# US 11,999,716 B2 · WDR5 inhibitors and modulators

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- Number: US 11,999,716 B2
- Document ID: US11999716B2
- Status: Granted
- Kind: B2
- Application number: 17/287,492
- Filed: 2019-10-24
- Published: 2023-01-12
- Granted: 2024-06-04
- Earliest claimed: 2018-10-24
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Taekyu Lee; Joseph R. Alvarado; Jianhua Tian; Kenneth M. Meyers; Changho Han; Jonathan J. Mills; Kevin B. Teuscher; Shaun R. Stauffer; Stephen W. Fesik; Rocco D. Gogliotti
- Web page: https://patentgrep.com/patent/US11999716B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- C07D 217/16: substituted by oxygen atoms
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/14: containing three or more hetero rings
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Isoquinolinone compounds and derivatives inhibit WDR5 and associated protein-protein interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject, such as cancer cell proliferation.

## Claims

### Claim 1

A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
n is 1;
R1 is —(CRaRb)-G1;
G1 is a 6 or 5-membered aromatic ring optionally containing 1-2 nitrogen atoms, wherein G1 is substituted with 1-3 substituents independently selected from the group consisting of —OC1-4alkyl, C1-4alkyl, halogen, and C3-6cycloalkyl;
Ra is C1-4alkyl, C3-6cycloalkyl, or hydrogen;
Rb is hydrogen;
R2a, R2b, R3a, and R3b are each hydrogen;
R4 is a 5 or 6-membered aromatic ring optionally containing 1-2 nitrogen atoms, wherein R4 is substituted with 2, 1, or 3 substituents independently selected from the group consisting of C1-4haloalkyl, C1-4alkyl, and halogen;
R5 is hydrogen;
R6 is hydrogen;
R7a and R7b are each hydrogen; and
R8 is a 5-membered heterocyclic ring containing 2-3 heteroatoms and 2 or 1 double bonds, wherein one of the 2-3 heteroatoms is a nitrogen and the remaining heteroatoms are independently selected from nitrogen and oxygen, wherein R8 is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-4alkyl, imino, C1-4haloalkyl, —NH(C1-4alkyl), halogen, cyano, NH2, —N(C1-4alkyl)2, C3-6cycloalkyl, and —C1-3alkylene-C3-6cycloalkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R8 is imidazolyl or
the imidazolyl being optionally substituted with 1-3 substituents independently selected from the group consisting of C1-4alkyl, —N(C1-4alkyl)2, C1-4haloalkyl, —NH(C1-4alkyl), halogen, cyano, NH2, C3-6cycloalkyl, and —C1-3alkylene-C3-6cycloalkyl; and
G3 is a 5-membered heterocyclic ring containing a first nitrogen at the point of attachment and optionally 1-2 additional heteroatoms selected from the group consisting of nitrogen and oxygen, G3 having the imine substituent ═NH adjacent to the first nitrogen and being optionally substituted with 1-3 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, and —C1-3alkylene-C3-6cycloalkyl.

### Claim 3 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R8 is
X3 is NR13 or O;
R10a and R10b are independently hydrogen, C1-4alkyl, or C1-4haloalkyl;
R13 is C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, or —C1-3alkylene-C3-6cycloalkyl;
R20a is hydrogen, C1-4alkyl, —NH(C1-4alkyl), NH2, —N(C1-4alkyl)2, or C3-6cycloalkyl; and
R20b, R20c, R20d, R20e, R20f, R20g, R20h, and R20i, are each independently hydrogen, C1-4alkyl, or C3-6cycloalkyl.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R8 is

### Claim 5 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein G1 is pyridinyl, phenyl, pyridazinyl, or pyrazolyl, and substituted with 1-3 substituents independently selected from the group consisting of —OC1-4alkyl, C1-4alkyl, halogen, and C3-6cycloalkyl.

### Claim 6 (depends on 4)

The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein G1 is

### Claim 7 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R4 is pyrazolyl, phenyl, or pyridinyl, and substituted with 2, 1, or 3 substituents independently selected from the group consisting of C1-4haloalkyl, C1-4alkyl, and halogen.

### Claim 8 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R4 is

### Claim 9 (depends on 8)

The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R4 is

### Claim 10 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 1)

A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the cancer cell proliferation.