# US 10,501,466 B2 · WDR5 inhibitors and modulators

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- Number: US 10,501,466 B2
- Document ID: US10501466B2
- Status: Granted
- Kind: B2
- Application number: 16/135,729
- Filed: 2018-09-19
- Published: 2019-03-21
- Granted: 2019-12-10
- Earliest claimed: 2017-09-19
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Stephen W. Fesik; Shaun R. Stauffer; James M. Salovich; William P. Tansey; Feng Wang; Jason Phan; Edward T. Olejniczak
- Web page: https://patentgrep.com/patent/US10501466B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/02: specific for leukemia
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Described are N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)benzamide and acetamide-containing compounds that inhibit WDR5 and associated protein-protein interactions, pharmaceutical compositions including the compounds, and methods of using the compounds and compositions for treating disorders and conditions in a subject.

## Claims

### Claim 1

A compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen or C1-4alkyl;
R2 is hydrogen, C1-6alkyl, C3-8cycloalkyl, or C3-8cycloalkyl-C1-3alkylene-;
X1 is a bond;
R3 is G1 or -L1-G2;
G1 and G2 are C3-8cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl, wherein G1 and G2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4haloalkyl, —O—C1-4alkyl, —O—C1-4haloalkyl, OH, oxo, —C(O)C1-4alkyl, —C(O)C1-4haloalkyl, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —NHC(O)C1-4alkyl, and —N(C1-4alkyl)C(O)C1-4alkyl;
L1 is —C1-3alkylene-;
R4a, at each occurrence, is independently hydrogen, halogen, cyano, C1-4alkyl, C1-4haloalkyl, —O—C1-4alkyl, or OH;
R4b, at each occurrence, is independently hydrogen, halogen, or C1-4alkyl; or R4a and R4b together with the carbon to which they are attached form a C3-6cycloalkyl;
n is 1 or 2;
X2 is C(R4a)(R4b) or N(R5);
R5 is hydrogen, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkylene-, —C(O)C1-4alkyl, —C(O)C3-6cycloalkyl, or —C(O)OC1-4alkyl;
R6a, R6b, R7a, R7b, R8a, and R8b are each hydrogen; and
R9, R10, and R11 are each hydrogen.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4a and R4b are each hydrogen.

### Claim 3 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X2 is CH2.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X2 is NR5.

### Claim 8 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R5 is —C(O)C1-4alkyl.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen or C3-8cycloalkyl-C1-3alkylene-;
G1 is
a 4- to 8-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur;
phenyl; or
a 5- to 6-membered monocyclic heteroaryl; and
G2 is phenyl;
wherein G1 and G2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, —O—C1-4alkyl, OH, —C(O)C1-4alkyl, —C(O)C1-4haloalkyl, and —NHC(O)C1-4alkyl.

### Claim 10 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen or C3-8cycloalkyl-C1-3alkylene-;
G1 is
a 4- to 8-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur;
phenyl; or
a 5- to 6-membered monocyclic heteroaryl; and
G2 is phenyl;
wherein G1 and G2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, —O—C1-4alkyl, OH, —C(O)C1-4alkyl, —C(O)C1-4haloalkyl, and —NHC(O)C1-4alkyl.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein G1 is 4- to 8-membered heterocyclyl, aryl, or heteroaryl; and G2 is aryl; wherein G1 and G2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, —O—C1-4alkyl, OH, —C(O)C1-4alkyl, —C(O)C1-4haloalkyl, and —NHC(O)C1-4alkyl.

### Claim 12 (depends on 11)

The compound of claim 11, or a pharmaceutically acceptable thereof, wherein:
G1 is:
a 4- to 8-membered heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur;
phenyl; or
a 5- to 6-membered monocyclic heteroaryl; and
G2 is phenyl;
wherein G1 and G2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, —O—C1-4alkyl, OH, —C(O)C1-4alkyl, —C(O)C1-4haloalkyl, and —NHC(O)C1-4alkyl.

### Claim 13 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein
R2 is hydrogen or C3-8cycloalkyl-C1-3alkylene-;
Rg is halogen, C1-4alkyl, C1-4haloalkyl, —O—C1-4alkyl, OH, or —NHC(O)C1-4alkyl;
p is 1-3; and
q is 1-4.

### Claim 14 (depends on 13)

The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R3 is:

### Claim 15 (depends on 13)

The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R3 is:

### Claim 16 (depends on 15)

The compound of claim 15, having formula (I-a):
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The compound of claim 1, selected from the group consisting of
N-(cyclopropylmethyl)-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-methoxybenzamide;
N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-4-methyl-3-(trifluoromethyl)benzamide;
N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-methoxy-4-methylbenzamide;
N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-ethoxybenzamide;
N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-methoxy-5-methylbenzamide;
2-(3,4-dichlorophenyl)-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)acetamide;
1-acetyl-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxamide;
N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-1-propionylpiperidine-3-carboxamide;
N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-1-(3,3,3-trifluoropropanoyl)piperidine-3-carboxamide;
N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-1-isobutyrylpiperidine-3-carboxamide;
(R)-2-(3,4-dichlorophenyl)-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)acetamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-methoxy-4-methylbenzamide;
1-acetyl-N—((R)-6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)piperidine-3-carboxamide;
(R)—N-(7-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methoxy-4-methylbenzamide;
(R)-2-(4-chloro-3-fluorophenyl)-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)acetamide;
N—((R)-6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-1-propionylpiperidine-3-carboxamide;
1-acetyl-N—((R)-7-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine-3-carboxamide;
N—((R)-7-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1-propionylpiperidine-3-carboxamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-6-methoxynicotinamide;
(R)-2-chloro-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)isonicotinamide;
(R)-2-chloro-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-5-methylnicotinamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-6-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide;
(R)-6-chloro-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-4-methylpicolinamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-methylisonicotinamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-hydroxy-4-methylbenzamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-5-methoxynicotinamide;
(R)-3-acetamido-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-4-methylbenzamide;
(R)-2-chloro-N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-6-methylnicotinamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3,5-dimethoxy-4-methylbenzamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-fluoroisonicotinamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide;
(R)—N-(6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-5-fluoronicotinamide; and
(R)—N-(1-acetyl-6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)-3-methoxy-4-methylbenzamide,
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 1)

A method of inhibiting the binding of mixed lineage leukemia 1 (MLL1) to WD40 repeat protein 5 (WDR5) in a patient with cancer comprising administering to the subject, a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 19)

The method of claim 19, wherein the cancer is selected from the group consisting of leukemia, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, stomach cancer, lung cancer, cervical cancer, uterine cancer, cancers of the blood, and cancers of the lymphatic system.