Fused bicyclic inhibitors of menin-MLL interaction

Patent metadata

Field	Value
Publication number	US-10611778-B2
Application number	US-201716331579-A
Country	US
Kind code	B2
Filing date	Sep 13, 2017
Priority date	Sep 14, 2016
Publication date	Apr 7, 2020
Grant date	Apr 7, 2020

Abstract

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to fused bicyclic 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 (1)

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 ;
L 1 is a 7- to 9-membered fused heterocycle of Formula (a)

wherein
a represents the position of linkage to the thienopyrimidinyl heterocycle;
m is equal to 0 or 1;
n is equal to 0 or 1;
p is equal to 0, 1 or 2;
q is equal to 0 or 1;
R is selected from the group consisting of hydrogen and oxo; and
-L 2 -R 3 is selected from (a), (b), (c), (d) or (e), wherein
(a) L 2 is selected from the group consisting of >SO 2 , >CR 4a R 4b , and —CHR 4a CHR 5 —; wherein
R 4a is selected from the group consisting of hydrogen; —C(═O)NR 7a R 7b ;
C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN, —OR 8 , and —NR 9a R 9b ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
R 4b is selected from the group consisting of hydrogen and methyl; or
R 4a and R 4b together with the carbon atom to which they are attached form a C 3-5 cycloalkyl or a C-linked 4- to 6-membered heterocyclyl containing an oxygen atom;
R 5 is selected from the group consisting of hydrogen; —OR 6 ; —NR 7a R 7b ; —C(═O)NR 7a R 7b ; C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN, —OR 8 , and —NR 9a R 9b ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein
R 6 , R 7a , R 7b , R 8 , R 9a and R 9b 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 10a R 10b , and C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 11 and —NR 10a R 10b ; wherein
R 10a , R 10b and R 11 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
R 3 is selected from the group consisting of Ar; Het 1 ; Het 2 ; and a 7- to 10-membered saturated spirocarbobicyclic system; or

(b) L 2 is selected from >CR 4c R 4d and —CHR 4c CHR 5a —; wherein R 4c , R 4d and R 5a are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; and
R 3 is selected from the group consisting of

 wherein R 12a , R 12b , and R 12c are each independently selected from the group consisting of C 1-6 alkyl optionally substituted with a —OH or a —NH 2 substituent; and —OC 1-6 alkyl; or

(c) -L 2 -R 3 is C 1-6 alkyl optionally substituted with one, two or three fluoro or —OH substituents; or
(d) -L 2 -R 3 is

 wherein
R 13 is selected from the group consisting of hydrogen; C 1-4 alkyl optionally substituted with a fluoro or a —CN substituent; and C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 14 and —NR 15a R 15b ; wherein
R 14 , R 15a and R 15b 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 16a R 16b ; C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 17 and —NR 16a R 16b ; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom; wherein
R 16a , R 16b and R 17 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; and
R 13a is selected from the group consisting of hydrogen, fluoro and C 1-4 alkyl;
R 13b is selected from the group consisting of hydrogen, fluoro, —OC 1-4 alkyl, and C 1-4 alkyl optionally substituted with 1, 2 or 3 fluoro substituents; or
R 13a and R 13b are bound to the same carbon atom and together form a C 3-5 cycloalkyl or a C-linked 4- to 6-membered heterocyclyl containing an oxygen atom; or

(e) -L 2 -R 3 is

 and wherein

Ar is phenyl or naphthyl, each of which may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, —CN, —OR 18 , —NR 19a R 19b , and C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN, —OR 20 , —NR 21a R 21b and —C(═O)NR 21a R 21b ;
Het 1 is a monocyclic heteroaryl selected from the group consisting of pyridyl, 4-, 5- or 6-pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 4- or 5-thiazolyl, isothiazolyl, and isoxazolyl; or a bicyclic heteroaryl selected from the group consisting of imidazothiazolyl, imidazoimidazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, indazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl; each of which may be optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, —CN, —OR 18 , —NR 19a R 19b , C 3-6 cycloalkyl, and C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN, —OR 20 , —NR 21a R 21b , and —C(═O)NR 21a R 21b , and
Het 2 is a non-aromatic heterocyclyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halo, —CN, —OR 18 , —NR 19a R 19b , —C(═O)C 1-6 alkyl, —C(═O)—O—C 1-6 alkyl, —C(═O)—C 3-6 cycloalkyl, —C(═O)—Ar 2 , —C(═O)—Het 3 , —C(═O)—Het 4 , and C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of fluoro, —CN, —OR 20 , —NR 21a R 21b , and —C(═O)NR 21a R 21b ,

Ar 2 is phenyl;
Het 3 is pyridyl;
Het 4 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl;
wherein
R 18 , R 19a , R 19b , R 20 , R 21a , and R 21b 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 and —C(═O)NR 22a R 22b , and C 2-4 alkyl substituted with a substituent selected from the group consisting of —OR 23 and —NR 22a R 22b ; wherein
R 22a , R 22b and R 23 are each independently selected from the group consisting of hydrogen; C 1 -4alkyl; and C-linked 4- to 7-membered non-aromatic heterocyclyl containing at least one nitrogen, oxygen or sulfur atom;
or a pharmaceutically acceptable salt or a solvate thereof.

2. The compound according to claim 1 , wherein -L 2 -R 3 is selected from (a), (b), (c), (d) or (e), wherein
(a) L 2 is selected from the group consisting of >SO 2 , >CR 4a R 4b , and —CHR 4a CHR 5 —; wherein
R 4a is selected from the group consisting of hydrogen; —C(═O)NR 7a R 7b ;
C 1-4 alkyl optionally s

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Angibaud Patrick Rene
• Pande Vineet
• Herkert Barbara
• Krosky Daniel Jason
• Querolle Olivier Alexis Georges
• Patrick Aaron Nathaniel

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title