# US 9,750,816 B2 · Methods to induce targeted protein degradation through bifunctional molecules

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- Number: US 9,750,816 B2
- Document ID: US9750816B2
- Status: Granted
- Kind: B2
- Application number: 15/148,262
- Filed: 2016-05-06
- Published: 2016-08-18
- Granted: 2017-09-05
- Earliest claimed: 2014-12-23
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: James Bradner; Dennis Buckley; Georg Winter
- Web page: https://patentgrep.com/patent/US9750816B2

## CPC

- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- C07D 401/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 495/14: Ortho-condensed systems
- C07J 43/003: {not condensed}
- C07J 3/005: {the carbon atom being part of a carboxylic function}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07J: STEROIDS (seco-steroids C07C)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.

## Claims

### Claim 1

A compound selected from:
or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
Y is a bond, (CH2)1-6, (CH2)0-6—O, (CH2)0-6—C(O)NR2′, (CH2)0-6—NR2′C(O), (CH2)0-6—NH, or (CH2)0-6—NR2;
X is C(C1-C3 alkyl)2;
each R1 is independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy;
R2 is C1-C6 alkyl, C(O)—C1-C6 alkyl, or C(O)—C3-C6 cycloalkyl;
R2′ is H or C1-C6 alkyl;
R3 is H or C1-C3 alkyl;
each R3′ is independently C1-C3 alkyl;
each R4 is independently H or C1-C3 alkyl; or two R4, together with the carbon atom to which they are attached, form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
R5 is H, deuterium, C1-C3 alkyl, F, or Cl;
m is 0, 1, 2 or 3;
n is 0, 1 or 2;
the Linker is
each W is independently absent, CH2, O, S, NH or NR5;
Z is absent, CH2, O, NH or NR5;
Q is absent or —CH2C(O)NH—;
p1 is selected from 0, 1, 2, 3, 4, 5, and 6;
p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p3 is selected from 1, 2, 3, 4, and 5;
the Targeting Ligand binds to a targeted protein selected from CREBBP, TRIM24, BRPF1, glucocorticoid receptor, estrogen receptor, androgen receptor, DOT1L, BRAF, HER3, Bcl-2, Bel-XL, HDAC, and PPAR-gamma;
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker;
R′ is
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
A is N or CH.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the targeted protein is CREBBP TRIM24, or BRPF1.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the targeted protein is DOT1L, BRAF, or HER3.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the targeted protein is Bcl-2, Bcl-XL, HDAC, or PPAR-gamma.

### Claim 5 (depends on 1)

The compound of claim 1 wherein X is C(CH3)2.

### Claim 6 (depends on 1)

The compound of claim 1, wherein X is C(CH2CH3)2.

### Claim 7 (depends on 1)

The compound of claim 1, wherein two R4, together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein two R4, together with the carbon to which they are attached, form a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R5 is H or deuterium.

### Claim 10 (depends on 1)

The compound of claim 1, wherein each R1 is independently selected from F, Cl, OH, methyl, ethyl, propyl, methoxy, ethoxy and propoxy.

### Claim 11 (depends on 1)

The compound of claim 1, wherein m is 0.

### Claim 12 (depends on 1)

The compound of claim 1, wherein m is 1.

### Claim 13 (depends on 1)

The compound of claim 1, wherein n is 0.

### Claim 14 (depends on 1)

The compound of claim 1, wherein n is 1.

### Claim 15 (depends on 1)

The compound of claim 1, wherein n is 2.

### Claim 16 (depends on 1)

The compound of claim 1, wherein each R1 is independently methyl, methoxy, ethoxy, or propoxy.

### Claim 17 (depends on 1)

The compound of claim 1, wherein Y is (CH2)0-6—O.

### Claim 18 (depends on 1)

The compound of claim 1, wherein Y is (CH2)0-6—NH.

### Claim 19 (depends on 1)

The compound of claim 1, wherein Y is (CH2)0-6—C(O)NR2′.

### Claim 20 (depends on 1)

The compound of claim 1, wherein Y is (CH2)0-6—NR2′C(O).

### Claim 21 (depends on 1)

The compound of claim 1, wherein Y is (CH2)0-6—NR2.

### Claim 22 (depends on 1)

The compound of claim 1 selected from:
or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
p1 is selected from 0, 1, 2, 3, 4, and 5.

### Claim 23 (depends on 22)

The compound of claim 22, wherein the Linker has 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 chain atoms.

### Claim 24 (depends on 22)

The compound of claim 22, wherein W is independently CH2, O, S, NH, or NR5.

### Claim 25 (depends on 22)

The compound of claim 22, wherein at least one W is CH2.

### Claim 26 (depends on 22)

The compound of claim 22, wherein at least one W is O.

### Claim 27 (depends on 22)

The compound of claim 22, wherein at least one W is S.

### Claim 28 (depends on 22)

The compound of claim 22, wherein at least one W is NH.

### Claim 29 (depends on 22)

The compound of claim 22, wherein at least one W is NR5.

### Claim 30 (depends on 22)

The compound of claim 22, wherein Q is absent.

### Claim 31 (depends on 22)

The compound of claim 22, wherein Q is —CH2C(O)NH—.

### Claim 32 (depends on 22)

The compound of claim 22, wherein W is absent.

### Claim 33 (depends on 22)

The compound of claim 22, wherein at least one of W is CH2 and Z is NH or O.

### Claim 34 (depends on 22)

The compound of claim 22, wherein at least one of W is O and Z is NH or O.

### Claim 35 (depends on 22)

The compound of claim 22, wherein at least one of W is S and Z is NH or O.

### Claim 36 (depends on 22)

The compound of claim 22, wherein at least one of W is NH and Z is NH or O.

### Claim 37 (depends on 22)

The compound of claim 22, wherein at least one of W is NR5 and Z is NH or O.

### Claim 38 (depends on 22)

The compound of claim 22, wherein Z is CH2.

### Claim 39 (depends on 22)

The compound of claim 22, wherein Z is O.

### Claim 40 (depends on 22)

The compound of claim 22, wherein at least one of Z is NH.

### Claim 41 (depends on 22)

The compound of claim 22, wherein at least one of Z is NR5.

### Claim 42 (depends on 1)

The compound of claim 1, wherein the Linker is of Formula L1 or L2:

### Claim 43 (depends on 1)

The compound of claim 1, wherein the Targeting Ligand is a CREBBP Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker;
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
A is N or CH.

### Claim 44 (depends on 1)

The compound of claim 1, wherein the Targeting Ligand is a TRIM24 or BRPF1 Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker; and
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

### Claim 45 (depends on 1)

The compound of claim 1, wherein the Targeting Ligand is a glucocorticoid receptor Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.

### Claim 46 (depends on 1)

The compound of claim 1, wherein the Targeting Ligand is an estrogen or androgen receptor Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.

### Claim 47 (depends on 1)

The compound of claim 1, wherein the Targeting Ligand is a DOT1L Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker;
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
A is N or CH.

### Claim 48 (depends on 1)

The compound of claim 1, wherein the Targeting Ligand is a BRAF Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.

### Claim 49 (depends on 1)

The compound of claim 1, wherein the Targeting Ligand is a HER3 Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker; and
R′ is

### Claim 50 (depends on 1)

The compound of claim 1, wherein the Bcl-2 or Bcl-XL Targeting Ligand is:
wherein:
R is the attachment point to the Linker.

### Claim 51 (depends on 1)

The compound of claim 1, wherein the HDAC Targeting Ligand is:
wherein:
R is the attachment point to the Linker.

### Claim 52 (depends on 1)

The compound of claim 1, wherein the Targeting Ligand is a PPAR-gamma Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.

### Claim 53

A compound selected from:
or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
Y is a bond, (CH2)1-6, (CH2)0-6—O, (CH2)0-6—C(O)NR2′, (CH2)0-6—NR2′C(O), (CH2)0-6—NH, or (CH2)0-6—NR2;
X is C(C1-C3 alkyl)2;
each R1 is independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy;
R2 is C1-C6 alkyl, C(O)—C1-C6 alkyl, or C(O)—C3-C6 cycloalkyl;
R2′ is H or C1-C6 alkyl;
R3 is H or C1-C3 alkyl;
each R3′ is independently C1-C3 alkyl;
each R4 is independently H or C1-C3 alkyl; or two R4, together with the carbon atom to which they are attached, form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
R5 is H, deuterium, C1-C3 alkyl, F, or Cl;
m is 0, 1, 2 or 3;
n is 0, 1 or 2;
the Linker is
each W is independently absent, CH2, O, S, NH or NR5;
Z is absent, CH2, O, NH or NR5;
Q is absent or —CH2C(O)NH—;
p1 is selected from 0, 1, 2, 3, 4, 5, and 6;
p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p3 is selected from 1, 2, 3, 4, and 5;
the Targeting Ligand binds to a targeted protein selected from BRD1, BRD2, BRD3, BRD4, BRDS, BRD6, BRD7, BRD8, BRD9, BRD10, and BRDT
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker.

### Claim 54 (depends on 53)

The compound of claim 53, wherein the targeted protein is BRD4.

### Claim 55 (depends on 53)

The compound of claim 53, wherein the Targeting Ligand is a BRD Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker; and
R′ is methyl or ethyl.

### Claim 56

A compound selected from:
or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
Y is a bond, (CH2)1-6, (CH2)0-6—O, (CH2)0-6—C(O)NR2′, (CH2)0-6—NR2′C(O), (CH2)0-6—NH, or (CH2)0-6—NR2;
X is C(C1-C3 alkyl)2;
each R1 is independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy;
R2 is C1-C6 alkyl, or C(O)—C1-C6 alkyl, or C(O)—C3-C6 cycloalkyl;
R2′ is H or C1-C6 alkyl;
R3 is H or C1-C3 alkyl;
each R3′ is independently C1-C3 alkyl;
each R4 is independently H or C1-C3; or two R4, together with the carbon atom to which they are attached, form a C(O), a C3-C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
R5 is H, deuterium, C1-C3 alkyl, F, or Cl;
m is 0, 1, 2 or 3;
n is 0, 1 or 2;
the Linker is
each W is independently absent, CH2, O, S, NH or NR5;
Z is absent, CH2, O, NH or NR5;
Q is absent or —CH2C(O)NH—;
p1 is selected from 0, 1, 2, 3, 4, 5, and 6;
p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p3 is selected from 1, 2, 3, 4, and 5;
the Targeting Ligand binds to a BET bromodomain-containing protein
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker.