Pyrimidines as EGFR inhibitors and methods of treating disorders

1. A method of treating non-small cell lung cancer comprising administering to a subject in need thereof an effective amount of a compound of Formula I:

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

Z 1 and Z 2 are each independently N and Z 3 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 5 ) 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 3 is N;

X 1 , X 2 , X 4 , X 5 and X 6 are each independently CH; 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 l -C 6 ) alkyl, N((C 1 -C 6 ) alkyl) 2 , or halogen.

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

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

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

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

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

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

8. The method of claim 1 , wherein R 8 is H or halogen.

9. The method of claim 1 , wherein R 9 is (C 1 -C 4 ) alkyl.

10. The method 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 .

11. The method of claim 1 , wherein R 4 is NR 9 R 10 and 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 .

12. The method 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.

13. The method 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.

14. The method of claim 1 , wherein at least one of X 1 , X 2 , X 4 , X 5 and X 6 is CR 15 .

15. The method of claim 1 , wherein R 15 is selected from methyl and CF 3 .

16. The method of claim 1 , wherein the compound is of Formula (Ia):

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

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

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 .

17. The method of claim 1 , wherein the compound is selected from the group consisting of:

N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide;

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;

N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;

N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide; and

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide.

18. The method of claim 1 , wherein the non-small cell lung cancer is characterized by a mutation in EGFR selected from the group consisting of T790M, L718Q, L844V, L858R, Del, Del/L718Q, Del/L844V, Del/T790M, L858R/T790M, Del/T790M/L718Q, Del/T790M/L844V, L858R/L844V, L858R/L718Q, L858R/T790M/L718Q, and exon 19 deletion/T790M.