BRM Targeting Compounds And Associated Methods Of Use

Patent metadata

Field	Value
Publication number	US-2023083376-A1
Application number	US-202117521195-A
Country	US
Kind code	A1
Filing date	Nov 8, 2021
Priority date	Nov 6, 2020
Publication date	Mar 16, 2023
Grant date	—

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

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 covalent bond, or chemical moiety that links PTM and ULM;
* 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 c3 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, or —P(O)(OR g ) 2 ; wherein Rand 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 small molecule E3 Ubiquitin Ligase binding moiety that binds a Cereblon E3 Ubiquitin Ligase.

2 . The compound according to claim 1 , wherein R 1 is a covalent bond.

3 . The compound according to claim 1 , wherein R 1 is a 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 )R 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.

4 . The compound according to claim 3 , 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 C(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 A2 and A4 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 -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, —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 R 1c and R 1d are each independently selected from the group consisting of H, D, optionally substituted C 1-4 alkyl, C 3-8 cyclcoalkyl, C 3-8 heterocyclcoalkyl, aryl, or heteroaryl.

5 . The compound according to claim 1 , wherein R 1 is a 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, —(CR 1a R 1b ) 1-5 , —(CR 1a ═CR 1b )—, —(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 - wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 —(CR 1a ═CR 1b )—(CR 1a R 1b ) 1-5 —, —(CR 1a R 1b ) 1-5 -(CR 1a ═CR 1b )—(CR 1a R 1b ) 1-5 -A- wherein A is O, S, or NR 1c , —(CR 1a R 1b ) 1-5 —(C≡C)—(CR 1a R 1b ) 1-5 —, —(CR 1a R 1b ) 1-5 -(C≡C)—(CR 1a R 1b ) 1-5 -A- wherein

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

• C07D487/14 Primary

  Ortho-condensed systems · CPC title

• 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

• C07D471/14

  Ortho-condensed 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