EGFR inhibitors
The present disclosure provides a compound represented by structural formula (I-0): or a pharmaceutically acceptable salt thereof useful for treating a cancer.
1 . A compound of Formula (I-0)
or a pharmaceutically acceptable salt thereof, wherein
X 1 , X 2 , X 3 , X 4 , and X 5 is CR 3c , N, or N + —O − , provided that at least 3 of X 1 , X 2 , X 3 , X 4 , and X 5 is CR 3c ;
X 6 is CH;
X 7 and X 8 is N
R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4- to 12-membered heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl represented by R 1 is optionally substituted with 1 to 4 groups independently selected from deuterium, halo, C 1 -C 4 alkyl, ═O, OH, C 1 -C 4 alkoxy, NR 1a R 1b , and 4 to 8 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with methyl, ethyl, or —(CH 2 ) m NR 1a R 1b ;
R 2 is halo, NR 1a R 1b , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, 4- to 12-membered heterocyclyl, or 5 or 6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycyl, and heteroaryl represented by R 2 are each optionally substituted with 1 to 4 groups selected from deuterium, halo, ═O (as valence permits), OH, NR 1a R 1b , C(O)CH 3 , C 1 -C 4 alkyl and C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 3 groups selected from deuterium, halo, OH, and OCH 3 ;
R 3a is H, deuterium, halo, OH, C 1-4 alkyl, or C 1 -C 4 alkoxy;
R 3b is H, deuterium, halo, OH, C 1-4 alkyl, or C 1 -C 4 alkoxy;
Each R 3c is independently selected from H, deuterium, halo, OH, C 1-4 alkyl, and C 1 -C 4 alkoxy, wherein no more than 3 R 3c are halo, OH, C 1-4 alkyl, or C 1 -C 4 alkoxy;
R 1a is H, deuterium, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl;
R 1b is H, deuterium, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl;
R 4 is H or deuterium;
R 5 is H or deuterium; and m is 0 or 1.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3 alkyl substituted with N(CH 3 ) 2 .
3 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of any of claim 1 , or a pharmaceutically acceptable salt thereof.
4 . A method of treating a cancer, comprising administering a subject in need thereof an effective amount of a compound of claim 1 , wherein the cancer is non-small cell lung cancer (NSCLC).
5 . The method of claim 4 , wherein the cancer in the subject in need thereof has metastasized and wherein the cancer is characterized by: (i) epidermal growth factor receptor EGFR L858R mutation or exon 19 deletion; ii) C797S mutation; and (iii) EGFR T790M mutation.
6 . The method of claim 4 , further comprises administering the subject in need thereof an effective amount of afatinib or osimertinib.
7 . A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein
X 1 , X 2 , X 3 , X 4 , and X 5 is CR 3c or N, provided that at least 3 of X 1 , X 2 , X 3 , X 4 , and X 5 is CR 3c ;
R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4 to 12 membered heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl represented by R 1 is optionally substituted with 1 to 4 groups independently selected from halo, C 1 -C 4 alkyl, ═O, OH, C 1 -C 4 alkoxy, NR 1a R 1b , and 4 to 8 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with —(CH 2 ) m NR 1a R 1b ;
R 2 is C 1 -C 4 alkoxy, 4 to 12 membered heterocyclyl, 5 or 6 membered heteroaryl, wherein the heterocycyl, and heteroaryl represented by R 2 are each optionally substituted with 1 to 4 groups selected from C 1 -C 4 alkyl and C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 3 groups selected from halo, OH and OCH 3 ;
R 3a is H, halo, OH, C 1-4 alkyl, or C 1 -C 4 alkoxy;
R 3b is H, halo, OH, C 1-4 alkyl, or C 1 -C 4 alkoxy;
Each R 3c is independently selected from H, halo, OH, C 1-4 alkyl, and C 1 -C 4 alkoxy, wherein no more than 3 R 3c are halo, OH, C 1-4 alkyl, or C 1 -C 4 alkoxy;
R 1a is H, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl;
R 1b is H, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl; and
m is 0 or 1.
8 . The compound of claim 7 , wherein the compound is of Formula (II), (IIA), (IIB), (IIC), (IID), (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE),
or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1 -C 5 alkyl optionally substituted with 1 to 3 groups independently selected from F, Cl, ═O, OH, OCH 3 , NR 1a R 1b , 3-oxabicyclo[3.1.0]hexanyl, azetidinyl, oxetanyl, tetrahydrofuranyl, and morpholinyl, wherein the oxetanyl is optionally substituted with N(CH 3 ) 2 or CH 2 N(CH 3 ) 2 ;
R 1a is H, methyl, cyclopropyl, or cyclobutyl; and
R 1b is methyl.
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 1 is ethyl substituted with oxetanyl.
11 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrazolyl optionally substituted with C 1 -C 4 alkyl or C 1 -C 4 alkoxy, each of which are optionally substituted with 1 to 3 groups selected from halo and OH.
12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrazolyl optionally substituted with methyl.
13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 3a is halo; R 3b is halo, and each R 3c is H; or
R 3a is H; R 3b is H, and each R 3c is H; or
R 3a is H; R 3b is halo, and each R 3c is H; or
R 3a is halo; R 3b is H, and each R 3c is H.
14 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1 -C 6 alkyl optionally substituted with 1 to 4 groups independently selected from halo, ═O, OH, C 1 -C 4 alkoxy, NR 1a R 1b , and 4 to 8 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with —(CH 2 ) m NR 1a R 1b ;
R 1a is H, C 1-4 alkyl, or C 3 -C 6 cycloalkoxy; and
R 1b is H or C 1-4 alkyl.
15 . The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 5 or 6 membered heteroaryl optionally substituted with 1 to 3 groups selected from C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy represented by R 2 are each optionally substituted with 1 to 3 groups selected from halo and OH.
16 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 3 -C 6 cycloalkyl optionally substituted with 1 to 4 groups independently selected from halo, C 1 -C 4 alkyl, ═O, OH, C 1 -C 4 alkoxy, and NR 1a R 1b ;
R 1a is H, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl; and
R 1b is H or C 1 -C 4 alkyl.
17 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is 4 to 8 membered monocyclic heterocyclyl optionally substituted with 1 to 2 groups independently selected from halo, C 1 -C 4 alkyl, ═O, OH, C 1 -C 4 alkoxy, and NR 1a R 1b ;
R 1a is H, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl; and
R 1b is H or C 1 -C 4 alkyl.
18 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is C 1 -C 4 alkoxy; or
R 2 is 4 to 12 membered heterocyclyl optionally substituted with 1 to 3 groups selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, wherein the alkyl represented by R 2 is optionally substituted with OH.