Estrogen-related receptor alpha based protac compounds and associated methods of use

Patent metadata

Field	Value
Publication number	US-10071164-B2
Application number	US-201514822309-A
Country	US
Kind code	B2
Filing date	Aug 10, 2015
Priority date	Aug 11, 2014
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

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

What is claimed is:

1. A compound of chemical structure:
ULM-L-PTM,

wherein:
the ULM is a small molecule ubiquitin ligase binding moiety that comprises a group substituted with a hydroxyl group or a functional group that can be metabolized in a subject to a hydroxyl group and that is represented by the chemical structure:

wherein:
W 3 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and

R 9 and R 10 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, and haloalkyl; or R 9 , R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
R 11 is selected from the group consisting of optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R 12 is selected from the group consisting of H and optionally substituted alkyl;
R 13 is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, and optionally substituted aralkyl;
R 14a and R 14b are each independently selected from the group consisting of H, haloalkyl, and optionally substituted alkyl;
W 5 is selected from the group consisting of phenyl and a 5-10 membered heteroaryl;
R 15 is selected from the group consisting of: H; halogen; CN; OH; NO 2 ; NR 14a R 14b ; OR 14a ; C(═O)NR 14a R 14b ; NR 14a C(═O)R 14b ; S(═O) 2 NR 14a R 14b ; NR 14a S(═O) 2 R 14b ; optionally substituted alkyl; optionally substituted haloalkyl; optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; and optionally substituted cycloheteroalkyl;
each R 16 is independently selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, and optionally substituted haloalkoxy;
o is 0, 1, 2, 3, or 4;
each R 18 is independently selected from the group consisting of halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy and a chemical linker; and

p is 0, 1, 2, 3, or 4;
the L is a bond or a chemical linker that is chemically linked to the ULM and the PTM; and
the PTM is capable of binding to Estrogen Related Receptor alpha (ERRα) and is selected from the group consisting of

wherein, upon binding of the EERα to the compound, the ERRα is ubiquitinated by a ubiquitin ligase; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof.

2. The compound of claim 1 , wherein:
L is -A 1 . . . A q -;
A 1 to A q are each independently selected from the group consisting of a bond, CR L1 R L2 , O, S, S═O, S(═O) 2 , NR L3 , S(═O) 2 NR L3 , S(═O)NR L3 , C(═O)NR L3 , NR L3 C(═O)NR L4 , NR L3 S(═O) 2 NR L4 , C(═O), CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(═O)R L1 , P(═O)OR L1 , NR L3 C(═N—CN)NR L4 , NR L3 C(═N—CN), NR L3 C(═C—NO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 0-6 substituents selected from the group consisting of R L1 and R L2 , C 3-11 heterocyclyl optionally substituted with 0-6 substituents selected from the group consisting of R L1 and R L2 , aryl optionally substituted with 0-6 substituents selected from the group consisting of R L1 and R L2 , and heteroaryl optionally substituted with 0-6 substituents selected from the group consisting of R L1 and R L2 , wherein:
R L1 and R L2 each independently can be linked to other A groups to form a cycloalkyl or heterocyclyl moeity that can be further optionally substituted with 0-4 R L5 groups;
R L1 , R L2 , R L3 , R L4 , and R L5 are each independently selected from the group consisting of H, C 1-8 alkyl, O(C 1-8 alkyl), S(C 1-8 alkyl), NH(C 1-8 alkyl), N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, O(C 1-8 cycloalkyl), S(C 1-8 cycloalkyl), NH(C 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 , C≡C—(C 1-8 alkyl), C≡CH, 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 , C(═O)(C 1-8 alkyl), CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NH(C 1-8 alkyl), SO 2 N(C 1-8 alkyl) 2 , S(═O)NH(C 1-8 alkyl), S(═O)N(C 1-8 alkyl) 2 , C(═O)NH(C 1-8 alkyl), C(═O)N(C 1-8 alkyl) 2 , N(C 1-8 alkyl)C(═O)NH(C 1-8 alkyl), N(C 1-8 alkyl)C(═O)N(C 1-8 alkyl) 2 , NHC(═O)NH(C 1-8 alkyl), NHC(═O)N(C 1-8 alkyl) 2 , NHC(═O)NH 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 , NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 , and NHSO 2 NH 2 ; and
q is an integer greater than or equal to 1.

3. The compound of claim 1 , wherein the ULM is represented by the chemical structure:

wherein
R 1′ is —OH;
R 2′ is —NH—CH 2 -Aryl-HET;
R 3′ is selected from the group consisting of optionally substituted alkyl, —(CH)R CR3′ —NH—C(═O)—R 3P1 , and —(CH)R CR3′ —R 3P2 ;
R CR3′ is optionally substituted C 1 -C 4 alkyl;
R 3P1 is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted oxetane, —(CH 2 ) n OCH 3 wherein n is 1 or 2, optionally substituted phenyl, and morpholino linked to the carbonyl at the 2- or 3-position;
R 3P2 is selected from the group consisting of

and optionally substituted aryl;
HET is selected from the group consisting of optionally substituted thiazole, oxazole, isoxazole, and isothiazole;
R HET is selected from the group consisting of H, halogen, CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, and optionally substituted aryl; and
the ULM group is covalently bonded to a linker group to which is attached a PTM group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

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

wherein the ULM group is covalently bonded to the L group to which is attached the PTM group, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph or prodrug thereof.

5. The compound of claim 2 , wherein the L is a polyethyleneglycol optionally substituted with aryl or phenyl, having from 1 to 100 ethylene glycol units.

6. The compound of claim 5 , wherein the L is a polyethyleneglycol group that is optionally substituted with aryl or phen

Assignees

• Univ Yale
• Arvinas Inc

Inventors

• Crew Andrew
• Crews Craig
• Dong Hanqing
• Ko Eunhwa
• Wang Jing

Classifications

• A61K47/481 Primary

  Human Necessities · mapped topic

• A61K47/48061

  Human Necessities · mapped topic

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K5/06026

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• C07K5/06052

  Val-amino acid · CPC title