Azepane inhibitors of menin-MLL interaction

Patent metadata

Field	Value
Publication number	US-10745409-B2
Application number	US-201716469174-A
Country	US
Kind code	B2
Filing date	Dec 14, 2017
Priority date	Dec 15, 2016
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

Abstract

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to azepane compounds, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, myelodysplastic syndrome (MDS) and diabetes.

First claim

The invention claimed is:

1. A compound of Formula (I)

or a tautomer or a stereoisomeric form thereof, wherein
R 1 is selected from the group consisting of CH 3 , CH 2 F, CHF 2 and CF 3 ;
R 2 is selected from the group consisting of hydrogen and CH 3 ;
Y 1 is selected from the group consisting of hydrogen; C 1-6 alkyl; C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom optionally substituted with a C 1-4 alkyl or cyclopropyl substituent; and C 1-4 alkyl substituted with a substituent selected from the group consisting of fluoro, —CN, phenyl, —OR 1Y , and —NR 2Y R 2YY ; wherein
R 1Y is selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN and —C(═O)NR 1y R 2y ; C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 3y and —NR 1y R 2y ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
R 2Y and R 2YY are each independently selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with a —C(═O)NR 1y R 2y substituent;
C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 3y and —NR 1y R 2y ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
Y 2 and Y 3 are each independently selected from the group consisting of hydrogen; OH; NH 2 ; —C(═O)NR 1y R 2y ; C 1-6 alkyl; and C 1-4 alkyl substituted with a substituent selected from the group consisting of fluoro, —CN, —OR 3Y , and —NR 4Y R 4YY ; with the proviso that when Y 2 and Y 3 are both substituents at the same carbon atom, and one of Y 2 or Y 3 is OH or NH 2 , then the other Y 3 or Y 2 is H, C 1-6 alkyl, C 1-4 alkyl substituted with a substituent selected from the group consisting of fluoro and —CN, or C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 3Y and —NR 4Y R 4YY ; wherein
R 3Y is selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN and —C(═O)NR 4y R 5y ; C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 6y and —NR 4y R 5y ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
R 4Y and R 4YY are each independently selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN and —C(═O)NR 1y R 2y ; C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 6y and —NR 4y R 5y ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein R 1y , R 2y , R 3y , R 5y and R 6y are each independently selected from the group consisting of hydrogen; C 1-4 alkyl; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and
-L-R 3 is selected from (a), (b), (c), (d), (e), or (f):
(a) -L-R 3 is NHR 1A , wherein R 1A is selected from the group consisting of hydrogen; C 1-6 alkyl optionally substituted with one, two or three fluoro substituents; and C 2-6 alkyl substituted with a substituent selected from the group consisting of —OR 1a and —NR 2a R 2aa , wherein R 1a , R 2a and R 2aa are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and cyclopropyl; with the proviso that when R 1A is hydrogen, then Y 1 is not hydrogen; or
(b) L is selected from the group consisting of —O—, —O—CR 1B R 1BB —, —N(R B )—, —N(R B )—CR 1B R 1BB —, and —(NR B )—CHR 1B —CHR 2B —; and R 3 is selected from the group consisting of Ar; Het 1 ; Het 2 ; and a 7- to 10-membered saturated spirocarbobicyclic system; wherein
R B is selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, phenyl and —CN; and C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 1b and —NR 2b R 2bb , wherein
R 1b , R 2b , and R 2bb are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and cyclopropyl;

R 1B is selected from the group consisting of hydrogen; —C(═O)NR 3B R 3BB ;
C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, phenyl, Het 1 , and —CN; C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 4B and —NR 5B R 5BB ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; and R 1BB is selected from the group consisting of hydrogen and methyl; or R 1B and R 1BB together with the carbon to which they are attached form a C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
R 2B is selected from the group consisting of hydrogen; —OR 6B ; —NR 7B R 7BB ; —C(═O)NR 8B R 8BB , C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN, —OR 4B , and —NR 5B R 5BB ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein
R 3B , R 3BB , R 4B , R 5B , R 5BB , R 6B , R 7B , R 7BB , R 8B and R 8BB are each independently selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN and —C(═O)NR 9B R 9BB ; and C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 10B and —NR 11B R 11BB ; wherein
R 9B , R 9BB , R 10B , R 11B and R 11BB are each independently selected from the group consisting of hydrogen; C 1-4 alkyl; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; or

(c) —L-R 3 is selected from the group consisting of —N(R C )—CHR 1C —CO 2 R 2C ;
—N(R C )—CHR 3C —CONR 4C R 4CC ; —N(R C )—COR 5C ; —N(R C )—SO 2 —NR 6C R 6CC ; wherein
R C is selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, phenyl and —CN; and C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 1c and —NR 2c R 2cc ;
R 1C and R 3C are each selected from the group consisting of hydrogen;
—C(═O)NR 3c R 3cc ; C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, phenyl, Het 1 , and —CN; C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 4c and —NR 5c R 5cc ; and
C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
R 4C and R 6C are each selected from the group consisting of hydrogen, and C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of NR 6c R 6cc , Ar, and Het 1 ;
R 2C is selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with Ar or Het 1 ; Ar; Het 1 ; Het 2 ; and a 7- to 10-membered saturated spirocarbobicyclic system;
R 5C is selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with —NR 2c R 2cc Ar or Het 1 ; Ar; Het 1 ; Het 2 ; and a 7- to 10-membered saturated spirocarbobicyclic system; wherein
R 1c , R 2c , R 2cc , R 3c , R 3cc , R 4c , R 5c and R 5cc are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; and
R 6c and R 6cc are each independently selected from the group consisting of hydrogen,

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Angibaud Patrick René
• Pande Vineet
• Herkert Barbara
• Krosky Daniel Jason
• Querolle Olivier Alexis Georges
• Patrick Aaron Nathaniel
• Pilatte Isabelle Noëlle Constance

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61P35/00

  Antineoplastic agents · CPC title