EGFR inhibitors
The present disclosure provides a compound represented by structural formula (I): or a pharmaceutically acceptable salt thereof useful for treating a cancer.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Z is O or NH;
each A 1 , A 2 , and A 3 is independently N or CR; wherein each R is independently H, halogen, or CH 3 ;
Ring A is 4-12 membered heterocyclyl;
each R 1 is independently halogen, CN, OH, NR a R b , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl or —O—C 3 -C 6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl represented by R 1 or in the group represented by R 1 is optionally substituted with 1 to 3 groups selected from deuterium, halogen, OH, NR a R b , C 1 -C 2 alkyl, and C 1 -C 2 alkoxy; and/or
m is 0, 1, 2, 3, 4, 5, or 6;
R 2 is H, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl represented by R 2 is optionally substituted with 1 to 3 groups selected from halogen and OH;
R 3 is H or methyl;
R 4 is H or methyl;
R 5 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered monocyclic heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl represented by R 5 is optionally substituted with 1 to 3 three groups selected from halogen, CN, OH, NR a R b , C 1 -C 2 alkyl, and C 1 -C 2 alkoxy;
R 6 is H or C 1 -C 4 alkyl optionally substituted with 1 to 3 three groups selected from halogen, CN, OH, NR a R b , and C 1 -C 2 alkoxy; and
each Ra and R b is independently H or C 1 -C 4 alkyl.
2. The compound of claim 1 , wherein the compound is represented by structural formula (II-A), (II-B), (II-C), (II-D), or (II-E):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is represented by structural formula (II-A):
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein Z is O.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H, fluorine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl represented by R 2 is optionally substituted with 1 to 3 groups selected from halogen and OH.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H, methyl, ethyl, C 1 -C 2 haloalkyl, or C 1 -C 2 aminoalkyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H; C 1 -C 4 alkyl optionally substituted with 1 to 3 three groups selected from halogen, CN, and NR a R b ; C 3 -C 6 cycloalkyl; or 4-6 membered monocyclic heterocyclyl optionally substituted with C 1 -C 4 alkyl; and wherein R a and R b are each independently selected from H, methyl and ethyl.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein Ring A is 4-7 membered monocyclic heterocyclyl optionally substituted with 1-6 R 1 .
9. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein Ring A is 7-12 membered bicyclic heterocyclyl optionally substituted with 1-6 R 1 .
10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3, 4, or 5; and
each R 1 is independently halogen, CN, OH, NR a R b , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —O—C 3 -C 6 cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl represented by R 1 or in the group represented by R 1 is optionally substituted with 1 to 3 groups selected from deuterium, halogen, OH, NR a R b , C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.
11. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H, F, methyl, ethyl, isopropyl, CH (CH 3 ) CH 2 F, CH (CH 3 ) CH 2 OH, CF 3 , OCH 3 , OCH 2 CH 3 , or cyclopropyl.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H, CH 3 , or CH 2 NH 2 .
13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with 1-6 R 1 , and Ring A is pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, 2-azabicyclo[2.2.1] heptanyl, 3-azabicyclo[3.2.1] octanyl, 6-oxa-2-azabicyclo[3.2.1] octanyl, 6-oxa-3-azabicyclo[3.2.1] octanyl, 8-oxa-3-azabicyclo[3.2.1] octanyl, hexahydro-1H-furo[3,4-b] pyrrolyl, hexahydro-1H-furo[3,4-c] pyrrolyl, 1-oxa-7-azaspiro[3.5] nonan-7-yl, 1,4-dioxa-8-azaspiro[4.5] decan-8-yl or 1,4-dioxa-9-azaspiro[5.5] undecan-9-yl.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein at least one R 1 is OH, C 1 -C 4 alkoxy, or —O—C 3 -C 6 cycloalkyl, wherein the alkoxy or cycloalkyl represented by R 1 or in the group represented by R 1 is optionally substituted with 1 to 3 groups selected from deuterium, halogen, OH, NR a R b , C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.
15. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently F, CN, OH, NH 2 , CH 3 , CH 2 CH 3 , CHF 2 , CH (OH) CH 3 , CH 2 OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , OCH 3 , OCD 3 , OCH 2 CH 2 OH, OCH 2 CH (OH) CH 3 , OCH 2 C (OH) (CH 3 ) 2, OCH 2 CH 2 OCH 3 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHCH 3 , OCH 2 CH 2 N (CH 3 ) 2 , —O-cyclopropyl, NHCH 3 , or N (CH 3 ) 2 .
16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein
17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H or isopropyl.
18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl optionally substituted with 1-6 R 1 .
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20. A method of treating lung cancer, comprising administering a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
21. A method of inhibiting epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.