Pyrimidines as EGFR inhibitors and methods of treating disorders
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.
1. A compound of Formula I:
or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:
Z 1 and Z 3 are each independently N and Z 2 is CR 8 ;
R 8 is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, 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 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 2 is H.
3. The compound of claim 1 , wherein R 3 is (C 1 -C 4 ) alkoxy.
4. The compound of claim 1 , wherein R 4 is —NR 9 R 10 .
5. The compound of claim 1 , wherein R 5 is —NR 12 C(O)R 13 .
6. The compound of claim 1 , wherein R 8 is H or halogen.
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 , wherein 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 11 is (C 1 -C 4 ) alkyl, 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 Formulae (Ib)
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 8 is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, or halogen;
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, —ON, and —NH 2 .
14. The compound of claim 1 , selected from the group consisting of:
N-(5-((6-(1H-indol-1-yl)pyrimidin-4-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
N-(5-((6-(1H-indazol-1-yl)pyrimidin-4-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)-amino)-4-methoxyphenyl)acrylamide; and
N-(5-((6-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-4-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide.
15. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
16. The compound of claim 1 , wherein the compound of Formula I is N-(5-((6-(1H-indol-1-yl)pyrimidin-4-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino) methoxyphenyl)acrylamide, or a pharmaceutically acceptable salt thereof.