Pyrimidines as EGFR inhibitors and methods of treating disorders

1. A compound of Formula (I′):

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

R 1 is phenyl substituted with one or more R 8 or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R 8 ;

each R 8 is independently halogen, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkoxy, OH, NH 2 , NH(C 1 -C 3 ) alkyl, or N((C 1 -C 3 )alkyl) 2 ;

R 2 is H or (C 1 -C 3 ) alkyl;

R 3 is

R 6 is (C 2 -C 4 ) alkenyl optionally substituted with one or more R 9 ;

each R 9 is independently NH 2 , NH(C 1 -C 3 ) alkyl, N((C 1 -C 3 ) alkyl) 2 , or heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, OH, and C(O)(C 1 -C 3 ) alkyl;

R 7 is H or (C 1 -C 3 ) alkyl;

R 4 is

R 10 is (C 1 -C 3 ) alkyl optionally substituted with C(O)NH—(C 1 -C 3 ) alkyl, C(O)N((C 1 -C 3 ) alkyl) 2 , or a heterocyclyl comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, or R 10 is heterocyclyl comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S optionally substituted with one or more (C 1 -C 3 ) alkyl;

each R 11 is independently (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy, (C 1 -C 3 ) haloalkoxy, or halogen;

n is 0, 1, or 2; and

R 5 is H or (C 1 -C 3 ) alkyl.

2. The compound of claim 1 , wherein R 1 is phenyl substituted with one or more R 8 .

3. The compound of claim 1 , wherein R 1 is pyridinyl optionally substituted with one or more R 8 .

4. The compound of claim 1 , wherein R 1 is benzothiophenyl optionally substituted with one or more R 8 .

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

6. The compound of claim 1 , wherein R 2 is methyl.

7. The compound of claim 1 , wherein R 6 is ethenyl.

8. The compound of claim 1 , wherein R 6 is ethenyl substituted with one or more R 9 .

9. The compound of claim 1 , wherein R 7 is H.

10. The compound of claim 1 , wherein R 5 is H.

11. The compound of claim 1 , wherein R 4 is

12. The compound of claim 1 , wherein R 4 is

13. The compound of claim 1 , wherein R 8 is halogen.

14. The compound of claim 13 , wherein R 8 is F.

15. The compound of claim 1 , wherein R 10 is unsubstituted methyl.

16. The compound of claim 1 , wherein R 10 is methyl or ethyl substituted with morpholino.

17. The compound of claim 1 , wherein R 10 is methyl or ethyl substituted with C(O)NH—(C 1 -C 3 ) alkyl.

18. The compound of claim 1 , wherein R 10 is heterocyclyl comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S optionally substituted with one or more (C 1 -C 3 ) alkyl.

19. The compound of claim 1 , having structural Formula (Ia) or (Ib):

or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof.

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

3-fluorobenzyl (3-acrylamidophenyl)(2-(1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;

3-fluorobenzyl (3-acrylamidophenyl)(2-(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (3-acrylamidophenyl)(2-(1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (3-acrylamidophenyl)(2-(1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

benzo[b]thiophen-2-ylmethyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;

benzo[b]thiophen-2-ylmethyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-chlorobenzyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;

4-chlorobenzyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

(5-fluoropyridin-2-yl)methyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;

(5-fluoropyridin-2-yl)methyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

(6-fluoropyridin-3-yl)methyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

(6-fluoropyridin-3-yl)methyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;

(R)-1-phenylethyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;

(R)-1-phenylethyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

(S)-1-phenylethyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;

(S)-1-phenylethyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

benzo[b]thiophen-3-ylmethyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;

benzo[b]thiophen-3-ylmethyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (3-acrylamidophenyl)(2-((1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (3-acrylamidophenyl)(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (3-acrylamidophenyl)(2-(1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (3-acrylamidophenyl)(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (E)-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(3-(4-(piperidin-1-yl)but-2-enamido)phenyl)carbamate;

4-fluorobenzyl (E)-(3-(4-(4-hydroxypiperidin-1-yl)but-2-enamido)phenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (E)-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(3-(4-morpholinobut-2-enamido)phenyl)carbamate;

4-fluorobenzyl (E)-(3-(4-(azepan-1-yl)but-2-enamido)phenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (E)-(3-(4-(dimethylamino)but-2-enamido)phenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

2,4-difluorobenzyl (3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (3-acrylamidophenyl)(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;

4-fluorobenzyl (3-acrylamidophenyl)(2-((1-(2-(methylamino)-2-oxoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate; and

4-fluorobenzyl (3-acrylamidophenyl)(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate,

or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof.

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

22. A method of inhibiting a kinase or epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

23. A method of treating a cell proliferation disease in which EGFR plays a role, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

24. The method of claim 23 , wherein the cell proliferation disease is lung cancer.

25. The method of claim 24 , wherein the lung cancer is non-small cell lung cancer (NSCLC).