Heterocyclic compounds for medical treatment

Patent metadata

Field	Value
Publication number	US-12528797-B2
Application number	US-202117465583-A
Country	US
Kind code	B2
Filing date	Sep 2, 2021
Priority date	Mar 6, 2019
Publication date	Jan 20, 2026
Grant date	Jan 20, 2026

Abstract

The present invention provides heterocyclic compounds that bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and their use for the treatment of abnormal cellular proliferation in a human or other host. The present invention also provides compounds that can be used as synthetic intermediates in the synthesis of bifunctional compounds used for targeted protein degradation.

First claim

What is claimed is:

1 . A compound of Formula:

or a pharmaceutically acceptable salt thereof;
wherein:
m is 0, 1, or 2;
A 1 is selected from the group consisting of —O—, —S—, —CH 2 —, —CF 2 — and —NH—, and A 2 is —CH 2 —; or
A 1 is selected from the group consisting of —O—, —S—, —CH 2 —, and —CF 2 —, and A 2 is —NH—;
W is CH or N;
R 2 is independently selected at each occurrence from the group consisting of: —(CH 2 ) 0-1 —(C 3-7 cycloalkyl)-aryl substituted by R 10 ; —(CH 2 ) 0-1 —(C 3-7 cycloalkyl)-aryl; —(CH 2 ) 0-1 -aryl substituted by R 10 ; —(CH 2 ) 0-1 -aryl; —(CH 2 ) 0-1 —C 3-7 cycloalkyl substituted by R 10 ; —(CH 2 ) 0-1 —C 3-7 cycloalkyl; —(CH 2 ) 0-1 -heteroaryl substituted by R 9 ; —(CH 2 ) 0-1 -heteroaryl; —C(═O)C 1-6 alkyl; —C(═O)—N(R 7 R 8 ); —C(═O)OC 1-6 alkyl; —C 1-6 alkoxy; —C 1-6 alkyl; —CH 2 —O—(CH 2 ) 0-1 -aryl substituted by R 10 ; —CH 2 —O—(CH 2 ) 0-1 -aryl; —O—(CH 2 ) 0-1 -aryl; -halogen; halogen-C 1-6 alkyl; hydroxy-C 1-6 alkyl; —N(R 5 R 6 ); —NO 2 ; —NH—C(═O)C 1-6 alkyl; and —SO 2 —N(R 5 R 6 );
R 3 is independently selected at each occurrence from the group consisting of: —(CH 2 ) 0-1 —(C 3-7 cycloalkyl)-aryl substituted by R 10 ; —(CH 2 ) 0-1 —(C 3-7 cycloalkyl)-aryl; —(CH 2 ) 0-1 -aryl substituted by R 10 ; —(CH 2 ) 0-1 -aryl; —(CH 2 ) 0-1 —C 3-7 cycloalkyl substituted by R 10 ; —(CH 2 ) 0-1 —C 3-7 -cycloalkyl; —(CH 2 ) 0-1 -heteroaryl substituted by R 9 ; —(CH 2 ) 0-1 -heteroaryl; —(CH 2 ) 0-1 -heterocycloalkyl; —C(═O)C 1-6 alkyl; —(CH 2 ) 0-2 —C(═O)—N(R 7 R 8 ); —C(═O)OC 1-6 alkyl; —C 1-6 -alkoxy; —C 1-6 alkyl; —OH; —NO 2 ; —C 1-6 alkyl-N(R 11 )—C(═O)—R 12 ; —CH 2 —O—(CH 2 ) 0-1 -aryl substituted by R 10 ; —CH 2 —O—(CH 2 ) 0-1 -aryl; —O—(CH 2 ) 0-1 -aryl; -halogen; halogen-C 1-6 alkyl; hydroxy-C 1-6 alkyl; hydroxy-C 1-6 alkyl-aryl; —N(R 5 R 6 ); —NH—C(═O)C 1-6 alkyl; and —NH—C(═O)OC 1-6 alkyl;
R 4 is independently selected at each occurrence from the group consisting of: —(CH 2 ) 0-1 —(C 3-7 cycloalkyl)-aryl substituted by R 10 ; —(CH 2 ) 0-1 —(C 3-7 cycloalkyl)-aryl; —(CH 2 ) 0-1 -aryl substituted by R 10 ; —(CH 2 ) 0-1 -aryl; —(CH 2 ) 0-1 —C 3-7 cycloalkyl substituted by R 10 ; —(CH 2 ) 0-1 —C 3-7 -cycloalkyl; —(CH 2 ) 0-1 -heteroaryl substituted by R 9 ; —(CH 2 ) 0-1 -heteroaryl; ═O as allowed by valence; —C(═O)C 1-6 alkyl; —C(═O)—N(R 7 R 8 ); —C(═O)OC 1-6 alkyl; —C 1-6 alkoxy; —C 1-6 alkyl; —CH 2 —O—(CH 2 ) 0-1 -aryl substituted by R 10 ; —CH 2 —O—(CH 2 ) 0-1 -aryl; -halogen; halogen-C 1-6 -alkyl; hydroxy-C 1-6 alkyl; —N(R 5 R 6 ); and —NH—C(═O)C 1-6 alkyl;
R 5 and R 6 are independently selected at each occurrence from the group consisting of H, C 1-6 alkyl and phenyl;
or R 5 and R 6 , taken together with the nitrogen to which they are attached, form a heterocycloalkyl ring;
R 7 and R 8 are independently selected at each occurrence from the group consisting of H and C 1-6 alkyl;
or R 7 and R 8 , taken together with the nitrogen to which they are attached, form a heterocycloalkyl ring;
R 9 is independently selected at each occurrence from the group consisting of C 1-6 alkoxy, C 1-6 alkyl, halogen, halogen-C 1-6 alkyl, heteroaryl, and heteroaryl substituted by C 1-6 alkyl or C 1-6 alkoxy;
R 10 is independently selected at each occurrence from the group consisting of C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl-C 1-6 alkoxy, halogen, and halogen-C 1-6 alkyl;
R 11 is independently selected at each occurrence from the group consisting of H and C 1-6 alkyl;
R 12 is independently selected at each occurrence from the group consisting of H, C 1-6 alkyl and C 3-7 cycloalkyl;
X 1 is bond, NR 34 , CH 2 , CHR 34 , C(R 34 ) 2 , O, or S;
X 22 is halogen, —NH 2 , —NHR 34 , —N(R 34 ) 2 , hydroxyl, thiol, —B(OH) 2 , —Sn(R 36 ) 3 , —Si(R 36 ) 3 , —OS(O) 2 alkyl, —OS(O) 2 haloalkyl, alkenyl, alkynyl, ethynyl, ethenyl, —C(O)H, —NR 34 C(O)alkene, —NR 34 C(O)alkyne, cyano, —SC(O)alkyl, OC(O)alkyl, heterocycle, —C(O)OH, hydrogen, alkyl, aryl, heteroaryl, or carbocyclic;
R 34 and R 34′ are independently selected at each occurrence from the group consisting of hydrogen, C 1 -C 6 alkyl C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycle, aryl, heteroaryl, —(CO)R 36 , —(CS)R 36 , —(C═NH)R 36 , —(SO)R 36 , and —(SO 2 )R 36 ;
R 36 is independently selected at each occurrence from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycle, aryl, heteroaryl, hydroxyl, C 1 -C 6 alkoxy, thio, C 1 -C 6 thioalkyl, —NH 2 , —NH(C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycle, aryl, or heteroaryl), and —N(independently C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycle, aryl, or heteroaryl) 2 ;
R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of covalent bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —SO 2 —, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R 26 )—, —CH(—NR 34 R 34′ )—, —C(—O—R 26 )alkyl-, —C(—NR 34 R 34′ )alkyl-, —C(R 40 R 40 )—, -alkyl(R 27 )-alkyl(R 28 )—, —C(R 27 R 28 )—, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NR 34 C(O)NR 34′ —, alkene, haloalkyl, alkoxy, alkyneheteroarylalkyl, aryl, arylalkyl, heterocycle, heteroaryl, lactic acid, glycolic acid, carbocycle, -(ethylene glycol) 1-6 -, -(lactic-co-glycolic acid) 1-6 -, -(propylene glycol) 1-6 -, —O—(CH 2 ) 1-12 —O—, —NH—(CH 2 ) 1-12 —NH—, —NH—(CH 2 ) 1-12 —O—, —O—(CH 2 ) 1-12 —NH—, —S—(CH 2 ) 1-12 —O—, —O—(CH 2 ) 1-12 —S—, —S—(CH 2 ) 1-12 —S—, —S—(CH 2 ) 1-12 —NH—, and —NH—(CH 2 ) 1-12 —S—;
each of which R 20 , R 21 , R 22 , R 23 , and R 24 is optionally substituted with one or more substituents selected from R 101 ;
wherein at least one of R 20 , R 21 , R 22 , R 23 , and R 24 is not a bond;
R 101 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, —COOalkyl, COOH, NO 2 , F, Cl, Br, I, CF 3 , NH 2 , NHalkyl, and N(alkyl) 2 ;
R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocyclic;
R 27 and R 28 are independently selected from the group consisting of hydrogen, alkyl, 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 with 1 or 2 heteroatoms selected from the group consisting of N and O, or form a 1 or 2 carbon bridged ring; and
R 40 is selected at each instance from the group consisting of: hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, —NH (alkyl), —N(alkyl) 2 , —NHSO 2 (alkyl), —N(alkyl)SO 2 alkyl, —NHSO 2 (aryl, heteroaryl or heterocyclic), —N(alkyl)SO 2 (aryl, heteroaryl or heterocyclic), —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic.

2 . The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , wherein the compound is:

o

Assignees

• C4 Therapeutics Inc

Inventors

• Nasveschuk Christopher G
• Norcross Roger
• Dey Fabian
• Goergler Annick
• Kusznir Eric Andre

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title