# US 10,869,860 B2 · Cereblon modulators and uses thereof

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- Number: US 10,869,860 B2
- Document ID: US10869860B2
- Status: Granted
- Kind: B2
- Application number: 16/503,415
- Filed: 2019-07-03
- Published: 2020-07-02
- Granted: 2020-12-22
- Earliest claimed: 2018-12-28
- Assignees: Vividion Therapeutics, Inc.; The Scripps Research Institute
- Applicants: Vividion Therapeutics, Inc.; The Scripps Research Institute
- Inventors: Benjamin F. Cravatt; Matthew Patricelli; Dean Stamos; Gabe Simon; Benjamin Horning; David Weinstein; Ekaterina Vinogradova
- Web page: https://patentgrep.com/patent/US10869860B2

## CPC

- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- C07D 211/46: having a hydrogen atom as the second substituent in position 4
- A61K 31/397: having four-membered rings, e.g. azetidine
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/501: not condensed and containing further heterocyclic rings
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 211/54: Sulfur atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 451/06: Oxygen atoms
- 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)

## Abstract

Disclosed herein are compositions and methods for modulating cereblon neosubstrates. A small molecule modulator of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof can be used to modulate cereblon neosubstrates.

## Claims

### Claim 1

A small molecule adduct of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof:
wherein,
A is N or C(R2)
B is N or C(R3);
D is N or C(R4);
E is H or
F is N or C(R5);
X is absent, —O—, —NR6—, or —S—;
Y is H, halogen, —OR6, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6haloalkyl;
L is —C(═O)—, —S(═O)—, or —S(═O)2—;
Z1 is —C(R)2—CR8R9— or —CR7═CR8—;
R2 is H, halogen, —CN, —N(R12)2, —OR6, —CH(OR6)R12, —C(═O)R2, —C(═O)N(R12)2, —S(═O)2R12, —S(═O)2N(R12)2, —N(R12)C(═O)R12, —N(R12)S(═O)2R12, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is H, halogen, —CN, —N(R12)2, —OR6, —CH(OR6)R12, —C(═O)R12, —C(═O)N(R12)2, —S(═O)2R12, —S(═O)2N(R12)2, —N(R12)C(═O)R12, —N(R2)S(═O)2R12, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R4 is H, halogen, —CN, —N(R12)2, —C(═O)R12, —C(═O)N(R12)2, —S(═O)2R12, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R5 is H, halogen, —CN, —N(R12)2, —OR6, —C(═O)R12, —C(═O)N(R12)2, —N(R12)C(═O)R12, —S(═O)2R12, —N(R12)S(═O)2R12, —S(═O)2N(R12)2, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R6 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, or substituted or unsubstituted C1-C10 heteroalkyl;
R7 is H, —CN, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, or substituted or unsubstituted aryl;
R8 is H, —NR10R11, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6aminoalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C1-6 alkylene-C6-10 aryl, or substituted or unsubstituted C2-C6heterocycloalkyl;
R9 is H or substituted or unsubstituted C1-C6alkyl;
R10 and R11 are each independently H, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C8heteroalkyl; or
R10 and R11 are taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C9heterocycloalkyl;
each R12 is independently H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, or substituted or unsubstituted aryl; or
two R12 on the same nitrogen are taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C9heterocycloalkyl;
each R13 is independently halogen, —CN, —OR6, —C(═O)N(R12)2, —N(R12)C(═O)R12, —N(R12)S(═O)2R12, —N(S(═O)2R12)2, —S(═O)2R12, —S(═O)2N(R12)2, —(CH2)p—(OCH2CH2)q-substituted C1-4 alkyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, or substituted or unsubstituted C1-C20heteroalkyl;
R14 is H or substituted or unsubstituted C1-C6alkyl;
each R15, R16, R17, and R18 is independently selected from the group consisting of H, F, —OR6, and substituted or unsubstituted C1-C6alkyl;
m is 0, 1, or 2;
n is 0 or 1;
each p is independently 0, 1, 2, or 3;
p is 1-6;
S represents the sulfur atom of a cysteine residue C287 as set forth in SEQ ID NO: 1, or cysteine residue C286 as set forth in SEQ ID NO: 2 or 3; and
CP represents the cereblon polypeptide set forth in SEQ ID NO: 1, 2, or 3.

### Claim 2 (depends on 1)

The small molecule adduct of claim 1, wherein the S is the cysteine residue C287 as set forth in SEQ ID NO: 1.

### Claim 3 (depends on 1)

The small molecule adduct of claim 1, wherein S is the cysteine residue C286 as set forth in SEQ ID NO: 2.

### Claim 4 (depends on 1)

The small molecule adduct of claim 1, wherein S is the cysteine residue C286 as set forth in SEQ ID NO: 3.

### Claim 5 (depends on 1)

The small molecule adduct of claim 1, wherein the compound of Formula (I*) has a structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

### Claim 6 (depends on 1)

The small molecule adduct of claim 1, wherein the compound of Formula (I*) has a structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:

### Claim 7 (depends on 1)

The small molecule adduct of claim 1, wherein R8 is H, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6aminoalkyl.

### Claim 8 (depends on 1)

The small molecule adduct of claim 1, wherein R8 is H, unsubstituted C1-C6alkyl; C1-C6alkyl substituted with one or more substituents selected from C6-10 aryl, C3-8 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, halogen, and amine; C1-6 alkylene-C6-10 aryl substituted with one or more substituents selected from C1-6 alkyl, alkoxyl, halogen, and amine; and substituted or unsubstituted C1-C6aminoalkyl.

### Claim 9 (depends on 1)

The small molecule adduct of claim 1, wherein A is C(R2).

### Claim 10 (depends on 9)

The small molecule of claim 9, wherein R2 is H, halogen, —CN, —N(R12)2, —OR6, —C(═O)N(R12)2, —S(═O)2R12, or —S(═O)2N(R12)2.

### Claim 11 (depends on 1)

The small molecule adduct of claim 1, wherein B is C(R3).

### Claim 12 (depends on 11)

The small molecule adduct of claim 11, wherein R3 is H.

### Claim 13 (depends on 1)

The small molecule adduct of claim 1, wherein D is C(R4).

### Claim 14 (depends on 13)

The small molecule adduct of claim 13, wherein R4 is H.

### Claim 15 (depends on 1)

The small molecule adduct of claim 1, wherein E is H.

### Claim 16 (depends on 1)

The small molecule adduct of claim 1, wherein E is

### Claim 17 (depends on 16)

The small molecule adduct of claim 16, wherein Y is:
H, —OR6, halogen, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6haloalkyl; or
H, —OH, —OCH3, —OCH2CH3, —OCF3, F, Cl, Br, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CF3, —CF2CH3, or —CH2CF3.

### Claim 18 (depends on 1)

The small molecule adduct of claim 1, wherein R1 is
and q is 1, 2, 3, 4, 5, or 6.

### Claim 19 (depends on 1)

The small molecule adduct of claim 1, wherein F is C(RS).

### Claim 20 (depends on 19)

The small molecule adduct of claim 19, wherein R5 is H.

### Claim 21 (depends on 1)

The small molecule adduct of claim 1, wherein X is absent or —O—.

### Claim 22 (depends on 1)

The small molecule adduct of claim 1, wherein R14 is H.

### Claim 23 (depends on 1)

The small molecule adduct of claim 1, wherein one or more of R15, R16, R17, and R18 is independently selected from the group consisting of H, F, —OR6, and substituted or unsubstituted C1-C4 alkyl.

### Claim 24 (depends on 1)

The small molecule adduct of claim 1, wherein m is 0 or 1 and p is 0, 1, or 2.

### Claim 25 (depends on 1)

The small molecule adduct of claim 1, selected from:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 26 (depends on 1)

The small molecule adduct of claim 1, wherein A is CR2, and B, D, and F are each CH.

### Claim 27 (depends on 26)

The small molecule adduct of claim 26, wherein R2 is CN.

### Claim 28 (depends on 1)

The small molecule adduct of claim 1, wherein E is

### Claim 29 (depends on 28)

The small molecule adduct of claim 28, wherein R13 is —(CH2)p—(OCH2CH2)q—O-substituted or unsubstituted C1-4 alkyl.

### Claim 30 (depends on 29)

The small molecule adduct of claim 29, wherein R13 is —(OCH2CH2)4—OCH2CN.