5 ;

Z 3 is N, or CR 6 ;

Z 4 is N, or CR 7 ;

Z 5 is N, or CR 8 ;

R 1 is CH 3 ;

R 2 is H;

R 3 is CH 3 , or NH 2 ;

R 4 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, OC 1-6 alkyl, or taken together with R 5 forms a 5 or 6 membered ring comprising one N atom;

R 5 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, OC 1-6 alkyl, or taken together with R 4 forms a 5 or 6 membered ring comprising one N atom;

R 6 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, or OC 1-6 alkyl;

R 7 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, or OC 1-6 alkyl;

R 8 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, or OC 1-6 alkyl;

each R 9 , when present, is independently H or C 1-6 alkyl;

provided that either:

(1) Z 1 and Z 2 are CR 4 and CR 5 , respectively, wherein R 4 together with R 5 forms a 5- or 6-membered ring comprising one N atom, or

(2) at least one of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is CCHF 2 .

2 . The compound of claim 1 , of formula:

or a pharmaceutically acceptable salt thereof, wherein

Z 1 is N, or CR 4 ;

Z 2 is N, or CR 5 ;

Z 3 is N, or CR 6 ;

Z 4 is N, or CR 7 ;

Z 5 is N, or CR 8 ;

R 3 is CH 3 , or NH 2 ;

R 4 is H, halogen, C 1-4 alkyl optionally substituted with one to four halogens, OC 1-4 alkyl, or taken together with R 5 forms a 5 or 6 membered ring comprising one N atom;

R 5 is H, halogen, C 1-4 alkyl optionally substituted with one to four halogens, OC 1-4 alkyl, or taken together with R 4 forms a 5 or 6 membered ring comprising one N atom;

R 6 is H, halogen, C 1-4 alkyl optionally substituted with one to four halogens, or OC 1-4 alkyl;

R 7 is H, halogen, C 1-4 alkyl optionally substituted with one to four halogens, or OC 1-4 alkyl;

R 8 is H, halogen, C 1-3 alkyl optionally substituted with one to four halogens, or OC 1-3 alkyl;

R 9 is H or CH 3 ;

provided that either:

(1) Z 1 and Z 2 are CR 4 and CR 5 , respectively, wherein R 4 together with R 5 forms a 5- or 6-membered ring comprising one N atom, or

(2) one of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is CCHF 2 .

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH(OH), or C(CH 3 )(OH).

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is NH 2 .

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 4 is CR 7 and R 7 is CHF 2 .

6 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

R 4 is H, CH 3 , F, Cl or taken together with R 5 forms a 6 membered ring comprising one N atom;

R 5 is H, F, Cl, CF 3 , or CF 2 H or taken together with R 4 forms a 6 membered ring comprising one N atom;

R 6 is H, F, Cl, CF 3 , or CF 2 H;

R 7 is H, F, Cl, CF 3 , or CF 2 H; and

R 8 is H, CH 3 , F or Cl.

7 . A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8 . The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof, wherein

Y is CR 9 R 9 , CR 9 OR 9 , or C═CH 2 ;

R 3 is CH 3 , or NH 2 ;

R 6 is H, halogen, C 1-4 alkyl optionally substituted with one to four halogens, or OC 1-4 alkyl;

R 7 is H, halogen, C 1-4 alkyl optionally substituted with one to four halogens, or OC 1-4 alkyl;

R 8 is H, halogen, C 1-4 alkyl optionally substituted with one to four halogens, or OC 1-4 alkyl; and

each R 9 , when present, is independently H or CH 3 .

9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:

Y is CH(CH 3 ), CH(OH), C(CH 3 )(OH), or C═CH 2 ;

R 6 is H, F, Cl, CH 3 , OCH 3 , CF 3 , or CF 2 H;

R 7 is H, F, Cl, CH 3 , OCH 3 , CF 3 , or CF 2 H; and

R 8 is H, F, Cl, CH 3 , OCH 3 , CF 3 , or CF 2 H.

10 . The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof, wherein:

X is O;

Y is CR 9 R 9 , or CR 9 OR 9 ;

A 1 is CH;

A 2 is CH;

Z 1 is N, or CR 4 ;

Z 2 is N, or CR 5 ;

Z 3 is N, or CR 6 ;

Z 4 is N, or CR 7 ;

Z 3 is N, or CR 8 ;

R 1 is CH 3 ;

R 2 is H;

R 3 is CH 3 , or NH 2 ;

R 4 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, or OC 1-6 alkyl;

R 5 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, OC 1-6 alkyl;

R 6 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, or OC 1-6 alkyl;

R 7 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, or OC 1-6 alkyl;

R 8 is H, halogen, C 1-6 alkyl optionally substituted with one to four halogens, or OC 1-6 alkyl;

each R 9 is independently H or CH 3 ;

provided that one of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is CCHF 2 H.

11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:

Y is CH(CH 3 ), CH(OH), or C(CH 3 )(OH); and

R 3 is NH 2 .

12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

R 4 is H, CH 3 , F, or CI;

R 5 is H, F, Cl, CF 3 , or CF 2 H;

R 6 is H, F, Cl, CF 3 , or CF 2 H;

R 7 is H, F, Cl, CF 3 , or CF 2 H; and

R 8 is H, F, or Cl.

13 . The compound of claim 1 , selected from:

or a pharmaceutically acceptable salt thereof.

14 . A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 3 is CH 3 , or NH 2 ;

R 4 is H, F, or C 1-3 alkyl optionally substituted with one to four F;

R 5 is CF 2 H;

R 6 is H;

R 7 is H, F, C 1-3 alkyl optionally substituted with one to four F;

R 8 is H, F, C 1-3 alkyl optionally substituted with one to four F; and

R 9 is H or CH 3 ,

provided that one of R 4 , R 5 , R 6 , R 7 and R 8 is CHF 3 .

15 . The compound according to claim 14 , or a pharmaceutically acceptable salt thereof, wherein:

R 4 is H or F;

R 7 is H or F; and

R 8 is H, or F.

16 . A composition comprising a compound of claim 14 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically carrier.

17 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:

Y is CH(CH 3 ), CH(OH), C(CH 3 )(OH), or C═CH 2 ;

R 6 is F, Cl, CH 3 , OCH 3 , CF 3 , or CF 2 H;

R 7 is F, Cl, CH 3 , OCH 3 , CF 3 , or CF 2 H; and

R 8 is F, Cl, CH 3 , OCH 3 , CF 3 , or CF 2 H.

18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is N.

19 . The compound of claim 1 , selected from:

or a pharmaceutically acceptable salt thereof.

20 . The compound of claim 1 , selected from:

or a pharmaceutically acceptable salt thereof.

21 . The compound of claim 1 , selected from:

or a pharmaceutically acceptable salt thereof.

22 . The compound of claim 1 , selected from:

or a pharmaceutically acceptable salt thereof.

23 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 2 are CR 4 and CR 5 , respectively, wherein R 4 together with R 5 forms a 6-membered ring comprising one N atom, wherein the ring is not aromatic.

24 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 6 , R 7 , and R 8 , is CF 2 H.

25 . The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof, wherein.

26 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

(1) Z 1 and Z 2 are CR 4 and CR 5 , respectively, wherein R 4 together with R 5 forms a 5- or 6-membered ring comprising one N atom, and

(2) at least one of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is CCHF 2 .

27 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of Z 1 , Z 2 , Z 3 , Z 4 , and Z 3 is CCHF 2 .

Assignments (2)

Continuity (2)

References Cited (257)