SUBSTITUTED PIPERIDINE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION
This invention provides amine-linked C 3 -glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.
1 . A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof;
wherein:
R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl;
R 12 is Linker-Targeting Ligand;
Linker is
X 1 is a bond, —NH—, —NR 25 —, —CH 2 —, —CHR 25 —, —C(R 25 ) 2 —, —O—, or —S—;
X 2 is a bond, —NH—, —NR 25 —, —CH 2 —, —CHR 25 —, —C(R 25 ) 2 —, —O—, or —S—;
R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R 26 )—, —CH(—NHR 21 )—, —CH(—NH 2 )—, —CH(—NR 25 2 )—, —C(—O—R 26 )alkyl-, —C(—NHR 23 )alkyl-, —C(—NH 2 )alkyl-, —C(—NR 25 2 )alkyl-, -alkyl(R 27 )-alkyl(R 28 )—, —CR 27 R 28 —, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, —N(H)C(O)N(R 25 )—, alkenyl, haloalkyl, alkoxy, alkynyl, aryl, heterocycle, heteroaryl, lactic acid, and glycolic acid;
R 25 is selected at each instance from the group consisting of alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl;
R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkenyl, or alkynyl;
R 27 and R 28 are independently selected from the group consisting of hydrogen, alkyl, and amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , a C 3 -C 6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from the group consisting of N and O; and
Targeting Ligand is a small molecule means for binding an androgen receptor that mediates a disease.
2 . The compound of claim 1 of formula
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 of formula
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 of formula
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 of formula
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 2 , wherein R 5 is F or Cl.
7 . The compound of claim 2 , wherein R 5 is F.
8 . The compound of claim 2 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 8 , wherein R 5 is F or Cl.
10 . The compound of claim 8 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 10 , wherein R 5 is F.
12 . The compound of claim 1 , wherein R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond, alkyl, and heterocycle.
13 . The compound of claim 12 , wherein heterocycle is selected from the group consisting of piperidinyl and piperazinyl.
14 . The compound of claim 11 , wherein R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond, alkyl, and heterocycle.
15 . The compound of claim 14 , wherein R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond,
and piperidinyl.
16 . The compound of claim 11 , wherein X 1 and X 2 are bond.
17 . The compound of claim 16 , wherein R 20 is
18 . The compound of claim 17 , wherein R 21 is CH 2 .
19 . The compound of claim 18 , wherein R 22 is piperidinyl.
20 . The compound of claim 19 , wherein R 23 and R 24 are bond.
21 . The compound of claim 20 , wherein the Targeting Ligand is selected from formulas drawn in FIG. 1 TT , wherein R is the point at which the Linker is attached.
22 . The compound of claim 21 , wherein the Targeting Ligand is of formula:
23 . A compound of formula:
or a pharmaceutically acceptable salt thereof;
wherein:
R 5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl;
R 12 is Linker-Targeting Ligand;
Targeting Ligand is
R is the point at which the Linker is attached;
Linker is
X 1 is a bond, —NH—, —NR 25 —, —CH 2 —, —CHR 2S —, —C(R 25 ) 2 —, —O—, or —S—;
X 2 is a bond, —NH—, —NR 25 —, —CH 2 —, —CHR 25 —, —C(R 25 ) 2 —, —O—, or —S—;
R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R 26 )—, —CH(—NHR 25 )—, —CH(—NH 2 )—, —CH(—NR 25 2 )—, —C(—O—R 26 )alkyl-, —C(—NHR 25 )alkyl-, —C(—NH 2 )alkyl-, —C(—NR 25 2 )alkyl-, -alkyl(R 27 )-alkyl(R 28 )—, —CR 27 R 28 —, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, —N(H)C(O)N(R 2S )—, alkenyl, haloalkyl, alkoxy, alkynyl, aryl, heterocycle, heteroaryl, lactic acid, and glycolic acid;
R 25 is selected at each instance from the group consisting of alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl;
R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkenyl, or alkynyl; and
R 27 and R 28 are independently selected from the group consisting of hydrogen, alkyl, and amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , a C 3 -C 6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from the group consisting of N and O.
24 . The compound of claim 23 , wherein R 5 is F.
25 . The compound of claim 24 , wherein X 1 and X 2 are bond.
26 . The compound of claim 25 , wherein R 20 is
27 . The compound of claim 26 , wherein R 21 is CH 2 .
28 . The compound of claim 27 , wherein R 22 is piperidinyl.
29 . The compound of claim 28 , wherein R 23 and R 24 are bond.
30 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
31 . A method for treating a human patient with an androgen receptor mediated abnormal cellular proliferation comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, to the human patient in need thereof.
32 . The method of claim 31 , wherein the abnormal cellular proliferation is a cancer.
33 . The method of claim 32 , wherein the cancer is a solid tumor.
34 . The method of claim 32 , wherein the cancer is prostate cancer.