BRM targeting compounds and associated methods of use

Patent metadata

Field	Value
Publication number	US-12448389-B2
Application number	US-202117521195-A
Country	US
Kind code	B2
Filing date	Nov 8, 2021
Priority date	Nov 6, 2020
Publication date	Oct 21, 2025
Grant date	Oct 21, 2025

Abstract

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

First claim

What is claimed:

1. A compound of Formula (I):
PTM-ULM  (I)

or a pharmaceutically acceptable salt or solvate thereof,
wherein PTM is a moiety of Formula IA:

wherein
R 1 is a chemical moiety that links PTM and ULM, wherein the chemical moiety represented by
the formula:
-(A)q-,

wherein:
q is an integer from 1 to 14;
each A is independently selected from the group consisting of a bond, CR 1a R 1b , O, S, SO, SO 2 , NR 1c , SO 2 NR 1c , SONR 1c , SO (═NR 1c ), SO(═NR 1c ) NR 1d , CONR 1c , NR 1c CONR 1d , NR 1c C(O) O, NR 1c SO 2 NR 1d , CO, CR 1a ═CR 1b , C═C, SiR 1a R 1b , P(O)R 1a , P(O)OR 1a , (CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 S (CR 1a R 1b ) 1-4 , —(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , NR 1c C(═NCN)NR 1d NR 1c C(═NCN), NR 1c C(═CNO 2 )NR 1d , 3-11 membered cycloalkyl, optionally substituted with 0-6 R 1a and/or R 1b groups, 3-11 membered heterocyclyl optionally substituted with 0-6 R 1a and/or R 1b groups, aryl optionally substituted with 0-6 R 1a and/or R 1b groups, or heteroaryl optionally substituted with 0-6 R 1a and/or R 1b groups,
wherein R 1a , R 1b , R 1c , R 1d and R 1e are each independently, —H, D,-halo, —C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, —C 1 -C 6 haloalkyl, —S—C 1 -C 8 alkyl, —NHC 1 -C 8 alkyl, —N(C 1 -C 8 alkyl) 2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, —O-(3-11 membered cycloalkyl), —S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N (3-11 membered cycloalkyl) 2 , N-(3-11 membered cycloalkyl) (C 1 -C 8 alkyl), —OH, —NH 2 , —SH, —SO 2 C 1 -C 8 alkyl, SO(NH)C 1 -C 8 alkyl, P(O)(OC 1 -C 8 alkyl) (C 1 -C 8 alkyl), —P(O)(OC 1 -C 8 alkyl) 2 , —C≡C—C 1 -C 8 alkyl, —C≡CH, —CH═CH (C 1 -C 8 alkyl), —C(C 1 -C 8 alkyl)═CH(C 1 -C 8 alkyl), —C(C 1 -C 8 alkyl)═C(C 1 -C 8 alkyl) 2 , —Si(OH) 3 , —Si(C 1 -C 8 alkyl) 3 , —Si(OH)(C 1 -C 8 alkyl) 2 , —C(O)C 1 -C 8 alkyl, —CO 2 H, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NO 2 , —SF 5 , —SO 2 NHC 1 -C 8 alkyl, —SO 2 N(C 1 -C 8 alkyl) 2 , —SO(NH)NHC 1 -C 8 alkyl, —SO(NH)N(C 1 -C 8 alkyl) 2 , —SONHC 1 -C 8 alkyl, —SON(C 1 -C 8 alkyl) 2 , —CONHC 1 -C 8 alkyl, —CON(C 1 -C 8 alkyl) 2 , —N(C 1 -C 8 alkyl)CONH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl)CON(C 1 -C 8 alkyl) 2 , —NHCONH(C 1 -C 8 alkyl), —NHCON(C 1 -C 8 alkyl) 2 , —NHCONH 2 , —N(C 1 -C 8 alkyl)SO 2 NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl)SO 2 N(C 1 -C 8 alkyl) 2 , —NHSO 2 NH(C 1 -C 8 alkyl), —NHSO 2 N(C 1 -C 8 alkyl) 2 , or —NHSO 2 NH 2 ; and
where R 1a or R 1b , each independently may be optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R 1e groups;
* is a point of attachment to ULM;
n=0-3;
each W is independently optionally substituted —CH 2 —, —C(O)—, —S(O)—, or —S(O) 2 —; wherein when n=2 or 3, only one W is —C(O)—, —S(O)—, or —S(O) 2 —, and the other W are —CH 2 — or substituted —CH 2 —;
R c1 and R d1 are independently H, D, Halo, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-4 alkoxyl;
R e3 is H, —C(O) R f , or —P(O)(OR g ) 2 ; wherein R f and R g are independently H, C 1-4 alkyl, C 1-4 substituted alkyl, C 3-8 cyclcoalkyl, C 3-8 substituted cyclcoalkyl, C 3-8 heterocyclcoalkyl, or C 3-8 substituted heterocyclcoalkyl;
Z and Y are each independently N; CR h wherein R h =H or absent; or, if R 1 is attached to Z, then Z is C and Y is N or CR h wherein R h is H; or if R 1 is attached to Y, then Y is C and Z is N or CR h wherein R h is H;
B is an optionally substituted 5-7 membered cycloalkyl ring, an optionally substituted 5-7 membered heteroaryl ring, or an optionally substituted 5-7 membered heterocyclic ring, wherein ring B is fused to ring G through Y and Z; and

ULM is a moiety having the Formula ULM-I

wherein:
is a point of attachment to PTM;
Ring A is a monocyclic, bicyclic or tricyclic aryl, heteroaryl or heterocycle group,
L 1 is a bond, —O—, —S—, —NR a —, —C(R a ) 2 —C(O) NR a —;
X 1 is a bond, —C(O)—, —C(S)—, —CH 2 —, —CHCF 3 —, SO 2 —, —S(O), P(O)R b — or —P(O)OR b —;
X 2 is —C(R a ) 2 —, —NR a — or —S—;
R 2 is H, D, optionally substituted C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 haloalkyl, —CN, —OR a , —OR b or —SR b ;
each R 3 is independently H, D, halogen, oxo, —OH, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, C 0 -C 1 alk-aryl, C 0 -C 1 alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —OR a , —SR a , —NR c R d , —NR a R c , —C(O)R b , —OC(O)R a , —C(O)OR a , —C(O)NR c R d , —S(O)R b , —S(O) 2 NR c R d , —S(O)(═NR b )R b , —SF 5 , —P(O)R b R b , —P(O)(OR b )(OR b ), —B(OR d )(OR c ) or —S(O) 2 R b ;
each R a is independently H, D, —C(O)R b , —C(O)OR e , —C(O)NR c R d , —C(═NR b )NR b R c , —C(═NOR b )NR b R c , —C(═NCN)NR b R c , —P(OR c ) 2 , —P(O)R c R b , —P(O)OR c OR b , —S(O)R b , —S(O)NR c R d , —S(O) 2 R b , —S(O) 2 NR c R d , SiR b 3 , —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —C 2 -C 10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;
each R b , is independently H, D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;
each R c or R d is independently H, D, —C 1 -C 10 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1 -C 6 alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or
R c and R d , together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group; and
is 1, 2, 3, 4, or 5.

2. The compound according to claim 1 , wherein q=5 and R 1 is a chemical moiety represented by the formula:-A 1 -A 2 -A 3 -A 4 -A 5 -; wherein:
each of A 1 , A 3 and A 5 is independently selected from the group consisting of a bond, —(CR 1a R 1b ) 0-4 O(CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 S(CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 NR 1c (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 SO(CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 SO 2 (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 SO 2 NR 1c (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 SONR 1c (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 SO(═NR 1c ) (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 SO(═NR 1c )NR 1d (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 CONR 1c (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 C(O)O(CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 NR 1c CONR 1d (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 NR 1c (O)O(CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 NR 1c SO 2 NR 1d (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 C(O)(CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 CR 1a —CR 1b (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 C═C(CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 SiR 1a R 1b (CR 1a R 1b ) 0- 4 , —(CR 1a R 1b ) 0-4 P(O)R 1a (CR 1a R 1b ) 0-4 , —(CR 1a R 1b ) 0-4 P(O)OR 1a (CR 1a R 1b ) 0-4 , (CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl, and heteroaryl;
each of A 2 and A 4 is independently selected from the group consisting of is independently selected from the group consisting of a bond, (CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl, and heteroaryl;
R 1a and R 1b are each independently selected from the group consisting of —H, D, -halo, —C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, —C 1 -C 6 haloalkyl, —S—C 1 -C 8 alkyl, —NHC 1 -C 8 alkyl, —N(C 1 -C 8 alkyl) 2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, —O-(3-11 membered cycloalkyl), —S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N (3-11 membered cycloalkyl) 2 , N-(3-11 membered cycloalkyl) (C 1

Assignees

• Prelude Therapeutics Inc

Inventors

• Lu Liang
• Combs Andrew Paul
• Basch Corey Howard
• Shetty Rupa
• Dai Chaofeng
• Bersch Klare Lazor
• Rose John A
• Beam Danielle Julie
• Mei Song

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title