WDR5 inhibitors and modulators

Patent metadata

Field	Value
Publication number	US-10501466-B2
Application number	US-201816135729-A
Country	US
Kind code	B2
Filing date	Sep 19, 2018
Priority date	Sep 19, 2017
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

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.

First claim

What is claimed is:

1. A compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or C 1-4 alkyl;
R 2 is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 3-8 cycloalkyl-C 1-3 alkylene-;
X 1 is a bond;
R 3 is G 1 or -L 1 -G 2 ;
G 1 and G 2 are C 3-8 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl, wherein G 1 and G 2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, OH, oxo, —C(O)C 1-4 alkyl, —C(O)C 1-4 haloalkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, and —N(C 1-4 alkyl)C(O)C 1-4 alkyl;
L 1 is —C 1-3 alkylene-;
R 4a , at each occurrence, is independently hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, or OH;
R 4b , at each occurrence, is independently hydrogen, halogen, or C 1-4 alkyl; or R 4a and R 4b together with the carbon to which they are attached form a C 3-6 cycloalkyl;
n is 1 or 2;
X 2 is C(R 4a )(R 4b ) or N(R 5 );
R 5 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene-, —C(O)C 1-4 alkyl, —C(O)C 3-6 cycloalkyl, or —C(O)OC 1-4 alkyl;
R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each hydrogen; and
R 9 , R 10 , and R 11 are each hydrogen.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b are each hydrogen.

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

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

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

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

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2 is NR 5 .

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —C(O)C 1-4 alkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is hydrogen or C 3-8 cycloalkyl-C 1-3 alkylene-;
G 1 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

G 2 is phenyl;
wherein G 1 and G 2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, OH, —C(O)C 1-4 alkyl, —C(O)C 1-4 haloalkyl, and —NHC(O)C 1-4 alkyl.

10. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is hydrogen or C 3-8 cycloalkyl-C 1-3 alkylene-;
G 1 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

G 2 is phenyl;
wherein G 1 and G 2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, OH, —C(O)C 1-4 alkyl, —C(O)C 1-4 haloalkyl, and —NHC(O)C 1-4 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is 4- to 8-membered heterocyclyl, aryl, or heteroaryl; and G 2 is aryl; wherein G 1 and G 2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, OH, —C(O)C 1-4 alkyl, —C(O)C 1-4 haloalkyl, and —NHC(O)C 1-4 alkyl.

12. The compound of claim 11 , or a pharmaceutically acceptable thereof, wherein:
G 1 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

G 2 is phenyl;
wherein G 1 and G 2 are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, OH, —C(O)C 1-4 alkyl, —C(O)C 1-4 haloalkyl, and —NHC(O)C 1-4 alkyl.

13. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is hydrogen or C 3-8 cycloalkyl-C 1-3 alkylene-;

R g is halogen, C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, OH, or —NHC(O)C 1-4 alkyl;
p is 1-3; and
q is 1-4.

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 3 is:

15. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 3 is:

16. The compound of claim 15 , having formula (I-a):

or a pharmaceutically acceptable salt thereof.

17. 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-propio

Assignees

• Univ Vanderbilt

Inventors

• Fesik Stephen W
• Stauffer Shaun R
• Salovich James M
• Tansey William P
• Wang Feng
• Phan Jason
• Olejniczak Edward T

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title