Compounds and methods for the enhanced degradation of targeted proteins

Patent metadata

Field	Value
Publication number	US-10730870-B2
Application number	US-201615074820-A
Country	US
Kind code	B2
Filing date	Mar 18, 2016
Priority date	Mar 18, 2015
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

First claim

The invention claimed is:

1. A compound having the structure:
PTM-L-ULM
wherein ULM is a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety (ULM),
(a) PTM is a small molecule protein binding moiety that binds an intracellular target protein or an intracellular target polypeptide sufficiently to facilitate target protein or target polypeptide ubiquitination when coupled to the ULM, wherein the PTM is a moiety that binds to one of a nuclear hormone receptor, a kinase, a BET-bromodomain protein, or a methyl transferase; and
(b) L is a chemical linker group represented by the formula -(A) q -, wherein q is an integer from 1-20, L is covalently bound to the ULM and the PTM, and each A is independently selected from a bond, CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 0-6 R L1 and/or R L2 groups, C 3-11 heteocyclyl optionally substituted with 0-6 R L1 and/or R L2 groups, aryl optionally substituted with 0-6 R L1 and/or R L2 groups, heteroaryl optionally substituted with 0-6 R L1 and/or R L2 groups, wherein R L1 or R L2 , each independently, can be linked to other A groups to form cycloalkyl and/or heterocyclyl moiety which can be further substituted with 0-4 R L5 groups; and
wherein R L1 , R L2 , R L3 , R L4 and R L5 are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl) 2 , N(C 1-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 -alkyl)CONH(C 1-8 -alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH 2 ;
(c) ULM is a group according to the chemical structure:

wherein, one of R 5 and R 6 is —OH and the other is H, or R 5 , R 6 , and the carbon atom to which they are attached form a carbonyl;
R 7 is H or optionally substituted alkyl;
E is C═O;
G is C═O;
M is optionally substituted heteroaryl, optionally substituted aryl, or

each R 9 and R 10 is independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted alkylthio, optionally substituted heteroaryl, or haloalkyl; or R 9 , R 10 , and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
R 11 is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

R 12 is H or optionally substituted alkyl;
R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate,
each R 14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl or optionally substituted heterocycloalkyl, wherein one R 14 is haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl or optionally substituted heterocycloalkyl;
R 15 optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;
each R 16 is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;
each R 25 is H;
R 23 is H or OH;
o is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt, or stereoisomer thereof, and
the chemical linker group (L) is covalently attached to the ULM via M, R 9 , R 10 , R 11 , R 14 , R 15 , or R 16 .

2. The compound of claim 1 , wherein R 15 is selected from the group consisting of:

wherein R 30 is H or an optionally substituted alkyl.

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

R 11 is

R 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and
p is 0, 1, 2, 3, or 4.

4. The compound of claim 3 , wherein R 11 is selected from the group consisting of:

5. The compound of claim 1 , wherein:
M is

R 11 is optionally substituted heteroaryl or heterocyclic or

q is 1 or 2;
R 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

R 21 is H or optionally substituted alkyl; and
R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl.

6. The compound of claim 1 , wherein:
M is

R 11 is an optionally substituted heterocycle, an optionally substituted heteroaryl, an optionally substituted aryl or

R 12 is H or optionally substituted alkyl;
R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate.

7. The compound of claim 6 , wherein R 11 is selected from the group consisting of:

Assignees

• Arvinas Inc
• Univ Yale
• Arvinas Operations Inc

Inventors

• Crew Andrew P
• Crews Craig M
• Chen Xin
• Dong Hanqing
• Ferraro Caterina
• Qian Yimin
• Siu Kam
• Wang Jing
• Jin Meizhong
• Berlin Michael
• Zimmermann Kurt
• Snyder Lawrence

Classifications

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• A61P25/24

  Antidepressants · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title