Allosteric EGFR inhibitors and methods of use thereof
The disclosure relates to compounds that act as an allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
A is a 6-10 membered aryl or a 5-10 membered heteroaryl;
W and W a are each, independently, CH, CR 6 , or N;
X and B are each, independently, N, CH, CF, or C—(C 1 -C 3 alkyl);
Y and Z are each independently N, CH, or CR 2 ;
provided that at least one of X, Y, Z, or B is CH;
R 1 is phenyl or pyridinyl, wherein phenyl or pyridinyl is optionally substituted one or two times, independently, with R 7 ;
R 2 is independently, at each occurrence, selected from the group consisting of halo, 6-10 membered aryl, 5-10 membered heteroaryl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 4-7 membered heterocycloalkyl, OR 4 , NR 4 R 4 , SO 2 R 4 , SO 2 NHR 4 , NHSO 2 R 4 , C(O)OR 4 , C(O)NHR 4 , C(O)R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein 6-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, and 3-6 membered cycloalkyl are optionally substituted with R 3 , and wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl are each optionally substituted one, two, or three times with R 4 ;
R 3 is selected from the group consisting of halo, —OH, —SH, —CN, —NO 2 , —NH 2 , OR 4 , NR 4 R 4 , SO 2 R 4 , SO 2 NHR 4 , NHSO 2 R 4 , C(O)OR 4 , C(O)NHR 4 , C(O) R 4 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, and 4-7 membered heterocycloalkyl, wherein 4-7 membered heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl-OH, halo, and ═O;
R 4 is independently, at each occurrence, selected from the group consisting of hydrogen, (CH 2 ) 0-3 -(3-7 membered cycloalkyl), (CH 2 ) 0-3 -(4-7 membered cycloalkenyl), (CH 2 ) 0-3 -(6-10 membered aryl), (CH 2 ) 0-3 -(5- to 6-membered heteroaryl), or (CH 2 ) 0-3 -(4- to 7-membered heterocycloalkyl), wherein 6-10 membered aryl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl are each optionally substituted one, two, or three times with R 5 ;
R 5 is independently, at each occurrence, selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, COOH, C(O)O(C 1 -C 6 alkyl), O(CH 2 ) 1-3 OH, NH 2 , OH, CN, (CH 2 ) 0-3 (6-10 membered aryl), (CH 2 ) 0-3 (5- to 6-membered heteroaryl), and (CH 2 ) 0-3 (4- to 7-membered heterocycloalkyl), wherein 6-10 membered aryl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 NH 2 , (CH 2 ) 1-2 OH, C(O)(CH 2 ) 1-2 OH, and C(O)O(C 1 -C 6 alkyl);
R 6 is independently, at each occurrence, C 1 -C 6 alkyl or halo; and
R 7 is independently, at each occurrence, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, halo, OH, SH, NO 2 , NH 2 , (CH 2 ) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH 2 , or CN.
2 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula II:
or a pharmaceutically acceptable salt thereof;
wherein:
A is a 6-10 membered aryl or a 5-10 membered heteroaryl;
W and W a are each, independently, CH, CR 6 , or N;
R 2 is independently, at each occurrence, selected from the group consisting of halo, 6-10 membered aryl, 5-10 membered heteroaryl, and 3-6 membered cycloalkyl, wherein 6-10 membered aryl, 5-10 membered heteroaryl, and 3-6 membered cycloalkyl are optionally substituted with R 3 ;
R 3 is selected from the group consisting of halo, —OH, —SH, —CN, —NO 2 , —NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-10 membered aryl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, and 4-7 membered heterocycloalkyl, wherein 4-7 membered heterocycloalkyl is optionally substituted with one or more substituent selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkyl-OH, halo, and ═O;
R 7 is selected from the group consisting of halo, —OH, —SH, —CN, —NO 2 , and —NH 2 ;
m is 0, 1, or 2; and
n is 1 or 2.
3 . The compound of claim 1 , wherein R 7 is absent or at least one R 7 is halo.
4 . The compound of claim 3 , wherein at least one R 7 is fluoro.
5 . The compound of claim 1 , wherein A is 5-6 membered heteroaryl.
6 . The compound of claim 1 , wherein A is thiazolyl or pyridinyl.
7 . The compound of claim 1 , wherein R 2 is selected from the group consisting of halo, 6-10 membered aryl, 5-10 membered heteroaryl, and 3-6 membered cycloalkyl, wherein 6-10 membered aryl is optionally substituted with R 3 .
8 . The compound of claim 1 , wherein R 2 is bromo or chloro.
9 . The compound of claim 1 , wherein R 2 is phenyl further substituted with R 3 .
10 . The compound of claim 9 , wherein R 3 is a 6-membered heterocycloalkyl optionally substituted with C 1 -C 4 alkyl.
11 . The compound of claim 10 , wherein R 3 is piperidinyl or piperazinyl, each further substituted with methyl.
12 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII:
or a pharmaceutically acceptable salt thereof, wherein n=1 or 2, and m=0, 1, or 2.
13 . The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
15 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , optionally in combination with a therapeutically effective amount of a second active agent.
16 . The method according to claim 15 , wherein the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer.
17 . The method according to claim 15 , wherein the cancer is non-small cell lung cancer (NSCLC).
18 . A method of inhibiting EGFR in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
19 . A method of treating or preventing an EGFR-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
20 . The method according to claim 19 , wherein the EGFR-mediated disorder is resistant to an EGFR-targeted therapy.