Cyano-pyrimidine inhibitors of EGFR/HER2
This disclosure provides compounds of Formula (I): or a pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising compounds of Formula (I) or a pharmaceutically acceptable salt thereof which are inhibitors of EGFR and HER2 useful for the treatment of EGFR/HER2 susceptible disorders such as cancer, including cancer of the lung, colon, breast, and thyroid.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
is an optional double bond;
A, B, and C are, independently at each occurrence, N, C, C—CN, or CH;
X is N or CH;
Y is N or O, provided that when Y is O, R 6 is absent;
R 1 is selected from the group consisting of hydrogen, halo, hydroxy, cyano, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, COR 11 , CO 2 R 11 , and C 1 -C 4 alkoxy, wherein R 1 is absent if B is N, C—CN, or CH, and C 1 -C 3 alkyl is optionally substituted with halo;
R 2 is selected from the group consisting of 5-7 membered heteroaryl and C 3 -C 8 cycloalkyl; wherein 5-7 membered heteroaryl and C 3 -C 8 cycloalkyl are optionally substituted with one, two, or three R 9 ; or R 2 is phenyl substituted one, two, or three times with a substituent selected from the group consisting of C 1 -C 6 alkyl, hydroxy, 5-10 membered heteroaryl, O-(5-10 membered heteroaryl), and C 1 -C 6 alkylamine, wherein C 1 -C 6 alkyl is optionally substituted with N(CH 3 ) 2 ;
R 3 is hydrogen or C 1 -C 6 alkyl;
R 4 is hydrogen or C 1 -C 4 alkyl;
R 5 is hydrogen or methyl; or
alternatively, R 2 and R 5 , together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring;
R 6 is hydrogen or C 1 -C 6 alkyl;
R 7 is C 1 -C 6 alkyl or —C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 ;
or, alternatively, R 6 and R 7 , together with the nitrogen to which they are attached, form a 4- or 5-membered heterocyclic ring; wherein the 4- or 5-membered heterocyclic ring is optionally substituted with one or two R 10 ;
R 8 is hydrogen or —CH 2 N(CH 3 ) 2 ;
R 9 is, independently at each occurrence, selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, 5-10 membered heteroaryl, O-(5-10 membered heteroaryl), and C 1 -C 6 alkylamine, wherein C 1 -C 6 alkyl is optionally substituted with one, two, or three halo or N(CH 3 );
or, alternatively, two R 9 groups, together with the atoms to which they are attached, form a 3-, 4-, or 5-membered ring;
R 10 is selected from the group consisting of OH, C 1 -C 4 alkoxy, and N(CH 3 ) 2 ; and
R 11 is independently, at each occurrence, selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl.
2 . The compound according to claim 1 , wherein R 4 is methyl.
3 . The compound according to claim 1 , wherein R 5 is hydrogen.
4 . The compound according to claim 1 , wherein is a double bond.
5 . The compound according to claim 1 , wherein the compound of Formula I is a compound of Formula II:
or a pharmaceutically acceptable salt thereof.
6 . The compound according to claim 1 , wherein the compound of Formula I is a compound of Formula III:
or a pharmaceutically acceptable salt thereof.
7 . The compound according to claim 1 , wherein the compound of Formula I is a compound of Formula IV:
or a pharmaceutically acceptable salt thereof.
8 . The compound according to claim 1 , wherein the compound of Formula I is a compound of Formula V:
or a pharmaceutically acceptable salt thereof.
9 . The compound according to claim 1 , wherein B is C and R 1 is selected from the group consisting of cyano, hydroxy, methoxy, cyclopropyl, and CF 3 .
10 . The compound according to claim 1 , wherein R 2 is
wherein:
m is 0, 1, or 2;
n is 1 or 2; and
p is 0, 1, 2, or 3.
11 . The compound according to claim 1 , wherein R 6 is methyl and R 7 is —CH 2 CH 2 N(CH 3 ) 2 .
12 . The compound according to claim 1 , wherein R 6 and R 7 , together with the nitrogen to which they are attached, form a 4- or 5-membered heterocyclic ring selected from the group consisting of
13 . The compound according to claim 1 , wherein R 2 is bicyclo[1.1.1]pentane or bicyclo[2.2.2]octane, both of which are optionally substituted with one, two, or three R 9 .
14 . The compound according to claim 1 , wherein R 2 is selected from the group consisting of:
15 . The compound according to claim 1 , wherein the compound of Formula I is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
16 . A pharmaceutical composition comprising a compound according to claim 1 , or a salt thereof, and at least one pharmaceutically acceptable carrier.
17 . A method of treating non-small cell lung cancer (NSCLC) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1 .
18 . A method of inhibiting EGFR and/or HER2 in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1 .
19 . The method according to claim 18 , wherein EGFR or HER2 is characterized by in-frame insertions in exon 20.