IP Library › Granted Patent US 12,331,037
Granted Patent B2
US 12,331,037 · App. 18/309,164 · Granted Jun 17, 2025

Pyrimidines as EGFR-inhibitors and methods of treating disorders

Inventors: Nathanael S. Gray (Boston, MA); Pasi Janne (Needham, MA); Hwan Geun Choi (Daegu, KR); Jaebong Jang (Boston, MA)
Assignee: Dana-Farber Cancer Institute, Inc.
C07D403/04C07D403/14C07D471/04C07D487/04
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Quick Facts
Patent No.
US 12,331,037
App. No.
18/309,164
Granted
Jun 17, 2025
Kind
B2
Abstract

The application relates to a compound having Formula (I): which modulates the activity of EGFR, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which EGFR plays a role.

Claims (47)

1. A compound of Formula (I):

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:

Z 1 , Z 2 , and Z 3 are each N;

R 1 is —H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, —NH 2 , —NH(C 1 -C 4 ) alkyl, —N((C 1 -C 4 ) alkyl) 2 , or halogen;

R 2 is —H or (C 1 -C 6 ) alkyl;

R 3 is (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, or halogen;

R 4 is —NR 9 R 10 or a 5—to 7-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S and optionally substituted with one or more R 11 ;

R 9 is —H or (C 1 -C 4 ) alkyl;

R 10 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyl-NH(C 1 -C 4 ) alkyl, or (C 1 -C 4 ) alkyl-N((C 1 -C 4 ) alkyl) 2 ;

or R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R 11 ;

each R 11 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, or halogen;

R 5 is —NR 12 C(O)R 13 or —C(O)NR 12 R 13 ;

R 12 is —H or (C 1 -C 6 ) alkyl;

R 13 is (C 1 -C 6 ) alkyl or (C 2 -C 6 ) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, and —NH 2 ;

R 6 and R 7 together with the nitrogen atom to which they are attached form a substituent of the formula

wherein

X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, CH or CR 15 ; and

each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, —OH, —NH 2 , —NH(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alkyl) 2 , or halogen.

2. The compound of claim 1 , wherein R 1 is —H or —NH 2 .

3. The compound of claim 1 , wherein R 2 is —H.

4. The compound of claim 1 , wherein R 3 is (C 1 -C 4 ) alkoxy.

5. The compound of claim 1 , wherein R 4 is —NR 9 R 10 .

6. The compound of claim 1 , wherein R 5 is —NR 12 C(O)R 13 .

7. The compound of claim 1 , wherein R 9 is C 1 -C 4 alkyl.

8. The compound of claim 1 , wherein R 10 is (C 1 -C 4 ) alkyl-NH (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) alkyl-N((C 1 -C 4 ) alkyl) 2 .

9. The compound of claim 1 , R 9 and R 10 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R 11 .

10. The compound of claim 1 , wherein R 12 is —H, and R 13 is (C 2 -C 6 ) alkenyl.

11. The compound of claim 1 , wherein R 11 is (C 1 -C 4 ) alkyl, R 12 is (C 1 -C 6 ) alkyl, and R 13 is (C 2 -C 6 ) alkenyl.

12. The compound of claim 1 , wherein R 15 is selected from (C 1 -C 6 ) alkyl and (C 1 -C 6 ) haloalkyl.

13. The compound of claim 1 having the following structural Formula (Ic):

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:

X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, CH, or CR 15 ;

each R 15 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, —OH, —NH 2 , —NH(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alkyl) 2 , or halogen;

R 1 is —H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, —NH 2 , —NH(C 1 -C 4 ) alkyl —N((C 1 -C 4 ) alkyl) 2 , or halogen;

R 2 is —H or (C 1 -C 6 ) alkyl;

R 91 is (C 1 -C 4 ) alkyl;

R 101 is (C 1 -C 4 ) alkyl-NH(C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkyl-N ((C 1 -C 4 ) alkyl) 2 ;

or R 91 and R 101 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R 11 ;

each R 11 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, or halogen; and

R 13 is (C 1 -C 6 ) alkyl or (C 2 -C 6 ) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, and —NH 2 .

14. The compound of claim 1 , selected from the group consisting of:

N-(5-((4-amino-6-(1H-indol-1-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide;

N-(5-((4-amino-6-(1H-indol-1-yl)-1,3,5-triazin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide; and

N-(5-((4-(1H-indol-1-yl)-1,3,5-triazin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide;

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

16. The compound of claim 1 , wherein the compound is N-(5-((4-amino-6-(1H-indol-1-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino) -4-methoxyphenyl)acrylamide, or a pharmaceutically acceptable salt thereof.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 19, 2023
From: GRAY, NATHANAEL S.; JANNE, PASI; CHOI, HWAN GEUN; JANG, JAEBONG
To: DANA-FARBER CANCER INSTITUTE, INC.
Reel/Frame 064313/0208 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 12, 2023
From: GRAY, NATHANAEL; JANNE, PASI; JANG, JAEBONG; CHOI, HWAN GEUN
To: DANA-FARBER CANCER INSTITUTE, INC.
Reel/Frame 064223/0960 →
Continuity (5)
Division 16950465 · Nov 17, 2020
Division 16290153 · Mar 1, 2019
Division 15536486
Provisional Application 62096053 · Dec 23, 2014
Related Publication 20230348434A1 · Nov 2, 2023
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