BRAF degraders
Present invention provides compounds that cause specifically the degradation of BRAF. The present compounds are useful for the treatment of various cancers.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof;
wherein
R 2 and R 3 are independently selected from H and C 1-6 -alkyl;
or R 2 and R 3 together form —CH 2 —;
X is selected from —CH 2 —, —NR 4 —, and —O—;
R 4 is selected from H and C 1-6 -alkyl;
A is selected from:
R e is independently selected from halogen, cyano, and C 1-6 -alkyl;
t is selected from 0, 1, and 2;
R f is independently selected from H, C 3-8 -cycloalkyl, and C 1-6 -alkyl;
B is absent or selected from:
R g is independently selected from halogen, hydroxy, and C 1-6 -alkyl;
R t is independently selected from H, C 3-8 -cycloalkyl, and C 1-6 -alkyl;
u is independently selected from 0, 1, and 2;
E is absent or selected from
R i is independently selected from halogen, hydroxy, C 3-8 -cycloalkyl, and C 1-6 -alkyl;
v is independently selected from 0, 1, and 2;
m and n are independently selected from 0, 1, 2, and 3;
R a , R b , R c and R d are independently selected from H and C 1-6 -alkyl;
A 4 is selected from a bond and —NR 101 —;
R 101 is selected from H and C 1-6 -alkyl;
w is selected from 0 and 1;
A 3 is selected from a bond, —O—, —NR 200 —, and
R 200 is selected from H and C 1-6 -alkyl;
C is selected from:
R m is independently selected from halogen, hydroxy, C 3-8 -cycloalkyl, and C 1-6 -alkyl;
y is independently selected from 0, 1, and 2;
D is selected from:
R p is independently selected from halogen, C 3-8 -cycloalkyl, halo-C 1-6 -alkyl, C 1-6 -alkyl, cyano, C 1-6 -alkyl sulfonyl, and C 3-8 -cycloalkylsulfonyl;
z is independently selected from 0, 1, and 2;
R 100 is selected from H, halogen, and C 1-6 -alkyl;
R 7 and R 8 are independently selected from H, C 1-6 -alkyl, and halogen;
A 1 is selected from —NR 5 — and —CHR 6 —;
R 5 is selected from H and C 1-6 -alkyl;
or R 1 and R 5 together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by R 14 , R 15 and R 16 ;
R 6 is selected from H and C 1-6 -alkyl;
or R 1 and R 6 together with the carbon atom to which they are attached form a cycloalkyl optionally substituted by R 14 , R 15 and R 16 ;
R 14 , R 15 and R 16 are independently selected from C 1-6 -alkyl and halogen; and
R 1 is selected from C 1-6 -alkyl and C 3-8 -cycloalkyl.
2 . The compound of claim 1 , wherein R 2 and R 3 are H.
3 . The compound of claim 2 , wherein X is —NR 4 —.
4 . The compound of claim 3 , wherein A is
5 . The compound of claim 4 , wherein R e is halogen and t is 1.
6 . The compound of claim 3 , wherein B is
7 . The compound of claim 6 , wherein R g is hydroxy and u is 1.
8 . The compound of claim 3 , wherein E is absent.
9 . The compound of claim 3 , wherein v is 0 or 1.
10 . The compound of claim 1 , wherein m is 0 and n is 0.
11 . The compound of claim 3 , wherein R a and R b are H.
12 . The compound of claim 3 , wherein R c and R d are H.
13 . The compound of claim 3 , wherein C is
14 . The compound of claim 13 , wherein y is 0.
15 . The compound of claim 3 , wherein C is
16 . The compound of claim 15 , wherein R m is hydroxy.
17 . The compound of claim 3 , wherein D is
18 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
20 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
21 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
23 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.