Compounds for targeted degradation of RET
Compounds of Formula (I) which act as protein degradation inducing moieties for proto-oncogene tyrosine-protein kinase receptor (RET), which may be either wild type RET or a mutant form of RET, are described. The compounds can be used to treat a disorder mediated by RET protein, for example a cancer or a tumor.
1 . A compound of Formula:
or a pharmaceutically acceptable salt thereof;
wherein
R 1a is hydrogen;
R 1b is hydrogen;
X 7 is CH;
Q 1 is NH;
X 3 , X 4 , X 5 , and X 6 are selected from the group consisting of CH and CR 3 ;
R 3 is independently at each occurrence selected from the group consisting of hydrogen, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, fluorine, and chlorine;
RET Targeting Ligand is selected from
is a 5 or 6 membered heteroaryl, 6 membered heterocycle, or phenyl;
X 9 is NR 4 , CR 4 R 11 , or O;
X 10 is CH or N;
X 11 and X 12 are CH;
X 13 is N, CH, or CR;
X 14 is CR 27 or N;
each R 4 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, —C(O)R 5 , 5 or 6 membered heteroaryl, phenyl, and 4-8 membered heterocycle, and —C 1 -C 4 alkyl-C(O)R 5 , each of which C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, 5 or 6 membered heteroaryl, phenyl, and 4-8 membered heterocycle, is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R 8 ;
R 5 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, 5 or 6 membered heteroaryl, phenyl, 4-8 membered heterocycle, —OR 6 , or-NR 6 R 7 , each of which C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, 5 or 6 membered heteroaryl, phenyl, and 4-8 membered heterocycle, is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R 9 ;
R 6 and R 7 are independently selected at each instance from the group consisting of hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, 5 or 6 membered heteroaryl, phenyl, 4-8 membered heterocycle, and benzyl, each of which R 6 and R 7 groups other than hydrogen is optionally substituted with 0, 1, 2, or 3 substituents independently selected from R 10 ;
R 8 is independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl, halogen, —OR 6 , —NR 6 R 7 , —OC(O)R 5 , —NR 6 C(O)R 5 , —C(O)R 5 , and -C 1 -C 4 alkyl-C(O)R 5 ;
R 9 is independently at each occurrence selected from the group consisting of hydrogen, phenyl, benzyl, 5 or 6 membered heteroaryl, 4-8 membered heterocycle, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl, halogen, —OR 6 , —NR 6 R 7 , —C(O)OR 6 , —C(O)NR 6 R 7 , -alkyl-C(O)OR 6 , and -alkyl-C(O)NR 6 R 7 , each of which phenyl, benzyl, 5 or 6 membered heteroaryl, and 4-8 membered heterocycle, is optionally substituted with 0, 1, 2, or 3 substituents selected from —S(O) 2 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl, halogen, —OR 6 , —NR 6 R 7 , —C(O)OR 6 , —C(O)NR 6 R 7 , -C 1 -C 4 alkyl-C(O)OR 6 , and -C 1 -C 4 alkyl-C(O)NR 6 R 7 ;
R 10 is independently at each occurrence selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, and halogen;
R 11 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, 5 or 6 membered phenyl, heteroaryl, 4-8 membered heterocycle, -C 1 -C 4 alkyl-OR 6 , —OC(O)R 6 , —OR 6 , -C 1 -C 4 alkyl-NR 6 R 7 , —NR 6 C(O)R 7 or-NR 6 R 7 ;
R is halogen;
R 27 is hydrogen or cyano;
R 28 and R 29 are hydrogen;
Linker is of Formula
X 1 and X 2 are independently at each occurrence selected from bond, 4-8 membered heterocycle, NR 2 , C(R 2 ) 2 , O, C(O), and S;
R 2 is independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 4 alkyl, 4-8 membered heterocycle, phenyl, 5 or 6 membered heteroaryl, —C(O) C 1 -C 4 alkyl;
R 20 , R 21 , R 22 , R 23 , and R 24 are independently at each occurrence selected from the group consisting of a bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —SO 2 —, —S(O)—, —C(S)-, —C(O)NR 2 —, —NR 2 C(O)—, —O—, —S—, —NR 2 —, —C(R 40 R 40 )—, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, bicycle, C 2 -Calkene, C 2 -C 4 alkyne, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, phenyl, naphthyl, 4-8 membered heterocycle, 5 or 6 membered heteroaryl; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 ;
R 26 is independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 4 alkyl, benzyl, C 2 -C 4 alkene, C 2 -C 4 alkyne, phenyl, 5 or 6 membered heteroaryl, and 4-8 membered heterocycle; and
R 40 is independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkene, C 2 -C 4 alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, amino, cyano, —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NHSO 2 (C 1 -C 4 alkyl), —NHSO 2 (phenyl, 5 or 6 membered heteroaryl or 4-8 membered heterocycle), —N(C 1 -C 4 alkyl) SO 2 (phenyl, 5 or 6 membered heteroaryl or 4-8 membered heterocycle), C 1 -C 4 haloalkyl, phenyl, 5 or 6 membered heteroaryl, and 4-8 membered heterocycle.
2 . The compound of claim 1 , wherein X 1 is bond and R 24 is
3 . The compound of claim 1 , wherein X 1 is bond and R 24 is
4 . The compound of claim 1 , wherein X 1 is bond and R 24 is
5 . The compound of claim 1 , wherein
is a 5 or 6 membered heteroaryl.
6 . The compound of claim 1 , wherein
7 . The compound of claim 1 , wherein
8 . The compound of claim 1 , wherein X 6 is CF.
9 . The compound of claim 8 , wherein X 5 is CH.
10 . The compound of claim 9 , wherein X 4 is CH.
11 . The compound of claim 10 , wherein X 3 is CH.
12 . The compound of claim 1 , wherein the RET Targeting Ligand is
13 . The compound of claim 1 , wherein the RET Targeting Ligand is
14 . The compound of claim 1 , wherein the RET Targeting Ligand is:
15 . The compound of claim 1 , wherein Linker is of formula
16 . The compound of claim 15 , wherein X 1 is bond.
17 . The compound of claim 15 , wherein X 1 is NR 2 .
18 . The compound of claim 15 , wherein X 1 is C(O).
19 . The compound of claim 15 , wherein X 2 is bond.
20 . The compound of claim 15 , wherein X 2 is NR 2 .
21 . The compound of claim 15 , wherein X 2 is C(O).
22 . The compound of claim 1 , wherein Linker is of formula
23 . The compound of claim 1 , wherein Linker is of formula
24 . The compound of claim 1 of structure:
or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 1 of structure:
or a pharmaceutically acceptable salt thereof.
26 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
27 . The pharmaceutical composition of claim 26 , wherein the compound of claim 1 is:
or a pharmaceutically acceptable salt thereof.